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Ice, Gillian H. "Proceedings of the Human Biology Association 32nd Annual Meeting, March 29, 2007, Sheraton Society Hill, Philadelphia, PA." American Journal of Human Biology 20, no. 2 (2008): 242–48. http://dx.doi.org/10.1002/ajhb.20761.
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Ruiz, Victor M., Lindsay Hill, Manasa Gadde, Christopher Bulow, Maurizio Morri, and Nicholas Goldner. "Abstract B030: Using the ResCu system for preclinical testing of KRAS G12C inhibitors." Molecular Cancer Research 21, no. 5_Supplement (May 1, 2023): B030. http://dx.doi.org/10.1158/1557-3125.ras23-b030.
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Abstract Introduction: Recent colorectal cancer trials with KRAS G12C inhibitors have faced resistance challenges, and a preclinical model is needed to test resistance inhibition strategies. Experimental Methods: We have developed a novel culturing system, ResCu, that allows for long-term culture of cells without the need for passaging, enabling us to determine treatment resistance that can develop over time in a physiologically relevant system that conserves the resistance pathways found in patients. Using this system, we evolved resistance to a KRAS G12C inhibitor, sotorasib, after only two weeks of culture. The evolved cells were characterized for cross-resistance and cross-sensitivity by exposing these cells to a panel of drugs for seven days. Cell viability was assessed by luminescence. Based on the drug screen results, the sotorasib evolved cells were further evolved to additional drug classes to identify novel therapeutic combinations. Whole population and single-cell transcriptomic analysis were used to identify resistance mechanisms and synthetic lethality. Results: Using the ResCu system, we evolved resistance to sotorasib, a KRAS G12C inhibitor, and other drugs in combination with sotorasib. We identified a synergistic combination of sotorasib and a secondary inhibitor that initially suppressed resistance in the sotorasib evolved cells. We identified potential mechanisms underlying this synergy using transcriptomic analysis to enable future mechanistic characterization. Subsequently, the ResCu system drove resistance evolution to the sotarasib synergistic combination. We identified splicing alterations associated with this resistance. Conclusion: We have developed a novel resistance culturing system, ResCu, that allows for preclinical testing of KRAS G12C inhibitors and determines the most promising compounds for inhibiting specific resistance pathways. This system allows for long-term culturing of cells without passaging, thereby maintaining the various phenotypes of the original populations that are commonly lost in traditional passaging cultures. Citation Format: Victor M. Ruiz, Lindsay Hill, Manasa Gadde, Christopher Bulow, Maurizio Morri, Nicholas Goldner. Using the ResCu system for preclinical testing of KRAS G12C inhibitors [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr B030.
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Anderson, Ashley, Tate Bertea, James Neiswender, Lisa Brenan, Megan Wong, Alina Simerzin, Sarah Wie, et al. "Abstract B014: Charting ovarian cancer dependencies with patient-derived organoids." Cancer Research 84, no. 5_Supplement_2 (March 4, 2024): B014. http://dx.doi.org/10.1158/1538-7445.ovarian23-b014.
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Abstract The Cancer Dependency Map aims to accelerate precision cancer medicine by identifying the landscape of cancer vulnerabilities across all tumors. To address underrepresented cancer types, we have optimized a genome-wide CRISPR KO screening pipeline, utilizing a condensed Cas12a library, for patient-derived 3D models. Here, we present characterization of a cohort of ovarian models which consist of underrepresented cancer subtypes along with treatment-resistant cancers. In particular, our organoid dataset includes low-grade serous carcinoma models, an ovarian cancer subtype that is understudied and not previously characterized in 2D DepMap screens. The increased representation of ovarian models will improve the potential of DepMap to uncover genetic drivers of ovarian cancers. Through genomic perturbation we showed that these 3D models achieved screen quality comparable to historically derived 2D models. Our methods provide a framework for screening future cancer models and discovering vulnerabilities in select patient populations. Citation Format: Ashley Anderson, Tate Bertea, James Neiswender, Lisa Brenan, Megan Wong, Alina Simerzin, Sarah Wie, Isabella Boyle, Lauren Golden, Barbara De Kegel, Josh Dempster, Yuen-Yi Tseng, David Root, Sarah Hill, Andrew Aguirre, Francisca Vazquez. Charting ovarian cancer dependencies with patient-derived organoids [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 B014.
