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1
Yang, Yuanchu J., Sam Rubinstein, and Jeremy Lyle Warner. "Markers of immune checkpoint inhibitor efficacy in the AACR Project GENIE database." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15091-e15091. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15091.
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e15091 Background: Although immune checkpoint inhibitors (ICIs) have been shown to be effective in many tumor types, some highly lethal cancers are not responsive to ICI. Potential biomarkers of ICI response include tumor mutational burden (TMB), which is thought to correlate with increased neoantigen production, and 9p24.1 copy number gain (CNG), which can result in over-expression of programmed death ligand 1 (PD-L1). 9p24.1 CNGs have been described in ICI-sensitive (ICI-S) hematologic malignancies (e.g., Hodgkin lymphoma), but are not well described in solid malignancy. We sought to investigate TMB and 9p24.1 CNG for ICI-S and ICI-resistant (ICI-R) tumor types in the publicly available AACR Project GENIE database, version 7.0. Methods: TMB was calculated by counting somatic mutations with tumor reference allele frequency ≥5% and sequencing depth ≥200X. Samples with < 0.5 MB sequenced were excluded. 9p24.1 CNG was extrapolated from gene-level data. Samples with two or more consecutive gene amplifications in the 9p24.1 region were determined to have 9p24.1 CNG. Samples whose sequencing assay did not include at least two genes in 9p24.1 were excluded. Using an overall response rate (ORR) of ≥10% to define ICI-S, we assessed three ICI-S cancers: hepatobiliary cancer (HBC), melanoma (MEL), non-small cell lung cancer (NSCLC); and two ICI-R types: metastatic breast cancer (MBC) & pancreatic ductal adenocarcinoma (PDAC). Groupwise TMB was compared using Wilcoxon rank-sum and 9p24.1 CNG was compared using Chi-squared. Results: MEL had the highest median TMB but a low 9p24.1 CNG rate; NSCLC had the highest rate of 9p24.1 CNG (Table). PDAC had both the lowest median TMB and 9p24.1 CNG rate. As a group, the ICI-S cancers had higher median TMB (p < .001) and 9p24.1 CNG rate (p < .001). Conclusions: Although rates of 9p24.1 CNG were low across the database as a whole, the NSCLC finding replicates findings described in early stage resected NSCLC (Inoue et al. 2016). Relatively high median TMB in MEL may explain ICI-sensitivity in this cancer type. The combination of low median TMB and low rates of 9p24.1 CNG in PDAC may explain the general lack of efficacy of ICIs in this disease. These findings demonstrate the utility of GENIE as a clinico-genomic database, and also highlight the need to identify better markers of responsiveness to these potentially effective but toxic therapies. [Table: see text]
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Emond, Wei B., Rajiv Sawant, Matthis Geitmann, Johan Winquist, Peter Brandt, Ulf Bremberg, Per Källblad, et al. "Abstract 705: Potentiation of immunotherapy by LSD1 modulation." Cancer Research 83, no. 7_Supplement (April 4, 2023): 705. http://dx.doi.org/10.1158/1538-7445.am2023-705.
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Abstract LSD1 has emerged as a potential therapeutic target to increase the effectiveness of cancer immunotherapy. We have developed a series of novel small molecules, exemplified by the lead substance BEA-17, that modulates LSD1 via binding to an allosteric site, without directly inhibiting its enzymatic activity. In cells, BEA-17 induces a reduction of LSD1 levels. In addition, BEA-17 upregulates the expression of endogenous retroviral genes and T cell-attractant chemokines and does so in an LSD1-dependent manner. In a co-culture of HeLa and PBMCs, BEA-17 increases cell kill of cancer cells by immune effector T cells, also in an LSD1-dependent manner. In a CT26 syngeneic animal model of colon cancer, BEA-17 potentiates the activity of anti-PD1 inhibitors. Finally, in a syngeneic GL261 animal model of glioblastoma, BEA-17 increases the effectiveness of standard-of-care temozolomide + radiation. Citation Format: Wei B. Emond, Rajiv Sawant, Matthis Geitmann, Johan Winquist, Peter Brandt, Ulf Bremberg, Per Källblad, Vendela Parrow, Claes Andersson, Kristin Blom, Nasrin Najafi, Tobias Bergström, Fredrik J. Swartling, Mats Hellström, Konrad F. Koehler. Potentiation of immunotherapy by LSD1 modulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 705.
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Lee, John J., Bernice C. Nounamo, Fariba Jousheghany, Issam Makhoul, Eric R. Siegel, Thomas Kieber-Emmons, and Behjatolah Monzavi-Karbassi. "Abstract 700: Induction of cancer-specific T-cell responses in patients immunized with P10s-PADRE vaccine." Cancer Research 83, no. 7_Supplement (April 4, 2023): 700. http://dx.doi.org/10.1158/1538-7445.am2023-700.
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Abstract Introduction: HR+/HER2− breast cancer is the most common form of breast cancer in the United States. HR+/HER2− tumors are known for a low number of tumor-infiltrating lymphocytes (TILs) and considered less immunogenic than other breast cancer subtypes. We have demonstrated that vaccination with P10s-PADRE, a carbohydrate-mimetic-based peptide, cancer vaccine in combination with standard-of-care chemotherapy in HR+/HER2− breast cancer patients led to an increase in TILs and stromal CD3+ T cells. The current study was performed to determine the vaccine specificity and anti-tumor functionality of T cells in treated patients. Methods: Peripheral blood mononuclear cells (PBMCs) collected at the baseline and after vaccination were used in T-cell assays by multi-color ELISpot, examining Th1, Th2, and cytotoxic responses. PBMCs were also interrogated for the vaccine-induced changes in immune gene expression by next-generation RNA-seq analysis. Results: We observed a significant increase in IFN-g, but not in IL-5 or IL-10, responses in post-immune PBMCs after stimulation with P10s, P10s-PADRE and polyclonal stimulation of T cells by anti-CD3/CD28 antibodies. Stimulation with cancer cell lysate resulted in a strikingly high IFN-g response in post-immune samples. Determining the trio of IFN-g, GzB, and IL-2 together with CD4/CD8 cell proliferation assays of consequent post vaccination specimens established the dynamics of effector T-cell populations. RNA-seq data clearly distinguished post-treatment samples by the increase in immune cell activation, cytokine response, and antigen presentation. Conclusions: The data indicate that immunization of HR+/HER2− breast cancer patients with P10s-PADRE in combination with chemotherapy leads to specific activation of T-cells that recognize breast cancer cells. Improving immunogenicity of such immunologically cold tumors could increase the effectiveness of standard therapeutic approaches. Citation Format: John J. Lee, Bernice C. Nounamo, Fariba Jousheghany, Issam Makhoul, Eric R. Siegel, Thomas Kieber-Emmons, Behjatolah Monzavi-Karbassi. Induction of cancer-specific T-cell responses in patients immunized with P10s-PADRE vaccine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 700.
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Miller, Madison E., Myah Bell, Priscella Holland, Vanessa Ibrahim, Gordon Jacobsen, and Monique Swain. "Abstract A069: The impact of race and glycemic control on triple negative breast cancer in type 2 diabetics." Cancer Epidemiology, Biomarkers & Prevention 32, no. 1_Supplement (January 1, 2023): A069. http://dx.doi.org/10.1158/1538-7755.disp22-a069.
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Abstract Although the association between type 2 diabetes (T2D) and breast cancer is well established, the relationship between glycemic control and breast cancer by hormone receptor subtype is poorly understood. We sought to investigate the relationship between glycemic control and the incidence of triple negative breast cancer (TNBC) among patients with T2D. Furthermore, we hoped to elucidate whether this hypothesized risk was further moderated by demographic factors, such as patient race. METHODS: A retrospective cohort study evaluating 1,679 patients with T2D diagnosed with breast cancer between 2010-2020 was conducted. Data including tumor hormone receptor status, Hgb A1c measured within 3 months of cancer diagnosis date, and patient race were ascertained via chart review. Tumor subtype was categorized as either hormone receptor-positive (ER+, PR+ or both) or triple-negative (ER/PR- and HER2/neu-). Based on Hgb A1c measurements, subjects were assigned to one of three categories of glycemic control: well-controlled (Hgb A1c less than 7.0), moderately controlled (Hgb A1c 7.0-9.4), or poorly controlled (Hgb A1c greater than or equal to 9.5) T2D. RESULTS: Accounting for all study subjects, the incidence of TNBC increased with worsening glycemic control (12.7% vs 15.2% vs 21.8%, P=0.040). Among non-Hispanic White patients, a significant increase in the incidence of TNBC with worsening glycemic control was also observed (9.2% vs 13.2% vs 21.9%, P=.010). Among Black patients, the incidence of TNBC did not significantly change across the three levels of glycemic control (17.6% vs 17.6% vs 22.7%, P=.700). Comparing the incidence rates of breast cancer by subtype between non-Hispanic White and Black patients across the three categories of glycemic control, a significant difference was only observed among patients with well-controlled T2D (17.6% of Black patients with TNBC versus 9.2% of non-Hispanic White patients, P<.001; 87.4% of non-Hispanic White patients with hormone receptor positive breast cancer versus 75.6% of Black patients, P<.001). CONCLUSION: Poor glycemic control is associated with a higher incidence of TNBC in patients with T2D overall. A significant increase in the incidence of TNBC with lesser degrees of glycemic control was only observed in the population of non-Hispanic white patients. Although previous studies have shown that Black patients are 2-3 times more likely to develop TNBC than their non-Hispanic White counterparts, a statistically significant racial difference in the rates of breast cancer by subtype was only noted among those with well-controlled T2D. Together our data not only suggests that T2D may serve as a modifiable risk factor for the development of TNBC, but also that the risk conferred by poor glycemic control may bear more significance for non-Hispanic White patients than Black patients. Citation Format: Madison E. Miller, Myah Bell, Priscella Holland, Vanessa Ibrahim, Gordon Jacobsen, Monique Swain. The impact of race and glycemic control on triple negative breast cancer in type 2 diabetics [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A069.
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Chen, Jiani, Jinhua Wu, Jeff Schubert, Fumin Lin, Elizabeth H. Denenberg, Alison Muir, Edward J. Romasko, et al. "The spectrum of RAF1 fusion positive solid tumors in children and young adults." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): e22013-e22013. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e22013.
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e22013 Background: The RAF1 gene encodes a kinase protein in the MAPK signaling pathway. Fusions involving RAF1 have been reported in solid tumors with a higher prevalence in melanoma, breast cancer, non-small cell lung cancer, and brain tumors. The fusions typically replace the N-terminal autoinhibitory domain with the 5’ partner genes leading to autonomous activation of RAF1 kinase. The efficacy of MEK inhibitors as a potential treatment for RAF1 fusion positive tumors is under investigation. Here we present a cohort of 8 RAF1 fusions involved in a spectrum of tumors in children and young adults. Methods: A retrospective search for tumors harboring RAF1 fusion was performed using our clinical database from 2016 to date. The RNA fusion analysis targets >700 exons of 117 genes for known and novel fusions. Additional genomic alterations, tumor type, and patient demographics were also collected. Results: A total of 8 cases positive for RAF1 fusion were identified from 2526 solid tumors including 6 brain tumors, 1 sarcoma, and 1 hepatoblastoma. Histologic diagnoses of the brain tumors were mostly low grade gliomas with no other driver mutations. Two pilocytic astrocytomas harbored RAF1 fusions without the pathognomonic KIAA1549: BRAF fusions. Although RAF1 fusions have been reported in rhabdomyosarcomas, it is the first time that a RAF1 fusion is associated with hepatoblastoma. 4 of the 8 RAF1 fusions identified are novel (noted with * in the table). The break points in RAF1 were at exon 7, 8, or 10, demonstrating the retention of the kinase domain. Conclusions: We report 8 RAF1 fusion positive solid tumors in children and young adults, mainly in low-grade gliomas. Although rare, the presence of a RAF1 fusion not only facilitates the tumor diagnosis but also provides genomic evidence for potential targeted therapies. References: 1. The AACR Project GENIE Consortium. AACR Project GENIE: powering precision medicine through an international consortium. Cancer Discovery. 2017;7(8):818-831. 2. McEvoy CR et al. Profound MEK inhibitor response in a cutaneous melanoma harboring a GOLGA4-RAF1 fusion. J Clin Invest. 2019; 129:1940-1945. [Table: see text]
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Wang, Zhishen. "Abstract 1419: Single molecule detection of human heparanase." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1419. http://dx.doi.org/10.1158/1538-7445.am2022-1419.
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Abstract Heparanase, a mammalian endo-β-D-glucuronidase, is the only known enzyme responsible for the cleavage of heparan sulfate (HS) side chains of heparan sulfate proteoglycans (HSPGs). Its activity is implicated in various disease conditions such as tumor growth, angiogenesis, metastasis, chronic inflammation and diabetic nephropathy. Detecting the activity of heparanase thus is a promising approach for the discovery of diagnostics and therapeutics for these diseases. We have developed an activity-based disaccharide probe for heparanase, which offers over 700-fold of fluorescence increase in the presence of human heparanase. In this project, we aim to build up an ultrasensitive single heparanase detection system by coupling a sensitive fluorogenic probe with a microwell-based device. The microwell-based device is designed to achieve single enzyme separation and significantly increase the sensitivity of detection. This system is being validated using recombinant human heparanase and will be used to analyze clinical samples from breast cancer patients. Citation Format: Zhishen Wang. Single molecule detection of human heparanase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1419.
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Pecoraro, Adam F., Tooba Rashid, Breanne A. Burgess, Corinne M. Linardic, and Michael D. Deel. "Abstract 700: Targeting transcriptional co-activators YAP1/TAZ in fusion-positive rhabdomyosarcoma demonstrates a novel strategy in ablating fusion-driven sarcoma transcriptional programing." Cancer Research 82, no. 12_Supplement (June 15, 2022): 700. http://dx.doi.org/10.1158/1538-7445.am2022-700.
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Abstract Background: Approximately one third of all sarcomas are characterized by recurrent chromosomal translocations, and these fusion-positive sarcomas remain among the most difficult to treat of all malignancies. Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood and a prototype fusion-oncogene-driven tumor. Fusion-positive rhabdomyosarcoma (FP-RMS) is driven by a chromosomal translocation encoding for the pathognomonic chimeric fusion product PAX3-FOXO1 (P3F). Because it is a large inherently disordered transcription factor lacking drug-binding sites, conventional efforts to directly target P3F have thus far proven futile, and 5-yr overall survival rates remain below 50%. Objective: We thus sought to identify therapeutically tractable co-activators or co-regulators that represent vulnerabilities to P3F transcriptional programing. Methods/Results: Interrogation of transcriptomic data and immunohistochemical (IHC) staining of human tissue microarrays demonstrated the transcriptional co-activators YAP1 and TAZ are highly abundant in FP-RMS tumors. We performed genetic gain- and loss-of-function experiments using RNAi and CRISPR/Cas9 to determine that YAP1/TAZ regulate many FP-RMS cancer phenotypes, including proliferation and xenograft tumor growth. Mechanistic studies using co-immunoprecipitation (co-IP) and co-IP-coupled mass spectrometry revealed a YAP1/TAZ-P3F physical interaction and that YAP1/TAZ and P3F share an enrichment for co-immunoprecipitated proteins involved in chromatin remodeling and DNA binding as well as transcriptional regulation. Functional studies using qRT-PCR, immunoblots, and reporter assays demonstrated YAP1/TAZ are positive regulators of P3F-mediated transcriptional activity. Unbiased approaches using RNA-Seq and quantitative tandem mass tag proteomics also demonstrated that YAP1/TAZ positively regulate the differential expression of P3F’s targets and gene signature. Pharmacologically targeting the YAP1/TAZ-P3F axis using novel NUAK1/2 kinase inhibitors that lead to YAP1/TAZ nuclear exclusion cause cell cycle arrest at the G2/M checkpoint as well as a decrease in FP-RMS cell viability through induction of apoptosis. Main Conclusions: Transcriptional co-activators YAP1/TAZ are highly abundant in FP-RMS tumors and are required for numerous FP-RMS cancer phenotypes. YAP1/TAZ physically associate with P3F to regulate P3F-mediated transcriptional activity. Therefore, while directly targeting P3F is not currently viable, we have identified YAP1/TAZ as therapeutically tractable dependencies to P3F transcriptional programing. Citation Format: Adam F. Pecoraro, Tooba Rashid, Breanne A. Burgess, Corinne M. Linardic, Michael D. Deel. Targeting transcriptional co-activators YAP1/TAZ in fusion-positive rhabdomyosarcoma demonstrates a novel strategy in ablating fusion-driven sarcoma transcriptional programing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 700.
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Zhu, Xiangzhu, Xiang Huang, Yinan Zheng, Wei Zhang, Lihua Shu, Reid Ness, Harvey J. Murff, et al. "Abstract CT534: Magnesium treatment on the demethylation of chemokine (C-X-C motif) ligand 9 (CXCL9) gene, results from the personalized prevention of colorectal cancer trial." Cancer Research 82, no. 12_Supplement (June 15, 2022): CT534. http://dx.doi.org/10.1158/1538-7445.am2022-ct534.