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Xiao, Weikun, Chae-Young Eun, Weian Zhao, and Reginald Hill. "Abstract 5848: Identification of mechanosensitive cancer associated fibroblasts in pancreatic cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 5848. http://dx.doi.org/10.1158/1538-7445.am2023-5848.
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Abstract The purpose of this study is to investigate whether a subpopulation of cancer associated fibroblasts (CAFs) are responsible for mechanosensation-mediated chemoresistance in pancreatic adenocarcinoma (PDAC). PDAC is one of the most lethal types of cancer with few effective treatments. The abundant stromal cells and the stiff desmoplastic microenvironment constitute more than 90% of the primary tumor bulk. However, there are few easily tunable models to recapitulate this stiff microenvironment. To address this issue, we have developed a Matrigel-based, orthogonally tunable 3-dimensional (3D) culture system to co-culture mouse derived PDAC organoids and host-matching cancer-associated fibroblasts (CAFs). Using this biomimetic model and a mechano-sensation-dependent reporter, we have identified a unique subpopulation of CAFs responsible for mechano-sensing the fibrotic matrix and facilitating CAF-mediated chemoresistance. Moreover, these mechanosensitive CAFs (mecCAFs) respond to increased stiffness through YAP-mediated pathways. Our results also demonstrate how ECM stiffness affects chemoresistance via the hypersecretion CAF-derived exosomes. Moving forward, therapies designed to interrupt the function of mecCAFs could be utilized to overcome matrix-mediated chemoresistance in PDAC. Citation Format: Weikun Xiao, Chae-Young Eun, Weian Zhao, Reginald Hill. Identification of mechanosensitive cancer associated fibroblasts in pancreatic cancer [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 5848.
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Oberholtzer, Nathaniel, Paramita Chakraborty, Mohamed Faisal Kassir, James Dressman, Zacharia Hedley, Gina Scurti, Monika Gooz, et al. "Abstract LB343: Golgihi T cells exhibit reduced susceptibility to exhaustion and improved tumor control." Cancer Research 84, no. 7_Supplement (April 5, 2024): LB343. http://dx.doi.org/10.1158/1538-7445.am2024-lb343.
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Abstract The role of tumor microenvironment mediated disruption of Golgi architecture and function,termed Golgi stress, in the regulation of T cell survival and function are largely unknown. Here weshow that the disruption of Golgi architecture, identified by the decreased expression of GM130,was reverted upon treatment with hydrogen sulfide (H2S) donor GYY4137, or over-expressingcystathionine β-synthase (Cbs), an enzyme involved in the biosynthesis of endogenous H2S -that promoted stemness, antioxidant capacity and exhibited increased protein translationmediated in part by ER-Golgi shuttling of Peroxiredoxin-4. In in vivo models of melanoma andlymphoma, anti-tumor T cells conditioned ex vivo with exogenous H2S or overexpressing Cbsdemonstrated superior tumor control upon adoptive transfer. Further, Golgihi T cells, with highGolgi content, exhibited unique metabolic and glycation signature with enhanced anti-tumorcapacity. These data suggest that strategies to mitigate Golgi network stress or using Golgihitumor-reactive T cells can improve tumor control upon adoptive transfer. Citation Format: Nathaniel Oberholtzer, Paramita Chakraborty, Mohamed Faisal Kassir, James Dressman, Zacharia Hedley, Gina Scurti, Monika Gooz, Lauren E. Ball, Elizabeth Hill, Anand S. Mehta, Eduardo N. Maldonado, Michael I. Nishimura, Besim Ogretmen, Shikhar Mehrotra. Golgihi T cells exhibit reduced susceptibility to exhaustion and improved tumor control [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB343.