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Abstract Background: Chemokine ligand 9 (CXCL9), a T-cell chemoattractant, plays a critical role in regulating antitumor immunity in cancer immunotherapy, i.e., clinical responses to anti-PD(L)-1 treatment. Very recently, CXCL9 was identified as the strongest contributor to the “inflammatory clock of aging”, linked to age-related chronic inflammation. Due to the critical role of magnesium (Mg) in regulating inflammatory responses, this study aims to investigate the effect of Mg treatment on DNA methylation changes in CXCL9. Methods: The Personalized Prevention of Colorectal Cancer Trial conducted at Vanderbilt University Medical Center was a double-blind 2 × 2 factorial randomized controlled trial of 240 participants who completed the study. Participants aged from 40 to 85 years, had a daily calcium intake 700-2000 mg and calcium:magnesium intake ratio ≥2.6 based on the average of the two baseline 24-hour dietary recalls. Results: Among three CpG sites, a 12-week personalized dose of Mg supplementation marginally increased the 5-hydroxymethylcytosine methylation, a measure of active demethylation, at CpG site 04038163 (3'UTR of CXCL9 gene) by 7.0% compared to the placebo group (p=0.07). Although the overall effect was not significant or of borderline significance, Mg treatment significantly reduced the levels of 5-hydroxymethylcytosine by 3.7% at the CpG site 12793812 (body of CXCL9 gene) among those with aged 60 years or above (p=0.03). Conclusions: These findings indicate that Mg treatment modified the demethylation process in the CXCL9 gene, a critical regulator of immune responses and inflammation. Future studies are needed to examine if Mg treatment also changes the circulating levels of CXCL9. Citation Format: Xiangzhu Zhu, Xiang Huang, Yinan Zheng, Wei Zhang, Lihua Shu, Reid Ness, Harvey J Murff, Chang Yu, Martha J Shrubsole, Lifang Hou, Qi Dai. Magnesium treatment on the demethylation of chemokine (C-X-C motif) ligand 9 (CXCL9) gene, results from the personalized prevention of colorectal cancer trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT534.
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Brake, Rachael, Zhaopeng Sun, Mo Dan, Lu Lv, Congcong Niu, Yang Zhang, Mingyue Shen, XiXin Hu, Xiwu Hui, and Andrew Kolodziej. "Abstract C121: Development of CRB-701 (SYS6002): A novel site-specific, Nectin-4 targeting ADC." Molecular Cancer Therapeutics 22, no. 12_Supplement (December 1, 2023): C121. http://dx.doi.org/10.1158/1535-7163.targ-23-c121.
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Abstract CRB-701 (SYS6002) is a clinical stage, next generation ADC targeting Nectin-4 wherein two monomethyl auristatin E (MMAE) moieties are site-specifically conjugated to a novel Nectin-4 targeting IgG1 antibody via a cleavable linker. Nectin proteins are cell adhesion molecules belonging to the immunoglobulin (Ig) superfamily that participate in cell-to-cell interactions and form adhesion junctions between cells. Nectin-4 is widely expressed in epithelial cancers including bladder, breast, lung, colorectal, pancreatic, and ovarian. By contrast the expression level of Nectin-4 is very low in healthy adult human tissues. Due to this differential expression, Nectin-4 has emerged as a robust tumor associated antigen (TAA) that has been clinically validated in urothelial carcinoma by Enfortumab Vedotin (EV). While approved, EV carries associated toxicity concerns including skin rash, peripheral neuropathy and ocular toxicities that can lead to EV discontinuations and lasting adverse effects. CRB-701 (SYS6002) has demonstrated high affinity Nectin-4 binding (~2ng/ml) across species and has selectivity for Nectin-4 among the Nectin family of proteins (>5000 ng/ml). The antibody retains potent in vitro activity against FcgRI and C1q (<10nM) conferring antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) activity in vitro. Compared to EV, CRB-701 (SYS6002) reduces free MMAE exposure by 4.8-9.7-fold when adjusted to ADC exposure (AUC) and there is a 2.2-7.4-fold reduction in MMAE in circulation based on Cmax in rats and non-human primates. Collectively these data reflect lower free MMAE in plasma, reducing the risk of MMAE-induced toxicities observed with EV in the clinic. This improved PK and safety profile coincides with a longer half-life of the ADC in plasma potentially reducing the frequency of administration to achieve efficacy. The internalization rate of CRB-701 (SYS6002) was 2-fold faster than EV when assessed in nectin-4 expressing cells. These data may explain the statistically significant reduction in tumor growth observed in a BL0597 patient derived xenograft model (PDX) of bladder cancer with low Nectin-4 protein expression by IHC (H score =50) when compared to EV at the same dose and frequency. Collectively these data suggest that CRB-701 (SYS6002) could demonstrate an improved therapeutic index and PK profile relative to EV and as such could achieve higher tolerated concentrations at lower dose frequency. The stability of the site-specific linker and the reduction in the drug-antibody ratio (DAR) could lead to a differentiated profile clinically that enables higher doses, longer treatment duration and a greater potential in drug combinations in nectin-4 positive tumors. CRB-701 (SYS6002) is currently being explored clinically in a phase 1 dose escalation with an anticipated completion date mid-2024. Citation Format: Rachael Brake, Zhaopeng Sun, Mo Dan, Lu Lv, Congcong Niu, Yang Zhang, Mingyue Shen, XiXin Hu, Xiwu Hui, Andrew Kolodziej. Development of CRB-701 (SYS6002): A novel site-specific, Nectin-4 targeting ADC [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C121.
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Wang, Stephanie. "Abstract A008: An in vivo screening platform based on Ba/F3 kinase-engineered cell lines for discovering next-generation kinase inhibitors." Molecular Cancer Therapeutics 22, no. 12_Supplement (December 1, 2023): A008. http://dx.doi.org/10.1158/1535-7163.targ-23-a008.
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Abstract Tongtong Liu, Feng He, Xuyang Duan, Shuliang Li, Chang Liu, Jingying Ning, Feng Hao* KYinno Biotechnology (Beijing) Co., Ltd. No.3 Building, Yizhuang Biomedical Park, Beijing, China. Correspondence: Feng.hao@kyinno.com Protein kinases have become very popular targets in the treatment of cancer and other diseases, and since 2001, the FDA has approved more than 70 kinase inhibitor drugs. However, due to innate or acquired resistance in tumors, most of these small molecule inhibitors only delay tumor progression. The development of next-generation kinase inhibitors with better specificity and lower resistance is still ongoing. Ba/F3 is a mouse pro-B cell line whose survival and proliferation depend on IL-3. After transduction with driver genes such as kinase genes or their mutants, Ba/F3 cells switch from IL-3 dependence to driver gene dependence, making Ba/F3 cells a powerful tool for discovering new kinase inhibitors. Our group has constructed over 700 Ba/F3 engineered cell lines stably transfected with kinase gene mutants. These Ba/F3 kinase cell lines have been fully validated by sequencing, western blotting, and inhibitor testing, covering many popular kinases including EGFR (>150 cell lines), RAS (80 cell lines), FGFR (55 cell lines), ERBB2 (49 cell lines), MET (41 cell lines), RET (39 cell lines), BCR-ABL (37 cell lines), EML4-ALK (33 cell lines), and FLT3 (26 cell lines), etc. Most of these transformed Ba/F3 cell lines can be used for xenograft models in immunodeficient mice. Based on these Ba/F3 kinase cell line-derived xenograft models, we have established an in vivo screening platform to evaluate the efficacy and toxicity of candidate drugs against specific kinase mutation types, as well as their comparison with previous generation drugs. Overall, our data suggest that xenograft models derived from Ba/F3 kinase cell lines are powerful models for discovering next-generation kinase inhibitors. Citation Format: Stephanie Wang. An in vivo screening platform based on Ba/F3 kinase-engineered cell lines for discovering next-generation kinase inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A008.
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Snow, Santina M., Dawn Albrecht, Paul A. Clark, Caroline P. Kerr, Joseph J. Grudzinski, Justin J. Jeffery, Hansel Comas Rojas, et al. "Abstract 700: Impact of heterogeneity for mismatch repair activity on colon tumor development and therapeutic response." Cancer Research 84, no. 6_Supplement (March 22, 2024): 700. http://dx.doi.org/10.1158/1538-7445.am2024-700.
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Abstract Background: Colorectal cancers (CRC) that are deficient for DNA mismatch repair (dMMR) proteins have high levels of genetic instability and consequently high mutational burden, creating numerous neoantigens that can elicit an immune response. Therefore, dMMR CRC are the best candidates for immune checkpoint inhibition (ICI) compared to proficient DNA mismatch repair (pMMR) CRC. Early clinical trials revealed that only 30-55% metastatic dMMR CRC responded to ICI. Recent studies utilizing allograft models have demonstrated that tumor immune landscape can be primed with radiopharmaceutical therapy (RPT). Although early results have been quite promising, allograft models often fail to accurately predict efficacy for many reasons, but most often are due to a lack of heterogeneity. Methods: To better understand how heterogenous MMR expression impacts tumor development and response to ICI alone or in combination with RPT, we developed a new mouse model that develops three tumor types: (1) homotypic dMMR tumors that express green fluorescent protein, (2) homotypic pMMR tumors that express red fluorescent protein, and (3) heterotypic tumors with a mixture of dMMR and pMMR cells. Surveillance bright field and fluorescent colonoscopies allow us to assess treatment response by measuring tumor size and proportion of dMMR and pMMR tumor cells in real-time. These outcomes are verified through ex vivo imaging and histological analysis. Results: Tumor response to anti-PD-L1 ICI was dependent on MMR status. Homotypic dMMR tumors exhibited the strongest response: significantly smaller in treated mice than controls, exhibited areas of vascular congestion and increased CD8+ cytotoxic T-cells infiltration. Response of heterotypic MMR tumors varied depending on percentage of dMMR cells; tumors with a high percentage of dMMR cells remained small, whereas tumors with a low percentage of dMMR had an outgrowth of pMMR cells. Treated and untreated homotypic pMMR tumors were indistinguishable. To enhance the response of all three tumor types, mice were treated with dual ICI treatment, anti-PD-L1 and anti-CTLA-4, or RPT. Animals administered the tri-therapy (dual ICI + RPT) survived significantly longer with fewer tumors than animals treated with either dual ICI or RPT alone. Conclusions: Our innovative mouse model allows for the highly detailed characterization of tumor response to therapies. Simplistic allograft models may not adequately account for the dynamic effects that neighboring cell death may have on radio-resistant cells, on tumor vascular perfusion and oxygenation, or on tumor immune infiltration and adaptive immune recognition of remaining cells. We begin to fill these critical gaps in knowledge and therefore the results from our studies will help guide the translation and integrated use of ICIs and RPTs in clinic. Citation Format: Santina M. Snow, Dawn Albrecht, Paul A. Clark, Caroline P. Kerr, Joseph J. Grudzinski, Justin J. Jeffery, Hansel Comas Rojas, Reinier Hernandez, Kristina A. Matkowskyj, Jamey P. Weichert, Zachary S. Morris, Richard B. Halberg. Impact of heterogeneity for mismatch repair activity on colon tumor development and therapeutic response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 700.
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Blagden, Sarah P., Stefan N. Symeonides, Aglaia Skolariki, Noor Md Haris, Zhuang Boh, In Hwa Um, Mustafa Elshani, et al. "Abstract C032: NUC-7738 in combination with pembrolizumab in patients with metastatic melanoma: Phase 2 results from the NuTide:701 study." Molecular Cancer Therapeutics 22, no. 12_Supplement (December 1, 2023): C032. http://dx.doi.org/10.1158/1535-7163.targ-23-c032.
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Abstract Background: 3’-deoxyadenosine (3’-dA) is a natural nucleoside analogue that demonstrated potent anti-cancer activity in vitro but was not successfully developed in the clinic due to rapid breakdown and limited activation to the anti-cancer metabolite (3’-dATP). NUC-7738 is a phosphoramidate modification of 3’-dA designed to overcome these shortcomings and generate higher levels of 3’-dATP. Primarily, 3’-dATP disrupts RNA polyadenylation and can cause metabolic stress, blockade of cell division and apoptosis. Secreted forms of PD-L1, associated with resistance to PD-1 inhibitors, are partially controlled by alternative polyadenylation and were found to be reduced by NUC-7738 in vitro and in some patient (pt) samples. NuTide:701 is a two-part, Phase 1/2 clinical study designed to establish the RP2D of NUC-7738 monotherapy and to investigate NUC-7738 at the RP2D in combination with pembrolizumab. NUC-7738 monotherapy has shown a favourable safety profile and anti-tumour activity (prolonged SD and tumour reductions). Here we focus on the Phase 2 NUC-7738 + pembrolizumab part of the study. Methods: Pts with advanced/metastatic cutaneous melanoma who had progressed on 1- 2 prior lines, one of which may have contained immunotherapy, are included in the ongoing NUC-7738 + pembrolizumab cohort and receive NUC-7738 1125 mg/m2 Q1W (with option to escalate to 1350 mg/m2 beyond C2D8) and pembrolizumab 200 mg/m2 Q3W until progression. In pts with accessible disease, biopsies were taken prior to and 28 days after initiation of treatment to assess tumour levels of NUC-7738 and its metabolites and evaluate changes in the tumour microenvironment. Results: At the time of data cut-off, 4 pts with cutaneous melanoma have received NUC-7738 + pembrolizumab. To date, 1 pt experienced reversable Grade 4 transaminitis, related to pembrolizumab, and 2 pts experienced Grade 3 abdominal pain, diarrhoea and fatigue. At the time of writing, all 4 remain on treatment, 1 pt has SD and 8 additional pts are being recruited. Conclusions: NUC-7738 has a favourable toxicity profile as monotherapy and has been well-tolerated to date in combination with pembrolizumab. Available clinical and translational data for all pts treated with NUC-7738 + pembrolizumab will be presented. Clinical trial information: NCT03428958 Citation Format: Sarah P Blagden, Stefan N Symeonides, Aglaia Skolariki, Noor Md Haris, Zhuang Boh, In Hwa Um, Mustafa Elshani, Alison L Dickson, Ying Zhang, David J Harrison, Fiona G McKissock, Elisabeth Oelmann, Jeffrey D Bloss, Natalie Cook, TR Jeffry Evans, E. Ruth Plummer. NUC-7738 in combination with pembrolizumab in patients with metastatic melanoma: Phase 2 results from the NuTide:701 study [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C032.
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Quan, Yu Hua, Kai Bao, Kyungsu Kim, Haoran Wang, Shinya Yokomizo, G. Kate Park, Byeong Hyeon Choi, et al. "Abstract 5975: Dual-channel near-infrared fluorescence imaging for simultaneous identification of lung cancer and intersegmental plane." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5975. http://dx.doi.org/10.1158/1538-7445.am2022-5975.
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Abstract Intraoperative delineation of the tumor with minimal negative margins is the holy grail of lung cancer surgery. Segmentectomy is a minimal resection surgery required for elderly patients or small sized early-stage lung cancer patients, in which accurate detection of tumor margins with simultaneous identification of the lung intersegment plane is the key to success. However, non-small cell lung cancer is difficult to detect intraoperatively, and the identification of intersegmental plane is challenging during minimal resection surgery. Here, we report dual-channel image-guided lung cancer surgery using renal clearable and physiochemically stable targeted fluorophores to visualize the tumor margins and intersegmental plane separately with different colors but simultaneously: cRGD-ZW800-PEG (800 nm channel) allows for tumor-specific targeting and ZW700-1C (700 nm channel) for discrimination of segmental planes. Armed with the dual-channel imaging, image-guided surgery enables complete tumor resection with minimal negative margins that can reduce the recurrence rate and increase the survival rate of lung cancer patients. Citation Format: Yu Hua Quan, Kai Bao, Kyungsu Kim, Haoran Wang, Shinya Yokomizo, G. Kate Park, Byeong Hyeon Choi, Jiyun Rho, Chungyeul Kim, Hak Soo Choi, Hyun Koo Kim. Dual-channel near-infrared fluorescence imaging for simultaneous identification of lung cancer and intersegmental plane [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5975.
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Kuo, Brian Yu-Ting. "Abstract 7040: Mutations in cytoskeleton genes SPTAN1/SPTBN1 serve as novel predictive markers for immunotherapy against bladder cancer." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7040. http://dx.doi.org/10.1158/1538-7445.am2024-7040.
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Abstract Cancer progression is often driven by somatic mutations. Despite several well-known driver mutations, more evidence has shown that genetic alterations in cytoskeleton organization enhance tumor aggressiveness and promote cancer progression, suggesting their roles as potential drivers. In this study, pan-cancer genetic analyses by using TCGA cohorts, more frequent mutation events were found in cytoskeleton-related genes as compared to total annotated genes, especially in cancers derived from hollow organs. High-dimensional analysis of molecular alterations in cancer (HD-MAC) suggested gene mutations in SPTAN1 and its partner SPTBN1 as potential prognostic biomarkers for clinical outcomes of patients with bladder cancer. Gene knockdown in either SPTAN1 or SPTBN1, mimicking silencing mutations in cancer tissues, caused cell morphology changes, DNA breaks, and alternations in cytokine profiles via activating cGAS-STING mediated interferon signaling. Xenograft tumor models also indicate accelerated tumor growth in SPTAN1- or SPTBN1-silenced cells, suggesting a more advanced cancer type. Based on immune staining in both human and mouse samples, increased CD8+ T cell infiltration was in tumor lesions with mutations or truncations in SPTAN1/SPTBN1 genes. In addition, several known substitution mutations were found as potent neo-antigens based on MHC II binding prediction, which could be utilized as targets for immune checkpoint therapy. This study provides a novel insight into how the cytoskeleton can contribute to cancer progression and find out predictive biological indicators with therapeutic values. Citation Format: Brian Yu-Ting Kuo. Mutations in cytoskeleton genes SPTAN1/SPTBN1 serve as novel predictive markers for immunotherapy against bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7040.
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Droll, Stephenie, Benny Zhang, Celia Xue, Maxwell Levine, and Xiaomin Bao. "Abstract 7070: MEK-ERK signaling maintains epidermal proliferation through H2A.Z deposition." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7070. http://dx.doi.org/10.1158/1538-7445.am2024-7070.
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Abstract Recent studies have connected dysregulation of H2A.Z deposition to glioblastoma as well as lung, pancreatic, and metastatic breast cancers. The H2AZ1 and H2AZ2 isoforms, collectively known as H2A.Z, are histone variants that regulate gene expression, stem cell identity, and differentiation during development and in homeostatic tissue. Most tumors originate from epithelial tissues. We utilize skin epidermis, an accessible model of epithelial tissue, to understand the regulatory mechanisms controlling proliferation and differentiation. Primary human epidermal keratinocytes retain their abilities to proliferate, differentiate, and stratify in vitro. First, we observed that progenitor keratinocytes express high levels of H2A.Z mRNA and protein, and that H2A.Z levels significantly and progressively decrease during four days of calcium-induced differentiation. Using ChIP-sequencing, we find a significant, genome-wide decrease in H2A.Z chromatin occupancy in differentiated keratinocytes. Therefore, we hypothesized that H2A.Z is critical for progenitor function. Knock down of either H2AZ1 or H2AZ2 significantly impaired keratinocyte proliferation in holoclone assays. Furthermore, H2AZ1 or H2AZ2 knockdown inhibited epidermal stratification in organotypic culture. Canonically, two chromatin remodeling complexes, SRCAP and EP400, deposit H2A.Z into nucleosomes. While both SRCAP and EP400 knockdown diminish keratinocyte proliferation, only SRCAP knockdown decreases H2A.Z deposition in epidermal keratinocytes. Finally, we find that MEK and ERK signaling is required to sustain expression of SRCAP, H2AZ1, and H2AZ2. MEK or ERK inhibition is sufficient to significantly decrease H2A.Z occupancy genome-wide in progenitor keratinocytes. Citation Format: Stephenie Droll, Benny Zhang, Celia Xue, Maxwell Levine, Xiaomin Bao. MEK-ERK signaling maintains epidermal proliferation through H2A.Z deposition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7070.
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Hoffe, Sarah E., Dae Won Kim, James Costello, Mokenge Peter Malafa, Todd Anthony Aguilera, Muhammad Shaalan Beg, Parag Parikh, et al. "GRECO-2: A randomized, phase 2 study of stereotactic body radiation therapy (SBRT) in combination with GC4711 in the treatment of unresectable or borderline resectable nonmetastatic pancreatic cancer (PC)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): TPS4175. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps4175.
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TPS4175 Background: While systemic treatment of PC has improved, rates of surgical resection - considered optimum treatment - remain low. Patients with un-resectable or borderline PC still have poor outcomes, with both toxicity and disease progression during induction chemotherapy limiting the number eligible for surgery. SBRT practice to enhance margin negative resection or to provide local control, if inoperable after neoadjuvant therapy, has shifted to higher dose delivery (Mellon 2015, Colbert 2018), but timing and appropriate patient selection are under constant debate. SBRT delivery over 50Gy exhibits superior cell killing compared to conventionally fractionated RT but carries potential GI toxicity risk (Zhong 2017). GC4711 is a selective superoxide dismutase mimetic that converts superoxide to hydrogen peroxide. As radiation response modifiers, dismutase mimetics have the potential to increase tumor control without compromising radiation safety (Sishc, AACR 2019). GC4711 consistently augmented tumor control by SBRT in PC experimental xenograft mouse models. In a pilot phase 1/2 trial (GC4419-101), subjects with locally advanced PC were randomized to receive SBRT plus either the selective dismutase mimetic GC4419 or placebo. This pilot trial has demonstrated acceptable safety with SBRT (5 × 10-11Gy), as well as apparent improvements in survival, surgical resection, locoregional control, and time to distant metastases. Altogether, these data support the hypothesis that GC4711 may improve tumor outcomes and the benefit-risk ratio of 5-fraction SBRT delivering 50Gy by improving efficacy without increasing GI-toxicity. Methods: GRECO-2 is a phase 2, multicenter, randomized, double-blind, placebo-controlled study to determine the effect on overall survival of adding GC4711 to SBRT following 4 months of chemotherapy in subjects with un-resectable or borderline non-metastatic PC. Approximately 160 subjects will be enrolled at over 20 sites to receive GC4711 100 mg or placebo IV given as IV infusion over 15 min, prior to each of 5 SBRT fractions of 10Gy). Subjects judged operable will be explored within 8 weeks after SBRT. All subjects will complete 2 additional months of adjuvant chemotherapy. Primary end point is overall survival and secondary endpoints address resection rates, local and distant disease progression, and safety, while exploratory studies include ctDNA, tumor exome/transcriptome sequencing, and immune profiling, patient-reported symptoms (PRO-CTCAE), CA19.9 normalization, and radiomics. Colbert L, Rebueno N, Moningi S et al Advances in Radiation Oncology (2018) 3, 693-700 Mellon EA, Hoffe SE, Springett GM, et al Acta Oncologica, 2015;54:7 Zhong J, Patel K, Switchenko J, et al. Cancer. 2017 Sep 15;123(18):3486-3493. Sishc BJ, Saha D, Story MD. AACR PADC 2019 C52. Clinical trial information: NCT04698915.
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Gao, Feng, Xuejiao Liu, Xiaojuan Wang, Chunyang Wang, Tonghui Ma, and Changsheng Yang. "Abstract 5755: Mutation profiling of homologous recombination-related (HRR) genes in sarcoma patients." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5755. http://dx.doi.org/10.1158/1538-7445.am2022-5755.
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Abstract BACKGROUND: Homologous recombination deficiency (HRD) is associated with tumorigenesis. Therapy directed toward HRD has been approved in breast and ovarian cancer, however, whether there is a chance of benefit for patients with other cancers remains unknown. Herein, we investigated the mutation characteristics of homologous recombination-related (HRR) genes in Chinese patients with sarcoma to explore possible benefit opportunities for sarcoma patients. METHODS: The genetic landscape of HRR genes was assessed in 700 Chinese sarcoma patients with different subtypes including Rhabdomyosarcoma (RMS, n = 67), Liposarcoma (LPS, n = 58), Osteosarcoma (n = 34), Synovial sarcoma (n = 30), Leiomyosarcoma (n = 29), Ewing's sarcoma (EWS, n = 27), Angiosarcoma (n = 20), other rare (n = 375) and unknown subtypes (n = 60). Molecular profiles were performed by using next generation sequencing (NGS)-based Onco Panscan plus࣪ at Genetronhealth, a laboratory accredited by College of American Pathologists and Clinical Laboratory Improvement Amendments. RESULTS: Among the 700 patients, the overall mutation frequency of HRR genes was 19.0%. Correspond to specific subtypes, the mutation frequency of HRR genes were higher in Leiomyosarcoma (27.6%, 8/29), Angiosarcoma (25.0%, 5/20) and LPS (17.2%, 10/58) compared with RMS (14.9%, 10/67), Osteosarcoma (14.7%, 5/34), Synovial sarcoma (13.3%, 4/30) and EWS (3.7%, 1/27). ATRX was the most commonly mutated gene (5.1%, n = 36) and was preferentially identified in Leiomyosarcoma (10.3%) and Angiosarcoma. (10.0%), followed by ARID1A (3.1%, n = 22), ATM (2.1%, n = 15) and FANCA/C/D2/E/F/G/L (1.7%, n = 12). The median tumor mutational burden (TMB) was 2.35 in patients with HRD and 0.94 in patients without HRD. Although BRCA1 and BRCA2 mutations were less common overall (1.1% and 0.7%), a significant proportion of BRCA1 and BRCA2 mutations was found in Angiosarcoma, Liposarcoma and Leiomyosarcoma (5.0%, 3.4% and 3.4%, respectively). CONCLUSION: Our results reported the genetic landscape of HRR genes in Chinese sarcoma patients, providing a reference for the clinical application of PARP inhibitors. Citation Format: Feng Gao, Xuejiao Liu, Xiaojuan Wang, Chunyang Wang, Tonghui Ma, Changsheng Yang. Mutation profiling of homologous recombination-related (HRR) genes in sarcoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5755.
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Shapira-Frommer, Ronnie, Ruth Perets, Mark Voskoboynik, Kathryn Mileham, Adnan Nagrial, Brian Stein, Vincent Chung, et al. "Abstract CT508: Safety and efficacy of vibostolimab (vibo) plus pembrolizumab (pembro) in patients (pts) with cervical cancer naive to PD-1/PD-L1 inhibitors." Cancer Research 82, no. 12_Supplement (June 15, 2022): CT508. http://dx.doi.org/10.1158/1538-7445.am2022-ct508.
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Abstract Background: The anti-TIGIT antibody vibo in combination with pembro was well tolerated across all doses in the dose-escalation phase of the ongoing phase 1 study in pts with advanced solid tumors (NCT02964013); promising antitumor activity of vibo + pembro was observed in anti-PD-1/PD-L1-naive NSCLC. We present initial results of the dose-expansion phase in pts with advanced cervical cancer naive to PD-1/PD-L1 inhibitors. Methods: Pts with histologically confirmed, locally advanced, or metastatic cervical cancer who failed prior standard-of-care chemotherapy or who experienced early progression on definitive chemoradiation and were naive to PD-1/PD-L1 inhibitors were randomly assigned 1:1 to receive 1 of 2 doses of vibo (200 or 700 mg) + pembro (200 mg) Q3W for ≤35 cycles (~2 y) or until PD, toxicity, or pt withdrawal. Primary end points were safety and tolerability. Secondary and exploratory end points included ORR, DOR, and PFS by investigator review per RECIST v1.1. Results: Median age of the 80 pts with cervical cancer was 49 y; 58% had an ECOG PS of 1; 53% received ≥2 prior lines of therapy; and 61% had PD-L1-positive tumors. 41 pts received vibo 200 mg, and 39 received vibo 700 mg. Median follow-up was 12 mo (range, 5-26). Treatment-related AEs (TRAEs) occurred in 27 pts in each treatment group (66%, vibo 200 mg; 69%, vibo 700 mg). The most frequent TRAEs (≥15%) were rash (22%), increased lipase (17%), and pruritus (17%) with vibo 200 mg + pembro and pruritus (28%), pyrexia (21%), rash (15%), and fatigue (15%) with vibo 700 mg + pembro. Grade 3 or 4 TRAEs occurred in 29% (vibo 200 mg + pembro) and 18% (vibo 700 mg + pembro). No deaths due to TRAEs were reported. Efficacy is reported in the Table. Conclusions: Vibo + pembro was safe in pts with advanced cervical cancer. Antitumor activity was comparable between the 2 doses of vibo studied and responses were observed irrespective of PD-L1 status. Based on these data, the RP2D for vibo remains 200 mg Q3W. Efficacy By Treatment Group By PD-L1 Statusa Vibo 200 mg + Pembro n = 41 Vibo 700 mg + Pembro n = 39 PD-L1-positive n = 49 PD-L1-negative n = 21 Confirmed ORR, % (95% CI) 15 (6-29) 23 (11-39) 20 (10-34) 14 (3-36) CR, n (%) 2 (5) 5 (13) 6 (12) 1 (5) PR, n (%) 4 (10) 4 (10) 4 (8) 2 (10) SD, n (%) 12 (29) 7 (18) 14 (29) 3 (14) PD, n (%) 18 (44) 19 (49) 20 (41) 12 (57) Median DOR, months (range)b Not reached (10 to 31+) Not reached (4+ to 35+) Not reached (4+ to 35+) Not reached (21 to 27+) Median PFS, months (95% CI) 2 (2-4) 2 (2-4) 4 (2-4) 2 (1-4) CR, complete response; DOR, duration of response; PD, progressive disease; ORR, objective response rate; PFS, progression-free survival; PR, partial response; SD, stable disease. aPD-L1 status was unknown in 10 patients; data were pooled across treatment groups. PD-L1 positivity was defined as combined positive score (CPS) ≥1 or when CPS was missing, as tumor proportion score ≥1% or mononuclear immune cell density score ≥2. b“+” indicates no PD present at the time of the last disease assessment. Citation Format: Ronnie Shapira-Frommer, Ruth Perets, Mark Voskoboynik, Kathryn Mileham, Adnan Nagrial, Brian Stein, Vincent Chung, Martin Gutierrez, Diana Chen, Tanya Keenan, Mohini Rajasagi, Jane Healy, Sun Young Rha. Safety and efficacy of vibostolimab (vibo) plus pembrolizumab (pembro) in patients (pts) with cervical cancer naive to PD-1/PD-L1 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT508.
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Kawase, Katsushige, Shusuke Kawashima, Joji Nagasaki, Takashi Inozume, Hiromasa Yamamoto, Masahito Kawazu, Toyoyuki Hanazawa, and Yosuke Togashi. "Abstract 707: High major histocompatibility complex class I expression overcomes cancer immunotherapy resistance due to interferon gamma signaling pathway defects." Cancer Research 83, no. 7_Supplement (April 4, 2023): 707. http://dx.doi.org/10.1158/1538-7445.am2023-707.
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Abstract IFN-γ signaling pathway defects such as JAK mutations are well-known mechanisms of resistance to immune checkpoint inhibitors (ICIs). However, some patients respond to ICIs despite IFN-γ signaling pathway defects, and the detailed mechanisms remain unclear. Here, we created JAK-deleted cancer cell lines and evaluated antitumor immunity. As a result, several tumors responded to PD-1 blockade despite JAK deletion. Such sensitive tumors had high major histocompatibility complex class I (MHC-I) expression despite IFN-γ signaling pathway defects, whereas MHC-I expression was reduced by JAK deletion in resistant tumors. In particular, if cancer cells had high MHC-I expression despite defects in IFN-γ signaling pathways, chemokines that recruit effector T cells were mainly produced by immune cells rather than cancer cells in the tumor microenvironment. Accordingly, we found a response to ICIs in a patient with JAK-negative head and neck squamous cell carcinoma, whose human leukocyte antigen class I (HLA-I) expression level was maintained. In addition, clustered regularly interspaced short palindromic repeats (CRISPR) screening to identify molecules with elevated MHC-I expression independent of IFN-γ signaling pathways demonstrated that guanine nucleotide-binding protein subunit gamma 4 (GNG4) maintained MHC-I expression via the NF-κB signaling pathway. Our results indicate that patients with IFN-ɤ signaling pathway defects are not always resistant to ICIs, and highlight the importance of MHC-I expression among the pathways, including inhibitory effects on cellular proliferation or chemokine production, and the possibility of NF-κB-targeted therapies to overcome such resistance. Citation Format: Katsushige Kawase, Shusuke Kawashima, Joji Nagasaki, Takashi Inozume, Hiromasa Yamamoto, Masahito Kawazu, Toyoyuki Hanazawa, Yosuke Togashi. High major histocompatibility complex class I expression overcomes cancer immunotherapy resistance due to interferon gamma signaling pathway defects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 707.
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Kami Reddy, Karthik Reddy, Jun Hyoung Park, Roni J. Bollag, Martha K. Terris, Seth P. Lerner, Minhaj Siddiqui, Yair Lotan, Jianjun Gao, Benny Abraham Kaipparettu, and Nagireddy Putluri. "Abstract 7060: Mitochondrial metabolism and racial disparity of bladder cancer." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7060. http://dx.doi.org/10.1158/1538-7445.am2024-7060.
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Abstract Bladder cancer mortality is significantly higher in African American patients compared to their European American counterparts. This inferior survival of African American cancer patients is driven at least in part by distinctive intrinsic tumor biology, more specifically altered metabolic activity. However, underlying molecular mechanism for the African American bladder cancer mortality are largely unexplored. Our pioneering metabolomic findings demonstrate alterations in metabolic pathways between African American and European American bladder cancer, specifically those involved in driving energy metabolism. Along these line, we observed increased electron transport chain activity and ATP production in African American bladder cancer could be a result of distinctive rewiring of energy metabolism compared to their European American counterparts. We further performed gene set enrichment analysis by mapping metabolites to genes and observed that oxidative phosphorylation pathway was uniquely enriched in African American tumors compared to European American tumors. In addition, from in vitro assays, mitochondrial complex protein and activity were altered in African American bladder cancer. To determine the role of glutamine mediated increased electron transport chain activity and ATP production in African American bladder cancer, we evaluated the metabolic flux using 13C labeled tracers in both African American and European American bladder cancer cell lines. Metabolic flux analysis revealed that African American cell lines are more glutamine dependent and that producing increased tricarboxylic acid intermediates. Overall, our data indicate that elevated mitochondrial metabolism and oxidative phosphorylation driven by enhanced glutaminolysis may facilitate African American bladder cancer progression. These findings provide the rationale to use mitochondrial-specific inhibitors to target at least a subset of African American bladder cancer patients. Citation Format: Karthik Reddy Kami Reddy, Jun Hyoung Park, Roni J. Bollag, Martha K. Terris, Seth P. Lerner, Minhaj Siddiqui, Yair Lotan, Jianjun Gao, Benny Abraham Kaipparettu, Nagireddy Putluri. Mitochondrial metabolism and racial disparity of bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7060.