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Tang, Fanying, Duo Xu, Shangqian Wang, Chen Khuan Wong, Alexander Martinez-Fundichely, Cindy Lee, Sandra Cohen, et al. "Abstract B026: Chromatin profiles classify castration-resistant prostate cancers suggesting therapeutic targets." Cancer Research 82, no. 23_Supplement_2 (December 1, 2022): B026. http://dx.doi.org/10.1158/1538-7445.cancepi22-b026.
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Abstract In castration-resistant prostate cancer (CRPC), the loss of androgen receptor (AR) dependence leads to clinically aggressive tumors with few therapeutic options. We used ATAC-seq (assay for transposase-accessible chromatin sequencing), RNA-seq, and DNA sequencing to investigate 22 organoids, six patient-derived xenografts, and 12 cell lines. We identified the well-characterized AR-dependent and neuroendocrine subtypes, as well as two AR-negative/low groups: a Wnt-dependent subtype, and a stem cell–like (SCL) subtype driven by activator protein–1 (AP-1) transcription factors. We used transcriptomic signatures to classify 366 patients, which showed that SCL is the second most common subtype of CRPC after AR-dependent. Our data suggest that AP-1 interacts with the YAP/TAZ and TEAD proteins to maintain subtype-specific chromatin accessibility and transcriptomic landscapes in this group. Together, this molecular classification reveals drug targets and can potentially guide therapeutic decisions. Citation Format: Fanying Tang, Duo Xu, Shangqian Wang, Chen Khuan Wong, Alexander Martinez-Fundichely, Cindy Lee, Sandra Cohen, Jane Park, Corinne Hill, Kenneth Eng, Rohan Bareja, Teng Han, Eric Minwei Liu, Ann Palladino, Wei Di, Dong Gao, Wassim Abida, Shaham Beg, Loredana Puca, Maximiliano Meneses, Elisa De Stanchina, Michael Berger, Anuradha Gopalan, Lukas Dow, Juan Miguel Mosquera, Himisha Beltran, Cora Sternberg, Ping Chi, Howard Scher, Andrea Sboner, Yu Chen, Ekta Khurana. Chromatin profiles classify castration-resistant prostate cancers suggesting therapeutic targets [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B026.
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Hill, Breana, Ioana Bondre, H. Meryem Soylu, Juliette Antoine, Xiao Lei Chen, Elise Tahon, Yichi Zhang, et al. "Abstract B024: Maintenance therapy inhibition of ptk2 yields decreased disease in preclinical HRP/HRD models of recurrent HGSOC." Cancer Research 84, no. 5_Supplement_2 (March 4, 2024): B024. http://dx.doi.org/10.1158/1538-7445.ovarian23-b024.
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Abstract High grade serous ovarian cancer remains the most lethal of the gynecologic malignancies, in part, because of the high incidence of recalcitrant and rapidly recurring disease. Disease recurrence is now better controlled due to maintenance therapy with PARP inhibitors, particularly in homologous repair deficient tumors. Efficacy in homologous repair proficient tumors represents an unmet need. We previously demonstrated that inhibitors of protein tyrosine kinase 2 (ptk2), a gene that is frequently gained in HGSOC, compromises the expression of tumor repair genes, decreases stemness, and limits immune evasion. The low toxicity of ptk2 inhibitors appears to be well suited for a maintenance role. Here, we tested the effect of six weeks of ptk2 inhibitor maintenance treatment, post-chemotherapy, in two preclinical models. In a homologous repair proficient model (KMF), and in a PARP inhibitor-resistant model (HGS2), ptk2 inhibitor treatment yielded lower tumor burden, fewer solid tumors, and decreased bloody ascites accumulation relative to treatment with Niraparib. The low toxicity and overall efficacy provide strong support for future clinical trials with ptk2 inhibitors in the maintenance role, for patients with HGSOC. Citation Format: Breana Hill, Ioana Bondre, H Meryem Soylu, Juliette Antoine, Xiao Lei Chen, Elise Tahon, Yichi Zhang, Marjaana Olajill, Sarah Kinkel, Terrie-Anne Cock, Pratibha Binder, Chris Burns, David Schlaepfer, Michael McHale T. McHale, Dwayne G Stupack. Maintenance therapy inhibition of ptk2 yields decreased disease in preclinical HRP/HRD models of recurrent HGSOC [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 B024.