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Behbakht, Kian, Cam Nguyen, Stephen Rotholz, Saketh Guntupalli, Barbara Goff, and Benjamin Bitler. "Abstract B042: Feasibility of an electronic medical records based ovarian cancer symptom screening patient questionnaire." Cancer Research 84, no. 5_Supplement_2 (March 4, 2024): B042. http://dx.doi.org/10.1158/1538-7445.ovarian23-b042.
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Abstract Objectives: Symptoms occur in 75% of women with early-stage ovarian cancer and are also common in the absence of cancer. We report the feasibility and results of a prospective four-question symptom screen applied to a gynecology preventive care visit. Methods: Starting February 2021, a patient-facing questionnaire was added to the electronic medical records for women requesting routine gynecology visit. The question asks patients if they have had any of the following symptoms for more than two weeks duration in the prior year: bloating, difficulty eating or feeling full soon after eating, pelvic or abdominal pain, or trouble with urination. In September 2021, the response “No symptoms” was added. Questionnaire responses, medical history and work up performed +/- 3 months of the preventive gynecologic visit were extracted from electronic medical records, compiled in REDCap, and analyzed using R. Results: Between February 2021 and November 2022, a total of 498 patients completed the questionnaire (72.7% White, 10.2% Black, 7.0% Asian/Pacific Islander, 9.8% Other, and 0.2% not stated). The median age was 50 years (range: 40-86). Nearly half (47.2%) reported at least one symptom. The most common isolated single symptom was urinary urgency or frequency (22.9%); 12.3% of these patients had a urinary tract infection. The least common single symptom was early satiety (8.8%). 12 patients (2.4%) reported all four symptoms, and most had explanatory existing diagnoses such as endometriosis, adenomyosis or chronic pelvic pain. No cancers have been diagnosed to date. Conclusions: Ovarian cancer symptom-based screening using electronic medical records is feasible, but alone may not be clinically beneficial. Patients reporting three or more symptoms were 6.6% of the respondents and may represent an ideal group for focused ovarian cancer screening efforts and selective enrolment to novel imaging/tumor marker and proximate fluid analyses. Citation Format: Kian Behbakht, Cam Nguyen, Stephen Rotholz, Saketh Guntupalli, Barbara Goff, Benjamin Bitler. Feasibility of an electronic medical records based ovarian cancer symptom screening patient questionnaire [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B042.
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Beckers, Claire, Lazaros Vasilikos, Alba Sanchez-Fernandez, Lorena Moor, and Martin Pruschy. "Abstract 704: Targeting hypoxic survival pathways to overcome radiotherapy-related treatment resistance." Cancer Research 84, no. 6_Supplement (March 22, 2024): 704. http://dx.doi.org/10.1158/1538-7445.am2024-704.
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Abstract Tumor cells undergo biological adaptations in order to survive stress conditions, such as hypoxia and nutrient deprivation. These biological adaptations include the activation of hypoxic survival pathways that play an important role in acquiring radioresistance which becomes most challenging with treatment regimens using high doses of radiation/fraction (e.g., hypofractionated radiotherapy). Therefore, inhibiting key regulators within these pathways and thereby exploiting these survival mechanisms, gives rise to new potential drug targets for combined treatment modalities. This novel strategy investigated in our laboratory relies on the concept of biological cooperation: while ionizing radiation kills primarily well-oxygenated cells, such inhibitors of survival kinases will drive quiescent tumor cells under hypoxia and/or nutrient deprivation either directly into cell death or into re-entry into a proliferative and thereby more ionizing radiation-sensitive state. One of the survival kinases we are investigating in combination with ionizing radiation (IR) is DYRK1B (dual-specificity tyrosine regulated kinase 1B). We demonstrated that the expression of DYRK1B was upregulated under serum-starvation and hypoxia, but not in response to IR. The small molecule DYRK1B inhibitor AZ191 and shRNA-mediated DYRK1B knockdown significantly reduced proliferative activity and clonogenicity of SW620 tumor cells alone and in combination with IR under serum-starved conditions, which correlated with increased ROS levels and DNA damage. Furthermore, AZ191 successfully targeted the hypoxic core of tumor spheroids while IR preferentially targeted normoxic cells in the rim of the spheroids. A combined treatment effect was also observed in patient-derived colorectal carcinoma organoids but not in healthy tissue organoids. This data shows that inhibition of DYRK1B in quiescent tumor cells could drive tumor cells on their own into crisis or into a more radiosensitive cell cycle phase and thus supports our strategy of biological cooperation. In the continuation of this project, we have performed a drug-screen with approx. 3’000 clinically relevant compounds in colorectal tumor cells lines under normoxic and hypoxic conditions in order to explore additional hypoxia-mediated survival pathways contributing to radioresistance. Thereby we aim to identify novel combined treatment modalities to overcome radiotherapy-induced hypoxia and hypoxia-related resistance mechanisms. Citation Format: Claire Beckers, Lazaros Vasilikos, Alba Sanchez-Fernandez, Lorena Moor, Martin Pruschy. Targeting hypoxic survival pathways to overcome radiotherapy-related treatment resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 704.
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Francis, Delfin Lovelina, and Saravanan SP. "Abstract B124: An assessment of awareness on oral cancer among smokeless tobacco users in the rural skirts of Tamil Nadu, India." Cancer Epidemiology, Biomarkers & Prevention 32, no. 12_Supplement (December 1, 2023): B124. http://dx.doi.org/10.1158/1538-7755.disp23-b124.
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Abstract Background In India, the number of newly diagnosed tobacco related cancers has been estimated at approximately 250 000 out of a total of 700 000–900 000 new cancers diagnosed each year. Smokeless tobacco (ST) is tobacco consumed orally, not smoked. It has been in use for as long as other forms of tobacco consumption and its use have increased. The deleterious effects of smokeless tobacco use are perhaps not as well-known as those produced by smoking. Smokeless tobacco use has been recognized as a cause of cancer. In developing countries, tobacco is mostly chewed with other ingredients. The aim of this study is to assess the awareness of health hazards of tobacco among smokeless tobacco users in Kancheepuram District, Tamil Nadu, India. METHODOLOGY The inhabitants of the villages in Kancheepuram district were recruited after ethical clearance from the institutional ethical board, permission from the Village panchayat leader and informed consent from the participants to conduct the study. Inhabitants of the villages aged 18 to 75 years and present on the day data collection and who were willing to participate in the study were included.Random sampling method was used and data was collected from a cross-sectional survey, using a pretested Questionnaire, which included Demographic data, tobacco habits, its frequency and form.Anti-tobacco counselling was given on the spot and followed.The data collected was analysed using SPSS version21. RESULT: The study population consisted of total 800 individuals, male 400 and females 400. From the results it is observed that more than 70% were unaware of the harmful effects of using tobacco products. Majority of the females use smokeless tobacco and smoking tobacco was common among males. Most common cause of tobacco use was pleasure 32.5% and inducing factor were friends 43.7%. High prevalence of potentially malignant lesion were found among this population. Effectiveness of anti-tobacco counselling is greater among the females compared to males. CONCLUSION: The dangers from smoking and chewing tobacco are well documented within the literature but the public’s lack of knowledge of the risks is a concern. Health professionals are encouraged to disseminate information on the subject as widely as possible and improve existing screening programmes to ensure that the public is made aware of these risks, especially those within high-risk groups. Citation Format: Delfin Lovelina Francis, Saravanan SP. An assessment of awareness on oral cancer among smokeless tobacco users in the rural skirts of Tamil Nadu, India [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B124.
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Wu, Chong, Zichen Zhang, Xiaochen Yang, and Bingxin Zhao. "Abstract 6237: Large-scale imputation models for multi-ancestry proteome-wide association analysis." Cancer Research 84, no. 6_Supplement (March 22, 2024): 6237. http://dx.doi.org/10.1158/1538-7445.am2024-6237.
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Abstract Proteome-wide association studies (PWAS) decode the intricate proteomic landscape of biological mechanisms for complex diseases. Traditional PWAS model training relies heavily on individual-level reference proteomes, thereby restricting its capacity to harness the emerging summary-level protein quantitative trait loci (pQTL) data in the public domain. Here we introduced a novel framework to train PWAS models directly from pQTL summary statistics. By leveraging extensive pQTL data from the UK Biobank, deCODE, and ARIC studies, we applied our approach to train large-scale European PWAS models (total n = 88,838 subjects). Furthermore, we developed PWAS models tailored for Asian and African ancestries by integrating multi-ancestry summary and individual-level data resources (total n = 914 for Asian and 3,042 for African ancestries). We validated the performance of our PWAS models through a systematic multi-ancestry analysis of over 700 phenotypes across five major genetic data resources. Specifically, we identified several novel and well-known genes for various cancers; we highlighted eight genes associated with six cancer traits across all three PWAS model cohorts, including CTSF, RSPO3, CRTAM, LAYN, CHRDL2, DPEP1, NFASC, and NAAA. Our results bridge the gap between genomics and proteomics for drug discovery, highlighting novel protein-phenotype links and their transferability across diverse ancestries. The developed PWAS models and data resources are freely available at www.gcbhub.org. Citation Format: Chong Wu, Zichen Zhang, Xiaochen Yang, Bingxin Zhao. Large-scale imputation models for multi-ancestry proteome-wide association analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6237.
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Champiat, Stephane, Martin Wermke, Johann de Bono, Aurelien Marabelle, Christiane Jungels, Cécile Vicier, Norbert Vey, et al. "Abstract CT188: ICT01, an anti-butyrophilin 3A targeted mAb activating g9d2 T cells, induces immune remodeling of the tumor microenvironment and clinical responses in combination with pembrolizumab in patients with advanced solid tumors who failed prior checkpoint inhibitor therapy: EVICTION Trial." Cancer Research 82, no. 12_Supplement (June 15, 2022): CT188. http://dx.doi.org/10.1158/1538-7445.am2022-ct188.
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Abstract Background: γ9δ2 T cells are part of the innate-like immune response to malignancies and have the ability to bridge to the adaptive immune response via cytokine release (e.g., IFNγ and TNFα). Butyrophilin 3A is a novel checkpoint molecule required to activate γ9δ2 T cells highly expressed on immune and malignant cells, and the target of a monoclonal antibody ICT01. ICT01 induces activation/migration of γ9δ2 T cells from the blood to induce immune remodeling of the tumor microenvironment at doses ≥700 μg being tested in the ongoing EVICTION clinical trial (NCT04243499) (AACR 2021, CT034). In vitro studies showed that ICT01 induces upregulation of PD-1 on γ9δ2 T cells and that the combination with pembrolizumab leads to enhanced cancer cell killing, providing scientific rationale for evaluating this combination. Methods: EVICTION is an ongoing Phase 1/2a, international, open-label trial with Group C assessing ICT01 (IV Q3W) plus pembrolizumab (200mg IV Q3W) in patients with bladder cancer, HNSCC, melanoma, or NSCLC who failed ≥1 CPI. Pharmacodynamic activity was monitored by immunophenotyping and cytokine level analysis. Tumor biopsies (baseline, Day 28) were used for immunohistochemistry of BTN3A and tumor-infiltrating lymphocytes, and gene expression profiling. Efficacy evaluations by i/RECIST 1.1 were conducted every 8 weeks. Results: Five Group C patient cohorts have been enrolled and treated with ICT01 doses of 700μg, 2mg, 7mg, 20mg or 75mg (n=30) plus pembrolizumab, with the 200mg ICT01 cohort enrolling currently. To date, no DLTs have been observed with the combination. First-dose fever and chills (Grade 1/2) were the most common AEs that increased in frequency up to 75mg (100%, n=6), without any increase in severity, and rarely recur with subsequent dosing. ICT01+pembrolizumab induced trafficking of >95% of circulating γ9δ2 T cells within 30 min post ICT01 (≥700 μg), which was sustained for 21 days at 75mg. Transient, dose-dependent increases in serum cytokines at 30 min (TNFα) or 4h (IFNγ) post-dose were correlated with baseline γ9δ2 T cell counts and returned to baseline by 24 hrs post dose. Baseline γ9δ2 T cell count also correlated with increases in tumor infiltration of γδ, CD3, and CD8 T cells, confirming the ability to remodel the TME, and the potential to select/enrich patients with higher baseline γ9δ2 T cell counts. Sixteen patients (9/16 pembro-experienced, 5/16 received >1 prior CPI) were efficacy-evaluable at ≥Week 8 by RECIST1.1 at ICT01 doses up to 20 mg, with an observed disease control rate of 44% including 3 confirmed PRs beyond 6 months: bladder (2mg), melanoma (2mg), NSCLC (7mg). The Ipi/Nivo-refractory melanoma patient with PR also achieving a CR on their non-target lesion brain metastasis at 6 months. Data from the 75 and 200mg cohorts will be presented. Conclusion: The immune remodeling of the TME by ICT01-activated γ9δ2 T cells is associated with clinical benefit in CPI-experienced patients when used in combination with pembrolizumab. The selection of patients with higher baseline γ9δ2 T cells may improve the response profile to this novel therapeutic combination in CPI-failure patients, which will be tested in the Phase 2a portion of EVICTION starting in Q2 2022. Citation Format: Stephane Champiat, Martin Wermke, Johann de Bono, Aurelien Marabelle, Christiane Jungels, Cécile Vicier, Norbert Vey, Catrin List, Katrin Wetzko, Leo Ruhnke, Elena Garralda, Vladimir Galvão de Aguiar, Patricia LoRusso, Nuria Kotecki, Aude De Gassart, Emmanuel Valentin, Patrick Brune, Marina Iché, Céline Leparquier, Daniel Olive, Paul Frohna. ICT01, an anti-butyrophilin 3A targeted mAb activating g9d2 T cells, induces immune remodeling of the tumor microenvironment and clinical responses in combination with pembrolizumab in patients with advanced solid tumors who failed prior checkpoint inhibitor therapy: EVICTION Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT188.
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Yan, Lin, Sneha Sundaram, Bret M. Rust, Matthew J. Picklo, and Michael R. Bukowski. "Abstract 709: Metabolomic differences between pulmonary metastasis of Lewis lung carcinoma and normal lungs from C57BL/6 mice fed an obesogenic high-fat diet." Cancer Research 82, no. 12_Supplement (June 15, 2022): 709. http://dx.doi.org/10.1158/1538-7445.am2022-709.
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Abstract Metastasis, the spread of malignant cells from a primary tumor to distant organs, is the most devastating aspect of cancer. To understand the metabolism of metastases, we compared the metabolomes of pulmonary metastases of Lewis lung carcinoma (LLC) with that of normal lung tissues from mice fed an obesogenic high-fat diet. In a 2x2 design, male C57BL/6 mice, with or without a subcutaneous LLC inoculation, were fed the standard AIN93G diet or a high-fat diet (HFD), which provided 16% or 45% of energy from soybean oil, for 12 weeks. At the end of the study, lung metastases from injected mice and the lungs from non-injected mice were harvested for untargeted metabolomic analysis of primary metabolism by gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). We identified 91 metabolites, 70 of which differed among the four groups. Pathway and network analyses along with the discriminant analysis showed that amino acid and carbohydrate metabolism were altered the most in metastases compared to the normal lung tissue (e.g., aminoacyl-tRNA biosynthesis pathways and the citric cycle). A 60% decrease in glutamine and a 25-fold elevation in sorbitol were observed in metastases. Cholesterol and its metabolite dihydrocholesterol were 50% lower in metastases than in the lungs. The HFD elevated arachidonic acid and its precursor linoleic acid in the lungs from non-LLC-bearing mice, which reflected dietary fatty acid composition of the HFD. However, such elevation did not occur in metastases from HFD-fed LLC-bearing mice, suggesting alterations in fatty acid metabolism during LLC metastatic progression. Differences in metabolomes between LLC pulmonary metastases and the normal healthy lungs identified in the present study can be useful in designing targeted studies for prevention and treatment of metastasis using this spontaneous metastasis model. Citation Format: Lin Yan, Sneha Sundaram, Bret M. Rust, Matthew J. Picklo, Michael R. Bukowski. Metabolomic differences between pulmonary metastasis of Lewis lung carcinoma and normal lungs from C57BL/6 mice fed an obesogenic high-fat diet [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 709.
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Kandimalla, Raghuram, Farrukh Aqil, Disha N. Moholkar, Suman K. Samanta, and Ramesh C. Gupta. "Abstract 707: Mahanine, a carbazole alkaloid attenuates lung cancer progression." Cancer Research 82, no. 12_Supplement (June 15, 2022): 707. http://dx.doi.org/10.1158/1538-7445.am2022-707.
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Abstract Lung cancer continues to be a major cause of cancer mortality. Emerging evidence suggests that cancer likely involves multiple mutations. Therefore, compounds targeting multiple signal transduction pathways would be ideal for the prevention and treatment of cancer. Mahanine, a carbazole alkaloid isolated from an Indian folklore medicinal plant Murraya koenigii (known as Curry Patta), widely consumed in traditional dishes, have been shown to possess anticancer activities and confound many oncogenic signaling events in breast, colon, and prostate cancers. In the current study, we determined the anticancer potential of mahanine against drug-sensitive and drug-resistant lung cancer cells and postulate the possible mechanism of action. Mahanine was isolated from the dried leaves of Murraya koenigii by hydro alcoholic extraction and fractionation with ethyl acetate, followed by preparative UPLC to isolate pure (>95%) compound and its identity was confirmed by LC-MS/MS and NMR spectroscopy. Antiproliferative activity of mahanine was determined against drug- sensitive (A549 and H1299) and taxol-resistant (A549-TR) human lung cancer cells. Mahanine showed a dose- and time-dependent inhibition of both drug-sensitive and drug-resistant lung cancer cell growth. Interestingly, the IC50 values of mahanine were essentially the same for drug sensitive (A549) (12.5 µM) and drug- resistant (12.5 µM) lung cancer cells; the IC50 value was somewhat lower (10 µM) against highly metastatic H1299 lung cancer cells. Mahanine attenuated the colony formation and reduced the wound healing of lung cancer cells. Mechanistically, mahanine dose dependently impeded the oncogenic markers such as KRAS, MET, AKT, mTOR and cMYC. Together, mahanine demonstrate ability to inhibit both drug- sensitive and drug-resistant lung cancer cells and modulate distinct oncogenic molecular targets providing potential to be developed for the treatment of drug-resistant and metastatic NSCLC (Supported from Duggan Endowment funds). Keywords: Mahanine, Lung cancer, Oncogenes, Plant therapeutics. Citation Format: Raghuram Kandimalla, Farrukh Aqil, Disha N. Moholkar, Suman K. Samanta, Ramesh C. Gupta. Mahanine, a carbazole alkaloid attenuates lung cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 707.
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Lee, Eunhyo, Seoree Kim, Jeana Kim, Minho Lee, Yoonho Ko, and Sang Hoon Chun. "Abstract 7020: Prognostic implications of microRNA 181a 2 3p expression in association with tumor budding in patients with stage III lung squamous cell carcinoma." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7020. http://dx.doi.org/10.1158/1538-7445.am2024-7020.
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Abstract Introduction: Tumor budding (Bd) has been known as an independent prognostic factor in various malignancies. MicroRNA (miRNA) are known to play an important role in regulating Bd. However, understanding the relationship between Bd and miRNA in Lung Squamous cell carcinoma (LUSC) remains limited. Methods: 115 LUSC patients who underwent curative resection were included in the discovery cohort. Bd was verified through immunohistochemical (IHC) stain. Bd was classified according to a three tier system: Bd1 with 0-4 buds, Bd2 with 5-9 buds, and Bd3 with 10 or more buds. MiRNA expression profiles were analyzed through RNA sequencing. Differences in survival outcomes for miRNA, as identified in the discovery cohort, were confirmed using LUSC data of The Cancer Genome Atlas (TCGA) as a validation cohort. Results: The relationship between Bd2 and the prolongation of recurrence-free survival (RFS) was statistically significant (p=0.0113), whereas Bd1 was correlated with Overall Survival (OS) (p=0.0468). Multivariate analysis indicated that both a high T stage (HR: 5.211, 95% CI: 1.168-23.250, p = 0.031; and HR: 5.107, 95% CI: 1.447-18.030, p < 0.011) and Bd3 (HR: 3.683, 95% CI: 1.370-9.900, p = 0.010; and HR: 1.600, 95% CI: 0.800-3.201, p = 0.018) are independently significant poor prognostic factors for both RFS and OS. MiRNA-181a-2-3p was identified through Differentially Expressed miRNA (DER) analysis. A higher expression of miRNA-181a-2-3p in stage III LUSC of the TCGA dataset was associated with OS (p=0.0463). Conclusions: Our study demonstrates that the miRNA 181a 2 3p expression is associated with improved OS. This association may be attributed to its inhibitory effect on Bd in advanced stages of LUSC. Citation Format: Eunhyo Lee, Seoree Kim, Jeana Kim, Minho Lee, Yoonho Ko, Sang Hoon Chun. Prognostic implications of microRNA 181a 2 3p expression in association with tumor budding in patients with stage III lung squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7020.
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Vageli, Dimitra, Panagiotis G. Doukas, and Benjamin L. Judson. "Abstract PO-047: A novel saliva miRNA panel of promising diagnostic biomarkers for oral cancer: The association of miR-21 with smoking history." Clinical Cancer Research 29, no. 18_Supplement (September 15, 2023): PO—047—PO—047. http://dx.doi.org/10.1158/1557-3265.aacrahns23-po-047.
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Abstract Introduction: Tobacco use is implicated in the carcinogenesis of oral squamous cell carcinoma (OSCC), which is associated with poor survival if not diagnosed early. It is urgent to develop a novel non-invasive and highly sensitive risk assessment and diagnostic method to screen OSCC. Here, we explored salivary miRNAs as a screening method for OSCC in a high-risk group of patients, such as smokers. Materials and methods: Saliva was collected from 44 individuals (23 HPV-negative OSCC; 21 controls; an equal number of smokers and non-smokers). Twenty head and neck cancer-related miRNA markers were analyzed by qPCR, using dual-labeled probes (miR-20A, miR-21, miR-27B, miR-29A, miR-29B, miR-29C, miR-31, miR-34a, miR-99a, miR-125a, miR-136, miR-139, miR-155, miR-192, miR-200A, miR-375, miR-425A, miR-451a, miR-504, miR-3928; RNU6 control), and by Welch’s t-test and ROC (receiver operating characteristic) curve; GraphPad Prism 7.0. Results: A panel of 4 miRNA markers (miR-21, miR-136, miR-3928, miR-29B) was found to be significantly overexpressed in the saliva of OSCC versus healthy controls with a diagnostic ability (p<0.05 by Welch’s t-test; AUC (area under the ROC curve): 64-85%, sensitivity: 50-67%, specificity: 32-38%; 95% confidence interval; by ROC curve analysis). “Oncomir” miR-21 levels (miR-21/RNU6) were found to be significantly higher in the saliva of OSCC patients with a smoking history (mean ± SD: 0.17 ± 0.19) versus never-smokers (mean ± SD: 0.0056 ± 0.0075) (p<0.05; by t-test) with a diagnostic ability (AUC: 90%, sensitivity: 68%, specificity: 30%; 95% confidence interval). Conclusions: We provide a novel panel of non-invasive, easy-to-apply, and sensitive biomarkers, for the diagnosis of oral cancer, including miR-21 in individuals with a smoking history, encouraging their validation in a large group of head and neck cancer patients. Citation Format: Dimitra Vageli, Panagiotis G. Doukas, Benjamin L. Judson. A novel saliva miRNA panel of promising diagnostic biomarkers for oral cancer: The association of miR-21 with smoking history [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-047.
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Oikkonen, Jaana, Alexandra Lahtinen, Mai T. N. Nguyen, Giovanni Marchi, Kari Lavikka, Anna Rajavuori, Kaisa Huhtinen, Sakari Hietanen, Anni Virtanen, and Johanna Hynninen. "Abstract PR-001: Stable subclones and acquired genomic events present after treatment of HGSC." Cancer Research 84, no. 5_Supplement_2 (March 4, 2024): PR—001—PR—001. http://dx.doi.org/10.1158/1538-7445.ovarian23-pr-001.
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Abstract Ovarian high-grade serous carcinoma (HGSC) is commonly diagnosed at an advanced stage, showing multiple genetically heterogeneous clones existing prior to therapeutic intervention. Most of the patients respond well to primary therapy, but cancer relapses within few years and develops treatment resistance. Genomics changes in tumors during therapy are poorly known. Thus, we characterized subclonal changes and their contribution to treatment resistance and outcome in over 150 patients with HGSC. We used over 700 longitudinal tissue and plasma samples from the prospective, longitudinal, multiregion DECIDER study. Patients were treated either with primary debulking surgery and platinum-taxane chemotherapy, or by neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) and adjuvant chemotherapy. Tumor samples from pre-chemotherapy, at IDS and at relapses underwent whole-genome sequencing (WGS), and plasma samples were sequenced with either whole-exome sequencing or targeted cancer-gene panels. Phylogenetic trees were constructed from WGS samples (2-12 per patient) and curated to use information gathered from plasma samples. Evolutionary states presenting within and between sample heterogeneity were evaluated through clonal complexity and divergence. Additionally, genetic differences between persistent and non-persistent subclones were studied to identify features affecting treatment resistance. Our results indicate that the majority of subclones survived treatment. Major subclonal replacement was detected only in few patients, whereas remaining heterogeneity with acquired focal copy-numbers and mutations was commonly detected. Within-sample heterogeneity was higher at plasma samples than ascites, which underlined the importance of ctDNA sampling to estimate persistent subclones. Additionally, evolutionary states were often altered by the changing selection pressure caused by treatments. Direction of these responses varied after NACT: some patients moved towards our earlier identified maintaining state (Lahtinen et al. Cancer Cell 2023) with similar subclonal compositions between sampled sites whereas others moved towards adaptive state with high number of sample-specific subclones. At late relapses, subclone compositions typical in maintaining state tumors were less common and higher number of acquired subclones were detected, suggesting further evolution of the persisting clones. Taken together, chemotherapy treatment does not suppress heterogeneity in HGSC tumors. Bottleneck events causing survival of only a few subclones were rare. Treatments altered evolutionary states of the cancers, and most tumors revealed acquired mutations at relapses. Overall, we detected various evolutionary trajectories from stable, persistent cancer subclone populations to highly dynamic subclone structures. Understanding these dynamics of tumor clonal heterogeneity during treatment is crucial to define better therapeutic interventions in these poor prognosis patients with advanced HGSC. Citation Format: Jaana Oikkonen, Alexandra Lahtinen, Mai T.N. Nguyen, Giovanni Marchi, Kari Lavikka, Anna Rajavuori, Kaisa Huhtinen, Sakari Hietanen, Anni Virtanen, Johanna Hynninen. Stable subclones and acquired genomic events present after treatment of HGSC [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr PR-001.
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Clarke, Megan A. "Abstract IA005: New directions in prevention and early detection of endometrial cancers." Clinical Cancer Research 30, no. 5_Supplement (March 1, 2024): IA005. http://dx.doi.org/10.1158/1557-3265.endo24-ia005.
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Abstract Most endometrial cancers and precursor lesions are preceded by postmenopausal bleeding (PMB), offering a window of opportunity for early detection and improved survival. Clinical guidelines recommend prompt evaluation of PMB to rule out endometrial cancer. Current diagnostic approaches including transvaginal ultrasound and endometrial biopsy are invasive and can be associated with discomfort and procedural pain, and we have shown that recommendations may not be consistent with underlying risk of endometrial cancer. Access to these procedures may be challenging for patients who live in rural areas or who experience other barriers to care. Current strategies may also have limited accuracy for detecting non-endometrioid cancers which are clinically aggressive, more common in Black women, and increasing in incidence and mortality in the U.S. Black women experience significant racial disparities in endometrial cancer survival and are more likely to experience diagnostic delays compared to their White counterparts. Because of the anatomical continuity of the lower genital tract, we and others have demonstrated the feasibility of pairing molecular assays with minimally invasive self-sampling approaches, such as vaginal tampons, for the detection of tumor DNA. In a recent study led by our colleagues at the Mayo Clinic, we identified over 28 methylation markers that were tested in self-collected tampon samples that showed good clinical performance for endometrial cancer detection. Such approaches can mitigate cancer disparities by offering an at-home early detection strategy to increase coverage and expand access to care. To date, few endometrial cancer studies have been conducted within diverse clinical populations. To address this gap, we designed the Discovery and Evaluation of Tests for Endometrial Cancer in Tampons (DETECT) study. DETECT is a case control study that includes patients undergoing hysterectomy for endometrial cancer and benign conditions at the University of Alabama at Birmingham (UAB). DETECT has enrolled over 700 patients to date, including over 360 with endometrial cancer (approximately 30% with non-endometrioid tumors). In this study, we collect extensive questionnaire data including information about symptoms, and novel risk factors such as feminine hygiene and hair product use. We obtain clinical information on diagnostic procedures, surgery, and treatment information from electronic medical records, and collect tampon, tissue, and blood samples from enrolled patients. In preliminary analyses, over two-thirds of participants self-collected a vaginal tampon sample, with collection varying by race (57% in Black vs. 76% in White patients). Next steps include pilot testing to compare the performance of biomarkers (somatic mutations and methylation markers) measured from tampon samples to tissue for endometrial cancer detection. Future goals of DETECT include the evaluation of endometrial cancer risk factors, biomarkers, outcomes, and disparities across the cancer continuum. Citation Format: Megan A. Clarke. New directions in prevention and early detection of endometrial cancers [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr IA005.
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Se Whee Park, Sammy, Nona Struyf, Tom Erkers, Sören Lehmann, Michael T. Meister, Jarno Drost, Frank C. Holstege, et al. "Abstract 706: Advancing radiotherapy strategies for high-risk rhabdomyosarcoma: Unveiling BCL-xL inhibition as a potent sensitizer to radiotherapy." Cancer Research 84, no. 6_Supplement (March 22, 2024): 706. http://dx.doi.org/10.1158/1538-7445.am2024-706.
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Abstract Pediatric soft-tissue sarcomas are a group of solid tumors that account for about 7% of childhood cancer cases. Rhabdomyosarcoma (RMS), the most common subtype, further stratifies into PAX3 or PAX7 and FOXO1 fusion-negative (FN) or fusion-positive (FP) RMS. FP RMS is the higher risk subtype and is more aggressive, metastatic, and less responsive to treatment. Front-line treatments for RMS FP patients have had limited progress in the recent years and existing treatments such as radiotherapy lacks tumor cell selectivity, resulting in toxic side effects. To address this, we conducted a high-throughput drug screen to identify radiosensitizers to enhance efficacy of RMS radiotherapy. Using three patient-derived FP RMS tumoroids, we screened a comprehensive drug library with and without radiation, comprising 528 drugs at varying stages of pre-clinical and clinical trials. A validation screen of the top 29 drugs was conducted on a larger cohort of samples including eight patient-derived FP RMS tumoroids and three non-cancer models. The screening revealed that drugs targeting the anti-apoptotic protein B-cell lymphoma-extra-large (BCL-xL) exhibited both potent radiosensitization and cytotoxicity selectively for FP RMS. Notably, the sensitivity to BCL-xL inhibitors correlated with elevated BCL2L1 expression and PAX3 fusion status. Additionally, drugs targeting polo-like kinase 1 (PLK1) and other cell cycle-related genes exhibited robust radioprotective effects across both RMS and non-cancer models. Our findings propose the therapeutic potential of BCL-xL inhibition, either as a standalone treatment or in combination with radiotherapy. In parallel, we show the protective potential of PLK1 inhibition to mitigate radiation toxicity. In the long term, we aspire to integrate the identified radiosensitizing and radioprotecting compounds with existing treatment regiments for RMS, maximizing precision and efficacy in RMS radiotherapy. Citation Format: Sammy Se Whee Park, Nona Struyf, Tom Erkers, Sören Lehmann, Michael T. Meister, Jarno Drost, Frank C. Holstege, Nikolas Herold, Päivi Östling, Jakob Stenman, Olli Kallioniemi, Jan-Inge Henter, Brinton Seashore-Ludlow, Kasper Karlsson. Advancing radiotherapy strategies for high-risk rhabdomyosarcoma: Unveiling BCL-xL inhibition as a potent sensitizer to radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 706.
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Bhattacharya, Debanjan, Riccardo Barrile, Donatien Kamdem Toukam, Vaibhavkumar S. Gawali, Laura Kallay, Taukir Ahmed, Hawley Brown, et al. "Abstract 703: GABA(A) receptor activation drives GABARAP-Nix mediated autophagy to radiosensitize primary and metastatic lung adenocarcinoma tumors." Cancer Research 84, no. 6_Supplement (March 22, 2024): 703. http://dx.doi.org/10.1158/1538-7445.am2024-703.
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Abstract In non-small cell lung cancer (NSCLC) treatment, targeted therapies help a subset of patients, and radiotherapy responses are not durable and toxicity limits therapy. Most advanced-stage NSCLC patients have brain metastases that render an abysmal prognosis. Standard-of-care radiation therapy for NSCLC brain metastasis includes stereotactic radiosurgery (SRS) if the number of lesions is less than ten, otherwise whole brain radiation therapy (WBRT) is administered. Challenges in applying radiotherapy include overcoming radiation resistance and reducing significant associated co-morbidities. Cancer neuroscience is an evolving area, and the purpose of this study is to determine if activation of GABA(A) receptors intrinsic to NSCLC cells can improve radiation efficacy in primary NSCLC and its brain metastasis. We find that a GABA(A) receptor activator, AM-101, impairs the viability and clonogenicity of NSCLC primary and brain metastatic cells. Employing a human-relevant ex vivo ‘chip’, AM-101 is as efficacious as docetaxel, a chemotherapeutic used with radiotherapy for advanced-stage NSCLC. In vivo, AM-101 potentiates radiation, including conferring a significant survival benefit to mice bearing NSCLC intracranial tumors generated using a patient-derived metastatic line. GABA(A) receptor activation stimulates a selective-autophagic response via multimerization of GABA(A) Receptor-Associated Protein (GABARAP), stabilization of mitochondrial receptor Nix, utilization of ubiquitin-binding protein p62, and upregulation of Beclin-1. A high-affinity peptide disrupting Nix binding to GABARAP inhibits the cytotoxicity of AM-101. This supports a model of GABA(A) receptor activation driving a GABARAP-Nix multimerization axis that triggers autophagy. In NSCLC brain metastases patients, GABA(A) receptor activation may improve radiation efficacy and tumor control while allowing radiation dose de-intensification to reduce toxicity. Citation Format: Debanjan Bhattacharya, Riccardo Barrile, Donatien Kamdem Toukam, Vaibhavkumar S. Gawali, Laura Kallay, Taukir Ahmed, Hawley Brown, Sepideh Rezvanian, Aniruddha Karve, Pankaj B. Desai, Mario Medvedovic, Kyle Wang, Dan Ionascu, Nusrat Harun, Chenran Wang, Andrew M. Baschnagel, Joshua A. Kritzer, James Cook, Daniel A. Pomeranz Krummel, Soma Sengupta. GABA(A) receptor activation drives GABARAP-Nix mediated autophagy to radiosensitize primary and metastatic lung adenocarcinoma tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 703.