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Hill, Katherine A., Cynthia M. Pérez, Adriana Pons, Karelys Canales Birriel, Andrea López Cepero, Norangelys Solís Torres, Zaydelis Tamarit Quevedo, and Vivian Colón-López. "Abstract C130: Cervical, breast, and colorectal cancer screening by COVID-19 booster and influenza vaccination status in a sample of women in Puerto Rico." Cancer Epidemiology, Biomarkers & Prevention 32, no. 1_Supplement (January 1, 2023): C130. http://dx.doi.org/10.1158/1538-7755.disp22-c130.
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Abstract Background: Recommendation by a healthcare provider is essential for women to seek preventative cancer screening. Research has shown patients are receptive to information about cancer screening given by health professionals administering influenza vaccines. Promotion of cancer screening during vaccination may be particularly important in Puerto Rico (PR), which, relative to the continental United States, has low cervical and colorectal cancer screening rates. Objective: This study aims to determine if receiving the influenza vaccine in the past year or ever receiving the COVID-19 booster is associated with an increased likelihood of women participating in cervical, breast, and colorectal cancer screening in the past year. Methods: Women older than 18 are recruited weekly in different ongoing community outreach events throughout Puerto Rico as part of the Puerto Rico Community Engagement Alliance (PR-CEAL) against COVID-19 disparities. The PR-CEAL outreach team completes an online community survey as part of their field activities. Initial data was collected from February 17th 2022 through May 28th 2022, with data collection currently ongoing. Pearson χ2 test or Fisher exact test, as appropriate, was used to quantify the association between participation in cancer screening and vaccination status. Results: As of May 31st, 253 women with a median age of 59 had been recruited. Of these, 56.1% had received the influenza vaccine in the past year, and 52.6% had received a COVID-19 booster. Nearly 52% of women with the booster and 65% without the booster received cervical cancer screening (p-value = 0.29). Women with the booster and those without the booster (75% each) received breast cancer screening (p-value = 0.99). Only 16.1% of women with the booster and 11.8% without the booster had received colorectal cancer screening (p-value = 0.99). Receipt of cancer screening according to influenza vaccine status was as follows: 59.3% vaccinated and 51.5% unvaccinated received cervical cancer screening (p-value = 0.35); 31.4% vaccinated and 41.2% unvaccinated received breast cancer screening (p-value = 0.56); and 13.1% vaccinated and 9.3% unvaccinated received colorectal cancer screening (p-value = 0.46).Conclusions: No differences in receipt of cancer screening were found by influenza or COVID-19 booster vaccination status among adult women in Puerto Rico. Routine vaccination appointments may therefore represent a missed opportunity to promote cancer screening. Citation Format: Katherine A. Hill, Cynthia M. Pérez, Adriana Pons, Karelys Canales Birriel, Andrea López Cepero, Norangelys Solís Torres, Zaydelis Tamarit Quevedo, Vivian Colón-López. Cervical, breast, and colorectal cancer screening by COVID-19 booster and influenza vaccination status in a sample of women in Puerto Rico [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 C130.
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Culp-Hill, Rachel, Collin Hill, Adele Blackler, and William Ricketts. "Abstract 2447: Identification of tumor marker gangliosides for early cancer detection: A mass spectrometry approach." Cancer Research 84, no. 6_Supplement (March 22, 2024): 2447. http://dx.doi.org/10.1158/1538-7445.am2024-2447.