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Alfsen, Maria Zeiler, Maria Thaysen, Nikoline Nielsen, Michael Wick, Luke Piggott, Sebastian Gnosa, and Carsten Haagen Nielsen. "Abstract 702: Development of a radioresistant PDX prostate cancer model to evaluate potential radiosensitizing compounds." Cancer Research 84, no. 6_Supplement (March 22, 2024): 702. http://dx.doi.org/10.1158/1538-7445.am2024-702.
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Abstract Prostate cancer is the second most common cancer diagnosis worldwide and the fifth leading cause of cancer related death among men. Several treatment strategies are used including the FDA approved 177Lu-vipivotide tetraxetan (177Lu-PSMA-617) for the treatment of prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer. However, not all patients respond to treatment due to tumor intrinsic resistance mechanisms. Therefore, the combination of targeted radionuclide therapy with inhibitors against e.g. DNA damage response, cell cycle progression or cell survival pathways are investigated to enhance the radiosensitivity of the tumor. Current models to study radioresistance in prostate cancer are based on cancer cell lines or cell-line derived xenograft models, but these models do not account for the heterogenous and complex biology of the disease. To overcome this issue, we have developed a radioresistant patient-derived xenograft (PDX) prostate cancer model (ST1273, XenoSTART), that is positive for PSMA. Resistance to radiation was initially established by sequential irradiation of the tumors with external beam radiation. Moreover, the model has proven to be resistant towards treatment with 30 MBq 177Lu-PSMA-617. Utilizing this radioresistant model we are now able to investigate the treatment response of 177Lu-PSMA-617 in combination with different drug inhibitor classes to evaluate their potential radiosensitizing effect. The PARP inhibitor, Olaparib, was administered at 50 mg/kg QDx48 alone or in combination with a single dose of 177Lu-PSMA-617 in radioresistant ST1273 tumor bearing NMRI nude mice. First results showed a prolonging treatment effect of Olaparib given in combination with 177Lu-PSMA-617 compared to 177Lu-PSMA-617 alone. Tumor relapse was observed 29 days after treatment with 177Lu-PSMA-617 alone, whereas it was observed 49 days after combination treatment. Olaparib given alone did not influence tumor growth. To further investigate the mechanism of resistance we are currently investigating the radiosensitizing potential of additional compounds and evaluating the tumors by RNA- and whole-exome- sequencing. Altogether, we successfully established a PSMA positive prostate cancer model resistant to PSMA targeted radionuclide therapy. With this model we are able to investigate the radiosensitizing effect of different drug classes. Citation Format: Maria Zeiler Alfsen, Maria Thaysen, Nikoline Nielsen, Michael Wick, Luke Piggott, Sebastian Gnosa, Carsten Haagen Nielsen. Development of a radioresistant PDX prostate cancer model to evaluate potential radiosensitizing compounds [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 702.
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Zhang, Zhenqing, Yunli Jia, Xiaoniu Miao, Weifeng Huang, Chao Wang, Zhijun Yuan, Wenchao Jiang, Zhiyuan Li, Liandi Chen, and Andy Tsun. "Abstract 6115: Development of functionally differentiating anti-CD73 antibodies for cancer therapy." Cancer Research 82, no. 12_Supplement (June 15, 2022): 6115. http://dx.doi.org/10.1158/1538-7445.am2022-6115.
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Abstract Background: Although the discovery and development of first-generation of immune checkpoint inhibitors (towards PD1 and CTLA-4) was a major milestone for cancer therapy, current clinical response rates are still considered very limited. Combination treatments are predicted to improve on these current immunotherapies including the targeting of the adenosine pathway (CD39, CD73 or A2AR), which has shown a lot of promise in preclinical and early clinical studies. CD73 is an ecto-5′-nucleotidase which transforms adenosine monophosphate (AMP) to adenosine. Adenosine is a soluble immunosuppressive metabolite that can suppress natural killer cells and cytotoxic CD8+ T cells. Blockade of CD73-mediated conversion of AMP to adenosine may therefore recover anti-tumor immunity through preventing the enrichment of adenosine in the tumor microenvironment. Method: In this campaign, two humanized and Fc-silenced IgG antibodies were generated named 7002-01 and 7002-04. The target binding epitopes of these candidates were revealed by binning experiments through bio-layer interferometry. Cell binding experiments were tested on human and cynomolgus CD73 overexpression CHO cell lines by flow cytometry. Cellular CD73 enzyme inhibition experiments were tested using A375, MDA-MB-231, H2030 and BT549 tumor cell lines via the CellTiter-Glo method. Soluble CD73 enzymatic tests were carried out on patient sera or recombinant CD73 protein using a similar method. T cell proliferation assays were performed using PBMC. In vivo efficacy studies were tested in B-NDG B2M-KO mice that were injected subcutaneously with A375 tumor cells and human PBMC. Results: Two candidates, 7002-01 and 7002-04, were selected based on their functional activity, that recognize different non-overlapping binding epitopes on CD73. Both candidates selectively bind to and can inhibit the activities of both membrane-bound and soluble human CD73 to high levels and seem to maintain inhibition at high dose-ranges without a hook effect. Both candidates can potently rescue adenosine-mediated T cell regulation. Additionally, 7002-01 and 7002-04 have combination synergy or additive effects for CD73 inhibition on soluble CD73, tumor cell lines that express CD73, and PBMC. 7002-01 and 7002-04 have single-agent anti-tumor efficacy and combination synergy with anti-PD1 antibodies in mice. 7002-01 has a typical antibody-like PK profile when rhesus monkeys were administered with a single intravenous dose at 25 or 50 mg/kg. No drug-related toxicities have been observed in GLP toxicity studies with dosages at 50, 250, and 500 mg/kg (QW, 4 weeks). Conclusion: Highly differentiating anti-CD73 antibodies were discovered that show maximal inhibition of both membranous and soluble CD73 without hook effects at high concentrations. 7002-01 was chosen as the lead molecule for its better overall activity profile and should be entering clinical trials by early 2022. Citation Format: Zhenqing Zhang, Yunli Jia, Xiaoniu Miao, Weifeng Huang, Chao Wang, Zhijun Yuan, Wenchao Jiang, Zhiyuan Li, Liandi Chen, Andy Tsun. Development of functionally differentiating anti-CD73 antibodies for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6115.
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Ofosu-Asante, Kweku. "Abstract B003: Inhibition of cell growth and migration by polyisoprenylated cysteinyl amide inhibitors of a mutant KRAS Black American lung cancer cell line involves MAPK pathway activation and disruption of the cytoskeleton." Cancer Epidemiology, Biomarkers & Prevention 32, no. 12_Supplement (December 1, 2023): B003. http://dx.doi.org/10.1158/1538-7755.disp23-b003.
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Abstract KRAS mutations are the most common oncogenic mutations in lung adenocarcinoma in Black Americans. Polyisoprenylated Cysteinyl Amide Inhibitors (PCAIs) constitute a group of potential cancer therapy agents that we designed to specifically disrupt and suppress hyperactive G-protein signaling, as caused by mutated RAS proteins. Here we investigate the effects of PCAIs on the viability, G-protein levels, downstream mediators, cytoskeletal structure, focal adhesion protein and apoptosis-related proteins on the KRAS-mutated, Black American-derived lung adenocarcinoma cell line, NCI-H23. Western blotting was used to determine the effect of the PCAIs on the phosphorylation levels of MAPK pathway enzymes. After 48-hour exposure to 5 μM of the PCAIs, 57 ± 3.6 to 150 ± 4.1 % increases of BRAF, MEK1/2, ERK1/2, and p90RSK phosphorylation along with a 60 ± 6.5 to 78 ± 4.0 % decrease of pRAF1 phosphorylation were observed, indicating significant changes in RAS signaling. Furthermore, 5 μM of NSL-YHJ-2-27 depleted the singly polyisoprenylated monomeric G-proteins RAC 1/2/3 and CDC42 by 77 ± 5.5 and 76 ± 2.0 %, respectively. The depletion of these key cytoskeletal proteins, and collapse of F-actin and vinculin punctates, may account for the observed inhibition of cell migration after 72-hour exposure to NSL-YHJ-2-27 and NSL-YHJ-2-46, respectively. The invasion area of 3D NCI-H23 spheroids after treatment with 10 μM of NSL-YHJ-2-27 and NSL-YHJ-2-46 decreased by 87 ± 0.1% and 92 ± 0.3 %, respectively. Treatment with 0.5 μM NSL-YHJ-2-27 and NSL-YHJ-2-46 caused cell rounding and reduction of mean cell areas by 30 ± 5.0 and 42 ± 0.6 %, respectively. Mean cell area occupied by vinculin punctates decreased by 51 ± 2.6 % and 31 ± 2.8 % after exposure to 0.5 μM NSL-YHJ-2-27 and NSL-YHJ-2-46, respectively. NSL-YHJ-2-27 (5 μM) depleted full-length inactive caspase 3 and 7 levels by 72 ± 5.8 and 91 ± 7.0 %, respectively. These findings show the direct effects of the PCAIs on the KRAS signaling pathway thereby supporting their continuous development as potential targeted therapies for cancers with RAS mutations. Citation Format: Kweku Ofosu-Asante. Inhibition of cell growth and migration by polyisoprenylated cysteinyl amide inhibitors of a mutant KRAS Black American lung cancer cell line involves MAPK pathway activation and disruption of the cytoskeleton [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B003.
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Feleke, Seifegebriel T., Kidist Z. Shita, Abdulaziz A. Sherif, Fisihatsion T. Woldegebriel, Christoph Weigel, Elshafa H. Ahmed, Tamrat A. Zeleke, and Robert A. Baiocchi. "Abstract 7001: Profiling the CpG methylation patterns of Epstein-Barr virus DNA in lymphoma patients from Ethiopia." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7001. http://dx.doi.org/10.1158/1538-7445.am2024-7001.
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Abstract Introduction: Epstein-Barr virus (EBV) is a tumor virus associated with various malignancies, driven by genetic mutations and epigenetic alterations, including DNA methylation. Abnormal CpG methylation holds promise as a diagnostic and therapeutic biomarker for EBV-associated tumors. However, the understanding of EBV's epigenetic mechanisms remain limited. Determining the methylation profile of EBV is crucial for gaining insights into the pathogenesis of EBV-associated tumors, developing diagnostic biomarkers, and exploring potential therapeutic strategies. Therefore, our study aimed to assess the CpG methylation profile of EBV DNA in lymphoma patients from Ethiopia. Methods: This study enrolled 115 lymphoma patients from Tikur Anbessa Specialized Hospital in Addis Ababa, Ethiopia. Plasma and formalin-fixed paraffin-embedded blocks were collected from the participants, and isolation of DNA was performed from these samples. The methylation analysis was performed using the methylation-iPLEX assay. iPLEX capture and extension primers were designed to amplify and target EBV CpGs from bisulfite-converted DNA sequences. Ethical approval was also obtained from respected institutions. Results: Among the 115 participants, 65.2% (n = 75) were male patients. The largest proportion (n = 35, 30.4%) fell within the 41-60 age group. Non-Hodgkin lymphoma (NHL) was diagnosed in 96 patients, while 19 had Hodgkin lymphoma (HL). In the NHL group, the majority (n = 27, 28.1%) were classified as diffuse large cell lymphoma, followed by follicular lymphoma (n = 24, 25%). Out of the different EBV genome methylation sites, we have identified 24 EBV genes to assess the methylation status of the EBV genome. Average methylation levels of these genes were ranged from 45% to 50%. Notably, the HL group exhibited significant heterogeneity in methylation levels, while the CpG methylation status of EBV genes in NHL subtypes demonstrated a consistent pattern. A significant proportion of our samples exhibited methylation loss in the lytic gene BZLF1 and at the origin of replication associated with lytic replication. Conclusions: This study presents the first data from East Africa, shedding light on the EBV DNA methylation status in a diverse group of lymphoma patients. Further investigations in different locations are necessary to elucidate the impact of EBV DNA methylation on tumor progression. Citation Format: Seifegebriel T. Feleke, Kidist Z. Shita, Abdulaziz A. Sherif, Fisihatsion T. Woldegebriel, Christoph Weigel, Elshafa H. Ahmed, Tamrat A. Zeleke, Robert A. Baiocchi. Profiling the CpG methylation patterns of Epstein-Barr virus DNA in lymphoma patients from Ethiopia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7001.
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Chatterjee, Soumya, Saurabh Singh, Stephen Barry, and Chandan Guha. "Abstract 709: Enhancing prostate cancer treatment: Synergistic effects of mechano-thermal focused ultrasound and radiation therapy." Cancer Research 84, no. 6_Supplement (March 22, 2024): 709. http://dx.doi.org/10.1158/1538-7445.am2024-709.
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Abstract Current treatments for prostate cancer primarily rely on radiation and hormone deprivation therapy, yet they often lack effective immunotherapeutic effects. Furthermore, long-term hormone ablation has side effects, such as, impotency and osteoporosis. Addressing this gap, we introduce an innovative dual-frequency focused ultrasound (FUS) platform for non-ablative focal therapy, which induces protein unfolding, ER stress, and increases heat-shock protein expression along with translocation of endoplasmic reticular chaperone proteins (e.g., calreticulin) on the tumor cell surface, thereby sensitizing them for phagocytosis by dendritic cells for efficient antigen presentation and cross priming. We hypothesized that FUS-mediated acoustic immune priming can be combined with ablative therapies, such as, hormone ablation and/or radiation therapy (RT) for induction of tumor-specific adaptive immune response and better tumor control than monotherapy in murine prostate cancer models. Utilizing murine prostate cancer cell lines, MyC-CaP and RM1, we explored the cellular responses to androgen deprivation, observing distinct sensitivities. Twenty-four hours after FUS treatment tumor cells experienced mechano-thermal stress response with 15-fold increase in Hspa1a expression. Transmission Electron Microscopy studies showed formation of myelin figures, nuclear membrane deformation, and lipid droplet formation. In vivo, the combination of FUS (220w/cm2 intensity for 3 sec at focal point) and RT (8-10 Gy daily x two fractions) markedly delayed tumor growth and achieved complete cure in 14-17% of animals. Through multicolor flow cytometry, we detected significant alterations in the immune microenvironment, including increased CD8+ T cell infiltration and reduced tumor-associated macrophages in the tumor bed. However, we also observed a compensatory rise in pro-tumor immune cells such as PMN-MDSCs and Tregs with significant suppression of eosinophils (p<0.05). Interestingly, there was suppression of splenic PMN-MDSCs, Mo-MDSCs, and tumor draining lymph node macrophages, suggesting systemic immune modulation in peripheral lymphoid organs of FUS+RT-treated tumor-bearing animals. Our findings reveal that the combination therapy of FUS and RT improves tumor control in murine prostate cancer and significantly modulates the systemic and tumor immune microenvironment. This approach offers new avenues for immunotherapy, potentially transforming the treatment landscape for prostate cancer, typically resistant to conventional immunotherapeutic strategies. Citation Format: Soumya Chatterjee, Saurabh Singh, Stephen Barry, Chandan Guha. Enhancing prostate cancer treatment: Synergistic effects of mechano-thermal focused ultrasound and radiation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 709.
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Karakyriakou, Barbara, Ze Zhang, Irma Vlasac, Pauline Mochama, Lucas Salas, and Brock Christensen. "Abstract 7006: Identification of endothelial-cell-specific DNA methylation alterations in breast cancer with deconvolution of the tumor microenvironment." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7006. http://dx.doi.org/10.1158/1538-7445.am2024-7006.
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Abstract The tumor microenvironment (TME) plays a pivotal role in cancer progression, with tumor endothelial cells (TECs) emerging as key orchestrators of angiogenesis and vascular remodeling. Tumor-associated vasculature can have increased permeability and irregular blood flow, impacting drug delivery and tumor immune response. Understanding the molecular alterations within TECs may help identify targeted therapies and improve treatment outcomes with existing therapies. We combined TME cell-type deconvolution with modeling to identify cell-specific methylation alterations of TECs in breast cancer. Genome-scale DNA methylation array data accessed in GEO and GTEx from preinvasive, mixed, and invasive breast cancer tissue (n=609) & normal breast tissue (n=230). We applied HiTIMED, a reference-based cell-type deconvolution algorithm, to estimate endothelial and other cell-type proportions in the TME. Next, we applied CellDMC, a statistical algorithm that identifies cell-specific driven differential methylation, to our cell fraction results, unraveling differentially methylated positions occurring in the endothelial compartment of the angiogenic component of our breast tissue DNA methylation profiles. We identified 29 TEC driven differentially methylated positions (FDR ≤ 8e-03), including loci within genes in angiogenic pathways regulated by VEGF, endothelial inflammation and activation genes, and tumor-associated vasculature factors in the TME. Our findings suggest that variation in DNA methylation between TECs and normal endothelial cells is crucial to understanding the TME and providing insights into unknown cancer cell behaviors that contribute to tumor growth and metastasis, thus leading to the design of novel efficient therapies that target the malignant vascular component. Our study demonstrates the power of combining cell-type deconvolution and a modeling framework that identifies cell-specific somatic alterations to unravel the intricate characteristics of TECs in breast cancer. Furthermore, this study highlights the potential of DNA methylation profiling as a robust tool for characterizing TEC heterogeneity and elucidating the molecular basis of angiogenesis beyond breast tissue in the context of diverse cancer types. Our integrative approach holds promise for advancing precision oncology, paving the way for effective and targeted therapies aimed at modulating the tumor vasculature to impede cancer progression in breast cancer and other cancer types. Citation Format: Barbara Karakyriakou, Ze Zhang, Irma Vlasac, Pauline Mochama, Lucas Salas, Brock Christensen. Identification of endothelial-cell-specific DNA methylation alterations in breast cancer with deconvolution of the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7006.
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Aceituno, Veronica Castro, Tiantian Cui, Haihua Feng, Linlin Yang, Sindhu Nair, and Terence M. Williams. "Abstract 7080: Regulation of caveolin-1 by RAS/RAF oncogenic signaling in cancer cells." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7080. http://dx.doi.org/10.1158/1538-7445.am2024-7080.
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Abstract Background and Purpose: Caveolin-1 (Cav-1), a scaffolding protein implicated in cellular signaling and membrane dynamics, undergoes intricate regulation at multiple levels. Recent evidence has suggested a potential association between oncogenic mutations and alterations in Cav-1 expression. Our study aimed to comprehensively explore how RAS/RAF mutations influence Cav-1 expression in cancer cells, as well as the underlying molecular mechanisms, using tetracycline (tet)-inducible cell lines and cancer cell lines harboring endogenous BRAF or KRAS mutations. Experimental Design: We assessed the regulation of Cav-1 expression using tet-inducible cell lines with BRAFV600E, KRASG12D, or KRASG12C mutations. We measured the half-life of Cav-1 at protein levels by using cycloheximide. We monitored Cav-1 localization and degradation dynamics by SNAP-based pulse-chase assay. Additionally, we performed protein and gene expression analyses by immunoblotting and qRT-PCR, luciferase reporter assay, and immunofluorescence to dissect the impact of BRAF and KRAS mutations on Cav-1 regulation at various stages of its life cycle. Results: We found a significant downregulation of Cav-1 at both mRNA and protein levels upon induction of BRAF or KRAS mutations. The use of KRASG12C, BRAFV600E, ERK, and/or MEK inhibitors in tet-inducible cell lines rescued the effects observed upon induction. The rescue effects have also been observed in H23, MiaPaCa-2 and 8505-C cancer cell lines bearing either BRAF or KRAS mutations. Notably, BRAFV600E exhibited a more pronounced reduction in Cav-1 expression than other mutations. We observed shortened half-life of Cav-1 at protein levels after induction of RAS/RAF mutations by using cycloheximide, and SNAP-based pulse-chase. These mutations accelerated lysosomal-mediated degradation of Cav-1 as determined by immunoblotting and immunofluorescence, which was reversed by lysosomal inhibitors. Conclusions: Our study establishes a novel regulatory paradigm wherein RAS/RAF mutations exert a multi-faceted influence on Cav-1 dynamics in cancer cells. The transcriptional and translational downregulation, coupled with accelerated lysosomal degradation, collectively contributes to the decreased half-life of Cav-1 following the induction of BRAF or KRAS mutations. These findings provide insights into the intricate molecular mechanisms underpinning the dysregulation of Cav-1 in the context of RAS/RAF mutations, offering potential avenues for therapeutic interventions. Citation Format: Veronica Castro Aceituno, Tiantian Cui, Haihua Feng, Linlin Yang, Sindhu Nair, Terence M. Williams. Regulation of caveolin-1 by RAS/RAF oncogenic signaling in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7080.
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Flory, Mark, Matthew Chang, Jessie May Cartier, Jane Lange, Travis Moore, James McGann, Ryan Kopp, et al. "Abstract 7090: A scaled proteomic discovery study for prostate cancer diagnostic signatures using Proteograph workflow with trapped ion mobility mass spectrometry." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7090. http://dx.doi.org/10.1158/1538-7445.am2024-7090.
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Abstract Background and Aims: The low cancer specificity of serum Prostate-Specific Antigen (PSA), the principal biomarker for prostate cancer detection, leads to a high frequency of unwarranted prostate biopsies. To alleviate this deficit, we executed a proteomic discovery study seeking PSA reflex signatures using the Proteograph™ Product Suite, a multi-nanoparticle-based deep plasma/serum proteomics workflow (Seer, Inc.), with timsTOF Pro mass spectrometry (Bruker) to interrogate over 900 serum specimens from patients that underwent prostate biopsy due to elevated PSA and/or abnormal digital rectal exam. Methods: Our study followed rigorous design principles including uniform collection, randomization and blinding of specimens, all of which were processed with the Proteograph Product Suite. Liquid chromatography-mass spectrometry (LC-MS) analyses leveraged the Bruker timsTOF Pro MS platform utilizing 30-minute reversed-phase chromatography and a label-free dia-PASEF (data independent acquisition - parallel accumulation serial fragmentation) data acquisition method. Peptides deriving from a chosen subset of specimens designed to maximize peptide diversity were pooled, fractionated and analyzed using DDA (data-dependent acquisition)-PASEF to build a spectral reference library. Results: The DIA-NN algorithm was employed through the cloud-based Proteograph Analysis Suite (PAS) to search LC-MS data. Leveraging our study-specific spectral library proteomic depth achieved was approximately 3600 protein groups identified (median) per patient serum specimen and more than 4400 in at least 25% of samples across the study. Customized machine learning workflows and the SeerML pipeline were used to identify and assess diagnostic power of new proteomic signatures. Conclusions: Our data demonstrate the remarkable proteomic depth achievable in a scaled patient serum specimen discovery study using a combination of Proteograph and timsTOF platforms. This significant effort revealed serum proteomic signatures with increased diagnostic performance over that provided by PSA blood measurement and traditional patient-associated metadata alone, providing a foundation for future clinical tests aimed to reduce the current high frequency of unnecessary prostate biopsy. Citation Format: Mark Flory, Matthew Chang, Jessie May Cartier, Jane Lange, Travis Moore, James McGann, Ryan Kopp, Michael Liss, Robin Leach, Brenna Albracht, James Dai, Michael Krawitzky, Eltaher Elgierari, Jessica Chu, Paul Pease, Max Mahoney, Shadi Ferdosi, Ryan Benz, Khatereh Motamedchaboki, Asim Siddiqui, Mahdi Zamanighomi, Amir Alavi, Harendra Guturu, Daniel Hornburg, Serafim Batzoglou. A scaled proteomic discovery study for prostate cancer diagnostic signatures using Proteograph workflow with trapped ion mobility mass spectrometry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7090.
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Leoni, Lorenzo M., Brian Crain, Brandi Bailey, Mimi Phillips, Heather Bendall, Qi Chao, Jack Reifert, Christina Niemeyer, and Gary Elliott. "Mechanism of Action and Safety of Second Generation Analogs of SDX-101 (R-Etodolac)." Blood 104, no. 11 (November 16, 2004): 3411. http://dx.doi.org/10.1182/blood.v104.11.3411.3411.
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Abstract SDX-101 (R-etodolac), which is currently being evaluated in clinical trials for treatment of chronic lymphocytic leukemia, down regulates the activity of the β-catenin pathway and inhibits the growth of non-Hodgkin’s Lymphoma Daudi tumor xenografts in vivo when dosed orally (AACR PROC 2004 Abs# 2061 and #4574). Initial co-immunoprecipitation experiments conducted on cell nuclear fractions identified a heteromeric nuclear protein complex containing β-catenin and PPAR-γ. Furthermore, we have demonstrated that SDX-101 treatment reduces nuclear β-catenin in the immunoprecipitated complex, indicating that this complex may represent a target of SDX-101 (AACR PROC 2004 Abs# 3672). We recently reported evaluation of novel structural analogs of SDX-101 and have shown that these analogs, whose structures were not disclosed, are 5–10 fold more potent in in vitro cytotoxicity assays than SDX-101 and that they are orally efficacious in vivo (NCI/EORTC 2004 Abs #383). Our current studies further characterize the mechanism of action and safety of these analogs and identify the structures of selected analogs. Novel functional assays were developed to test and compare SDX-101 and the analogs at 4 hours post-treatment, a time before appreciable loss of viability was detected. Best results were obtained using a functional assay co-transfecting a β-catenin-dependent reporter construct (TOPFLASH) and β-catenin and RXR expression vectors. The average IC50 of analogs in this β-catenin reporter system ranged from 50 to 160 μM. These values were approximately five- to ten- fold lower than the IC50 for SDX-101 (~700 μM). Similar results were obtained assessing the inhibition of PPAR-γ-mediated transcription, using a PPAR-dependent reporter and co-transfection with PPAR-γ and RXR expression vectors. The average IC50s of the analogs ranged from 50–150 μM in this functional assay, demonstrating an approximately 10-fold increase in potency of the analogs when compared to SDX-101 (~1000 μM). No effect was observed at the 4 hour time point using a constitutive SV40-based control reporter vector. These results suggest that the primary target for these compounds may be a nuclear complex containing β-catenin, PPAR-γ and RXR, supporting a hypothesis developed upon evaluation of earlier results generated with SDX-101. To evaluate the safety of two SDX-101 analogs in vivo, normal mice were administered each analog at 240, 120 and 60 mg/kg/d (M-F) for four weeks. Mortality, morbidity, clinical signs, hematology/chemistry were monitored. There were no mortalities, overt toxicities or abnormal observations at necropsy with either of the analogs at any of the tested dose levels. There was a transient body weight loss (<5%) and a mild dose-independent increase in platelets and a reversible decrease in total bilirubin. Results of the histopathological examination of critical organs are pending. These results suggest, when given at doses previously shown to be efficacious in a DAUDI murine lymphoma model, these analogs were well tolerated. In conclusion, these data demonstrate that the second generation analogs of SDX-101 display more potent in vitro and in vivo activity while retaining a mechanism of action similar to that of SDX-101.
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Marchi, Giovanni, Mai T. N. Nguyen, Anna Rajavuori, Taru Muranen, Kaisa Huhtinen, Sinikka Oksa, Sakari Hietanen, Johanna Hynninen, Jaana Oikkonen, and Sampsa Hautaniemi. "Abstract B102: Mutational and copy number-based ctDNA profiles mirror high-grade serous cancer tumors and enable detection of genetic changes appearing at recurrence." Cancer Research 84, no. 5_Supplement_2 (March 4, 2024): B102. http://dx.doi.org/10.1158/1538-7445.ovarian23-b102.
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Abstract Circulating tumor DNA (ctDNA) is the cancer-derived fraction of extracellular DNA fragments present in the bloodstream as cell-free DNA (cfDNA). Consequently, ctDNA harbors the distinct genomic information specific to the cancer from which it derives. Therefore, ctDNA from liquid biopsies provides a non-invasive, universally available alternative to traditional tumor biopsies. ctDNA amount may provide insight into tumor burden, as its concentration is typically highest during diagnosis and relapse. The non-invasive nature of this method facilitates frequent monitoring, enabling longitudinal tracking of the disease's trajectory and response to treatments. By focusing on the key genomic changes, either short mutations or copy number aberrations (CNA), liquid biopsy allows the investigation of cancer progression and evolution over time, providing invaluable insight into the behavior and adaptability of the cancer. We collected 152 longitudinal plasma samples and 92 fresh tissue samples from 29 patients enrolled in the DECIDER cohort (NCT04846933), after a diagnosis of high-grade serous carcinoma (HGSC), the most common and deadliest histological subtype of ovarian cancer. With ultra-deep targeted sequencing of a gene panel of more than 700 cancer-related genes we were able to comprehensively evaluate the cancer-related genomic changes. The concordance rate between mutations in plasma compared to tumor tissue was 83 % at diagnosis and 90 % at relapse, confirming the reliability of exploiting ctDNA in monitoring genomic alterations. Furthermore, by comparing plasma- and tissue-derived mutations, we demonstrated that comparable levels of ctDNA are released from adnexa, intra-abdominal lesions, and ascites, proposing that a liquid biopsy represents mutations from various locations. Analysis of CNA showed that our approach successfully detected concordant profiles in most plasma samples, even with tumor content as low as 3%. Additionally, highly amplified regions were identified in samples with approximately 1% tumor content. Longitudinal analysis of both mutations and CNA revealed genomic changes in plasma samples at relapse. Twenty-four new exonic mutations were identified in eight patients at relapse; two of these alterations were related to HRD status, supporting PARP-inhibitors as a valid treatment option. Furthermore, mutations in FGFR3, JAK2, FLT3 and CDKN2A could be investigated as target indications for extended use of currently available therapies. Eleven patients had high tumor content in their plasma samples at the time of relapse. We detected altered CNA profiles in seven of these eleven patients, so that five patients harbored only a few novel focal amplifications or losses, while two patients showed significant changes in their copy-number profile during the therapy. In conclusion, our study identified recurrence-specific genomic aberrations, proposing that ctDNA more accurately represents the metastatic tumor and provides possibilities for personalized therapy options. Citation Format: Giovanni Marchi, Mai T.N. Nguyen, Anna Rajavuori, Taru Muranen, Kaisa Huhtinen, Sinikka Oksa, Sakari Hietanen, Johanna Hynninen, Jaana Oikkonen, Sampsa Hautaniemi. Mutational and copy number-based ctDNA profiles mirror high-grade serous cancer tumors and enable detection of genetic changes appearing at recurrence [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B102.
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Su, L. Joseph, Ping-Ching Hsu, Aniruddha Rathod, Yulun Liu, Jacopo Ferruzzi, Syed Kazmi, and Emina Huang. "Abstract 7005: Distinct DNA methylation patterns between early-onset and average-onset colorectal cancer patients." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7005. http://dx.doi.org/10.1158/1538-7445.am2024-7005.
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Abstract Objective: Early onset colorectal cancer (EO CRC) is rising at an alarming rate. While average onset colorectal cancer (AO CRC) affects patients mostly above 65 years of age, EO CRC affects patients under 50 years of age, disproportionately affecting males from low-income communities and racial/ethnic minorities. Chronic inflammation has been identified as a strong contributor to pathogenesis. We hypothesize that methylation of DNA may serve as a potential mechanism associated with chronic inflammation that contributes to the etiology differentially between EO and AO CRC. Methods: Formalin-fixed paraffin-embedded (FFPE) tissue specimens from four AO and EO CRC patients each were retrieved from the Tissue Repository. Paraffin curls containing tumor and adjacent normal tissues were generated from appropriate EO and AO CRC patient tissues. The Qiagen GeneRead DNA FFPE genomic DNA kit was then used to extract the DNA from the paraffin curls. Illumina Methylation EPIC v2.0 kit was used to evaluate DNA methylation (DNAm) patterns after the restoration process from deamination in the fixed/embedded sample using the Uracil-N-Glycosylase enzyme. Unreliable and non-specific probes were removed before statistical analysis for differentially methylated CpG sites. Age acceleration for each tissue was calculated by comparing the estimated DNAm age with chronological age using the Horvath approach. Results: A clear clustering of DNAm patterns by age of onset were observed for both normal and tumor tissues. However, there was no difference when comparing tumor and normal tissues after multiple corrections. Four-way ANCOVA adjusting for race, gender, BMI, and tissue type suggested that age onset was the most significant factor. We also found that age acceleration in EO CRC tissue is greater than in AO CRC. After applying Bonferroni correction, significant differentially methylated regions (DMRs) were found in the promoter and the gene body of SNTB1, NFATC3, SLC25A24, RABGAP1L, WDSUB1, WWOX, SELB, SLC28A3, and PPP6R2 in EO CRC patients when compared to AO CRC. SNTB1 regulates colorectal cancer progression and stemness, while NFATC3 has been associated with inflammation and cancer. Conclusions: The preliminary results from this study showed a significant difference in the DNAm profile of FFPE samples between AO and EO CRC. The finding suggests that epigenetics may play a role in the etiology of CRC, potentially involved in the chronic inflammation pathway. The analysis of a larger patient number is underway to strengthen these findings. Citation Format: L. Joseph Su, Ping-Ching Hsu, Aniruddha Rathod, Yulun Liu, Jacopo Ferruzzi, Syed Kazmi, Emina Huang. Distinct DNA methylation patterns between early-onset and average-onset colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7005.
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O'Hersey, Chrissy, Yang Zhao, Thomas R. Pisanic, Tian-Li Wang, Ie-Ming Shih, and Tza-Huei Jeff Wang. "Abstract 7003: Microfluidic platform for DNA methylation profiling towards early detection of ovarian cancer." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7003. http://dx.doi.org/10.1158/1538-7445.am2024-7003.
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Abstract We present a microfluidic platform for molecule-by-molecule detection of heterogeneous epigenetic patterns of rare tumor-derived DNA by highly parallelized digital melt. The platform digitizes DNA molecules in a 4-module, 40,000 1-nL array microfluidic device and observes sequence-dependent fluorescence changes during temperature ramping. The platform is applied to quantify DNA methylation heterogeneity of a biomarker panel within Pap specimens in a small cohort of healthy and ovarian cancer patients, and demonstrates an accuracy of 0.9. DNA hypermethylation of tumor-suppressor genes is an epigenetic phenomena that occurs early in tumorigenesis. Variable methylation patterns are observed in ovarian cancer precursor tissue, and trace amounts of ovarian-tumor-derived DNA can be found in Pap specimens, albeit at low frequencies (<0.01%). This suggests that methylation profiles of DNA extracted from routinely-obtained Pap specimens could contain early cancer biomarkers. However, due to the scarcity of these molecules, current techniques, such as sequencing and digital PCR (dPCR), have technical limitations precluding their ability to profile methylation patterns reliably. Sequencing, although comprehensive, has limited sensitivity, undermining its utility for routine detection of fractions below 0.1%. dPCR achieves high sensitivity, but is limited to known sequences, thus cannot provide comprehensive analysis of molecular heterogeneity. To overcome these limitations, we developed a technique called digital high resolution melt (dHRM), a thermodynamics-based approach to detecting molecular variability by observing the sequence-specific release of a DNA-intercalating dye under a thermal ramp. dHRM can discriminate methylation patterns on CpG-by-CpG basis and detect methylated epialleles at frequencies as low as 0.00005%. Here, DNA from Pap specimens was loaded on a microfluidic chip that digitizes rare target molecules into individual reaction chambers. A thermal-optical platform was developed to perform parallelized dPCR and dHRM. Methylation patterns of a biomarker panel were analyzed to produce a probability score that the Pap specimen contained tumor-derived DNA. 12 healthy and 12 ovarian cancer Pap specimens were assessed for methylation heterogeneity of 9 genes. Optimal methylation density thresholds were determined, and data above each threshold was combined into a single score for each possible combination of biomarkers. In this small cohort, methylation heterogeneity analysis of just 2 loci produced an area under the receiver-operator characteristics curve (AUC) of 0.9. This highly sensitive methylation profiling technology demonstrates promising utility towards early cancer detection. Future work aims to expand the testing cohort for ovarian cancer detection and permit further studies on the impact of methylation heterogeneity on early cancer development. Citation Format: Chrissy O'Hersey, Yang Zhao, Thomas R. Pisanic, Tian-Li Wang, Ie-Ming Shih, Tza-Huei Jeff Wang. Microfluidic platform for DNA methylation profiling towards early detection of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7003.
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Zhao, Yu, and Lindsey Cambria. "Abstract 7009: Quantification of DNA methylation using methylation-sensitive restriction enzymes and digital PCR." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7009. http://dx.doi.org/10.1158/1538-7445.am2024-7009.
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Abstract DNA methylation is a common epigenetic modification, characterized by the presence of the signature 5-methylcytosine without altering the sequence of DNA. The study of DNA methylation in mammals has gained significant attention due to its broad impact on numerous biological processes and its critical role in the onset and progression of many diseases, such as cancer and aging. Consequently, there is a pressing need for a rapid and precise method to assess methylation status. Currently, most approaches for quantifying DNA methylation rely on sodium bisulfite treatment. However, such approaches do not align with the uracil DNA glycosylase PCR system. In this study, we demonstrate the application of methylation-sensitive restriction enzymes (MSRE) and digital PCR to determine the methylation status of the Ras association domain family 1 isoform A (RASSF1A) in cancer cell lines. Digital PCR enables the precise detection and absolute quantification without the reliance on reference standards. We developed a multiplex digital PCR assay that includes the target gene RASSF1A, along with two reference genes for the purpose of monitoring digestion completion and correcting DNA input. Each sample of interest was measured both before and after a MSRE digestion. To ensure the quantification accuracy, we employed the commercially available CpGenome human methylated DNA standard with a known concentration from MilliporeSigma, treating it with and without a MSRE, and subsequently performing digital PCR experiments using Roche Digital LightCycler® IVD system with a Universal nanowell plate featuring 28,000 partitions. The expected concentrations lay within the 95% confidence interval, affirming the accurate quantification achieved through digital PCR. Next, we measured the fraction of methylated alleles in various lung cancer and breast cancer cell lines, as well as in healthy human gDNA. The methylation of RASSF1A promoter in healthy human gDNA is ~0.7%, while a broad range of methylation levels was observed in cancer cell lines, ranging from ~0.7% to ~100.2%. Notably, the influence of GC bias was identified in this study. To overcome this critical challenge, we optimized the usage of several high GC enhancers. The results demonstrated that the concentration of 5-7.5% DMSO, 7.5% glycerol, and commercially available OneTaq or Q5 GC enhancers from New England Biolabs were effectively incorporated into the Roche digital PCR system, thereby enhancing the accuracy of quantification from 30% to 100%. Together, we demonstrated a remarkable approach for DNA methylation analysis using Roche digital PCR system in combination with MSREs and suitable high GC enhancers. This study suggests a promising rapid, accurate and cost-effective tool to advance research in the field. *Data on file at Roche Diagnostics, Wilmington, MA, USA Citation Format: Yu Zhao, Lindsey Cambria. Quantification of DNA methylation using methylation-sensitive restriction enzymes and digital PCR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7009.
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Day, Charles, Florina Grigore, Alyssa Langfald, David J. Daniels, James Robinson, and Edward Hinchcliffe. "Abstract 705: Inhibition of H3.3 S31 phosphorylation by the pediatric glioma driver mutation, H3.3 K27M, results in chromosomal instability, loss of p53 regulation, and tumorigenesis." Cancer Research 82, no. 12_Supplement (June 15, 2022): 705. http://dx.doi.org/10.1158/1538-7445.am2022-705.
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Abstract The heterozygous H3.3 K27M mutation is found in the majority of pediatric High-Grade Glioma’s (pHGG). H3.3 K27M is thought to promote tumor formation through altered epigenetic gene regulation. However, it is unclear if epigenetic reprogramming alone is sufficient for glioma formation. H3.3 contains a unique Serine at position 31 which is phosphorylated in early mitosis (where it functions in chromosome segregation) and again in late M/early G1 when a mitotic error has occurred (triggering p53 expression). We found that pHGG cell lines harboring H3.3 K27M have significantly reduced S31 phosphorylation as compared to both pHGG and non-transformed H3.3 WT cells. When compared to WT H3.3 in an in vitro kinase assay, H3.3 K27M exhibits an ~60% reduction in S31 phosphorylation by Chk1, the mitotic S31 kinase. In normal diploid cells, expression of K27M or non-phosphorylatable S31A mutant significantly increased chromosome missegregation. Yet expressing a phosphomimetic double mutant (K27M/S31E) did not significantly alter the rate of chromosome mis-segregation compared to WT. Furthermore, patient-derived pHGG lines harboring K27M have significantly higher rates of chromosome mis-segregation compared to an H3.3 WT pHGG line or H3.3 WT non-transformed human cells. We used CRISPR gene editing to remove the H3.3 K27M allele or replace it with WT H3.3. In both cases, loss of K27M elevated pS31 levels and reduced chromosome mis-segregations. Yet, when K27M was replaced with S31A, the mis-segregation rate remained similar to the parental K27M cells. In normal cells, chromosome missegregation stimulates p53-dependent cell cycle arrest in G1 to prevent the proliferation of aneuploid daughters. However, cells expressing H3.3 K27M or S31A failed to arrest following missegregation - despite having WT p53. To determine if the induction of chromosomal instability would alter tumor formation, we expressed H3.3 WT, K27M or S31A in combination with PDGFβ in a glioma mouse model. Expression of WT H3.3 failed to generate high-grade tumors. But 66% of mice expressing K27M and 93% of those expressing H3.3 S31A developed diffuse high-grade brain tumors by 100 days. Our results suggest that loss of phospho-S31 alone is oncogenic because H3.3 S31A-expressing cells are WT for K27me3. Our results demonstrate that H3.3 K27M inhibits Ser31 phosphorylation both in vitro and in vivo, leading to both chromosome missegregation and loss of subsequent G1 arrest - thus creating diffuse midline gliomas with both dynamic, complex karyotypes and epigenetic reprogramming. Citation Format: Charles Day, Florina Grigore, Alyssa Langfald, David J. Daniels, James Robinson, Edward Hinchcliffe. Inhibition of H3.3 S31 phosphorylation by the pediatric glioma driver mutation, H3.3 K27M, results in chromosomal instability, loss of p53 regulation, and tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 705.
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Xie, Fengyang, Jia Wei, Lan Deng, Chao Wang, Ben Zhao, Robert J. Lee, and Yuxin Angela Men. "Abstract 701: Evaluation of an AKT-1 antisense oligonucleotide in combination with Lenvatinib and Everolimus in Renca-luciferase syngeneic orthotopic murine tumor model." Cancer Research 83, no. 7_Supplement (April 4, 2023): 701. http://dx.doi.org/10.1158/1538-7445.am2023-701.
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Abstract Background: The combination of 18mg Lenvatinib and 5mg Everolimus per day is used in the clinic for advanced renal cancer patients. However, due to the severe side effects of Lenvatinib, the dose is often reduced to 12mg. Archexin, a fully phosphorothioated 20-mer antisense oligonucleotide, inhibits AKT-1 mRNA translation and inhibits tumor growth. Combination of Archexin with reduced-dosed Lenvatinib and Everolimus may reduce adverse reactions while enhancing therapeutic efficacy. Methods: First, Lenvatinib and Everolimus monotherapies were evaluated for antitumor efficacy in an orthotopic Renca-luciferase syngeneic model. 45 mice were randomly divided into 9 groups (5 in each group), vehicle control, Lenvatinib (5, 10, 20, and 30 mg/kg) and Everolimus (0.2, 0.5, 1, 2, and 4 mg/kg) via daily oral administration for 20 days. Next, we investigated the anti-tumor effect of the two- and three-drug combination. 35 mice were randomly divided into 7 groups (5 in each group), including vehicle control, Lenvatinib/Everolimus combinations (5+0.2, 10+0.2 and 10+0.5 mg/kg) and Archexin/Lenvatinib/Everolimus combinations (60+5+0.2, 60+10+0.2 and 60+10+0.5 mg/kg) via tail vein injection (vehicle/Archexin, Q3D*6 times) or oral administration (Lenvatinib and Everolimus, QD*18 days). Body weight was monitored daily. Tumor burden was measured by bioluminescence through whole-body fluorescence images, performed twice a week. Results: The results showed that Everolimus inhibited tumor growth in a dose-dependent manner. Partial response was observed in mice treated with varying doses of Lenvatinib(TGIs: 57.94%,76.65% and 60.22%), and no significant dose-effect correlation was found. The dose of Lenvatinib and Everolimus that partially inhibited the orthotopic tumor growth had also been identified and selected for subsequent study investigating drug combinations. The drugs combination study showed that three drug combinations (Archexin/Lenvatinib/Everolimus) had superior efficacy compared to the Lenvatinib and Everolimus combination. The fluorescence signal intensities (Lg10) of the three-drug combination were significantly lower than that of the two-drug combination group with P value <0.05. No severe adverse effects were observed in the three drug combinations group. Conclusion: Three drugs combination of Archexin, Lenvatinib and Everolimus, demonstrated superior anti-tumor efficacy compared to the two-drug combination currently used in the clinic. This finding suggests the three-drug combination warrant investigation in the clinical trial in the patients with advanced renal cancer. Citation Format: Fengyang Xie, Jia Wei, Lan Deng, Chao Wang, Ben Zhao, Robert J. Lee, Yuxin Angela Men. Evaluation of an AKT-1 antisense oligonucleotide in combination with Lenvatinib and Everolimus in Renca-luciferase syngeneic orthotopic murine tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 701.
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Daugherty, Bruce L. "Abstract 704: MDSC-targeted TFF2-MSA suppresses tumor growth and increases survival in anti-PD-1 treated MC38 and CT26.wt murine colorectal cancer models." Cancer Research 83, no. 7_Supplement (April 4, 2023): 704. http://dx.doi.org/10.1158/1538-7445.am2023-704.
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Abstract Aims: Myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment are a potential therapeutic target in immune checkpoint cancer therapy, but MDSC-targeted therapies have yet been shown to improve survival. Trefoil factor family 2 (TFF2), a secreted anti-inflammatory peptide, can suppress MDSC expansion and activate tumor immunity in part through agonism of the CXCR4 receptor. The aim of this study is to investigate whether a novel TFF2 - albumin fusion peptide (TFF2-MSA) can improve survival in anti-PD-1 treated syngeneic colorectal cancer (CRC) mouse models. Methods: Two syngeneic colon carcinoma mouse models were developed using cell lines grafted subcutaneously into mice. MC38 CRC cells were engrafted into C57BL/6 mice while CT26.wt CRC cells were implanted into BALB/C mice We generated a recombinant fusion protein, designated TFF2-MSA, which contains murine TFF2 fused to murine serum albumin (MSA), for the purpose of increasing half-life and reducing dose frequency. Mice subsequently received either TFF2-MSA or anti-PD-1 antibody (clone 29F.1A12) or both, and tumor volume, and survival were measured. At the endpoint, flow cytometry was performed to examine treatment-induced effects on immune profiles. Results: In the MC38 model, administration of TFF2-MSA suppressed tumor growth (TGI 38%), the combination of TFF2-MSA and anti-PD-1 had an additive effect and suppressed tumor growth dramatically (TGI 74%). The combination also exhibited a survival rate of 90% after 50 days, while vehicle and single TFF2-MSA therapy were 30% and 65%, respectively. The percentage of exhausted CD8+ T cells was markedly reduced in the draining lymph node by the combination treatment, as measured by flow cytometry using antibodies against LAG3, TIM3 and PD-1. In the CT26.wt model, administration of TFF2-MSA alone exhibited little effect, but the combination of anti-PD-1 and TFF2-MSA showed a profound effect. In the CT26.wt model, administration of TFF2-MSA suppressed tumor growth (TGI 17%), anti-PD-1 alone (TGI 43%) and the combination of TFF2-MSA and anti-PD-1 (TGI 54%). Conclusion: Targeting MDSCs using TFF2-MSA fusion protein synergizes well with PD-1 blockade therapy in advanced and metastatic syngeneic mouse models of colorectal cancer. In a separate abstract, additive effects between TFF2-MSA and anti-PD-1 antibody were also demonstrated in a separate ACKP (Atp4b-Cre; Cdh1-/-; LSL-KrasG12D; Trp53-/-) gastric cancer model, suggesting combination therapy may also be applicable to gastric cancer. Citation Format: Bruce L. Daugherty. MDSC-targeted TFF2-MSA suppresses tumor growth and increases survival in anti-PD-1 treated MC38 and CT26.wt murine colorectal cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 704.
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Jungles, Kassidy M., Zhuwen Wang, Caroline Bishop, Cydnee Wilson, Meilan Liu, Jadyn James, Michael Green, James M. Rae, Corey W. Speers, and Lori J. Pierce. "Abstract 708: Targeting aurora kinase B (AURKB) as a radiosensitizing strategy in syngeneic models of triple negative breast cancer (TNBC)." Cancer Research 84, no. 6_Supplement (March 22, 2024): 708. http://dx.doi.org/10.1158/1538-7445.am2024-708.
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Abstract Purpose: Triple negative breast cancer (TNBC) is an aggressive breast cancer (BC) subtype with few treatment options. Radiation therapy (RT) is a mainstay therapy for the treatment of BC, but local recurrence following RT therapy is common. Consequently, decreasing local recurrence in patients with TNBC is a critical clinical need. Prior work demonstrated that AURKB is overexpressed in TNBC, and over-expression correlates with poor prognosis. Here, we examined the effects of AURKB inhibition as a novel radiosensitizing strategy in syngeneic TNBC models. Methods: Cell viability assays were used to determine the half-maximal inhibitory concentrations (IC50) of the AURKB inhibitors Barasertib-HQPA and SP-96 72 hours post treatment. Clonogenic survival assays were used to assess the radiosensitivity of TNBC murine cell lines to AURKB inhibition. In these assays, AURKB inhibitors were delivered at sub-IC50 concentrations 24 hours prior to RT, and radiation enhancement ratios (rERs) were calculated. Immunofluorescent microscopy using DAPI stain assessed micronuclei. Propidium iodide staining to assess aneuploidy was completed via flow cytometry. To assess the radiosensitizing effects of AURKB inhibition in vivo, the 4T1 syngeneic TNBC cell line was injected bilaterally into Balb/c mice and treated with Barasertib and RT. Tumor volume was recorded twice weekly throughout the study. Results: Aurora kinase B inhibitors (500-750 nM Barasertib-HQPA, 100-200 nM SP-96) delivered 24 hours prior to radiation therapy induced radiosensitization in the murine TNBC cells 4T1 (rER: 1.24-1.56) and Py8119 (rER: 1.51-1.72). Mechanistically, combined AURKB inhibition and RT significantly increased micronuclei formation in 4T1 cells 24 hours after RT compared to vehicle control (p<0.0001). Furthermore, combined AURKB inhibition and RT induced aneuploidy in murine TNBC cell lines 24 hours after radiation therapy compared to vehicle control. Combined AURKB inhibition (Barasertib 25 mg/kg, IP) and RT (8 Gy RT in 1 fraction) significantly decreased tumor volume compared to mice that had received vehicle control (777 ± 61 mm3 vs 1623 ± 126 mm3; p <0.0001). Conclusion: AURKB inhibition induces radiosensitization in syngeneic models of TNBC and leads to increased micronuclei and aneuploidy, suggesting a mechanism of sensitization. These results suggest that AURKB is a potential radiosensitizing strategy for the treatment of triple negative disease. Ongoing studies are further refining the underlying mechanisms of AURKB inhibition and RT on the antitumoral immune response. Citation Format: Kassidy M. Jungles, Zhuwen Wang, Caroline Bishop, Cydnee Wilson, Meilan Liu, Jadyn James, Michael Green, James M. Rae, Corey W. Speers, Lori J. Pierce. Targeting aurora kinase B (AURKB) as a radiosensitizing strategy in syngeneic models of triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 708.