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Abstract Tumor-marker gangliosides (TMGs) have enormous potential for early-stage cancer detection as diagnostic biomarkers despite being relatively understudied in this context. AOA Dx is focused on the development of a mass spectrometry platform for the quantitation of TMGs in human serum, particularly disialogangliosides GD2 and GD3. The development of a mass spectrometry platform for TMG quantitation may allow for the identification of diagnostic signatures for early-stage cancer detection. Briefly, we monitored fragment moieties characteristic of gangliosides in an untargeted fashion by mass spectrometry. We then identified those differentially altered in cancerous groups compared to normal, and subsequently performed targeted MRM analysis. Through these investigations, we have identified multiple TMGs, specifically multiple types of GD2 and GD3 species characterized by unique lipid tails across different cancer types in human serum from confirmed cancer diagnoses. Other ganglioside classes including GMs and relatively understudied GTs were also identified in this study. Notably, the serum of melanoma and ovarian cancer patients exhibited significantly increased levels of several ganglioside species compared to age-matched healthy serum, highlighting the potential of TMGs as a promising avenue for cancer diagnosis. Further experiments will focus on refining this mass spectrometry method and expand demographic representation to confirm our initial findings and identify additional TMGs of interest. In addition, we intend to apply immune-based platforms such as thin-layer chromatography and ELISA, which have already shown promising results in the detection and quantitation of these compounds. Taken together, AOA Dx is advancing the development of a high-throughput mass spectrometry platform designed for the detection of TMGs, with a primary focus on GD2 and GD3. Our objective is the identification of a diagnostic disease signature for early-stage cancer detection. The validation of this type of diagnostic panel would allow for expedited diagnosis and treatment of cancers currently diagnosed at late stages, ultimately reducing healthcare costs and increasing survival rates. Future research will aim to validate these biomarkers in independent prospective studies. Citation Format: Rachel Culp-Hill, Collin Hill, Adele Blackler, William Ricketts. Identification of tumor marker gangliosides for early cancer detection: A mass spectrometry approach [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 2447.
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Brown, Edward, Danielle Desa, Robert M. Brown, Edward B. Brown, Robert L. Hill, and Bradley M. Turner. "Abstract P5-06-13: Second-harmonic generation imaging reveals neoadjuvant chemotherapy-induced changes in breast tumor collagen." Cancer Research 82, no. 4_Supplement (February 15, 2022): P5–06–13—P5–06–13. http://dx.doi.org/10.1158/1538-7445.sabcs21-p5-06-13.
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Abstract Breast cancer is the most common invasive cancer in women, with most deaths attributed to metastases. Neoadjuvant chemotherapy (NACT) may be prescribed prior to surgical removal of the tumor for subsets of breast cancer patients but can have diverse undesired and off-target effects including increased appearance of the ‘tumor microenvironment of metastasis’ or TMEMs, image-based multicellular signatures which are prognostic of metastasis. In this study we explored whether NACT alters other image-based prognostic/predictive signatures, specifically second-harmonic generation (SHG) directionality, which is indicative of collagen fiber internal structure, as well as the disorganization in collagen fiber alignment. This was performed in paired biopsy/excision samples from 22 patients with HER2 overexpressing invasive ductal carcinoma as well as 22 patients with triple negative breast cancer (TNBC). We found that collagen fiber internal structure, measured using the SHG forward-to-backward-scattered ratio (F/B), is altered in the bulk of the tumor in both tumor types (p = 0.015 and 0.038, respectively), but not the adjacent tumor-stroma interface (p = 0.54 and 0.92, respectively), where F/B is prognostic of metastatic outcome. Overall disorganization in collagen fiber alignment was not significantly changed by NACT in HER2 overexpressing disease (p = 0.41) but was decreased in TNBC (p = 0.0051). These results suggest that NACT alters the collagenous extracellular matrix in diverse ways, with implications for the use of F/B and collagen fiber alignment as prognostic and predictive tools. Citation Format: Edward Brown, Danielle Desa, Robert M Brown, Edward B Brown, Robert L Hill, Bradley M Turner. Second-harmonic generation imaging reveals neoadjuvant chemotherapy-induced changes in breast tumor collagen [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-06-13.
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Brown, Powel H., Abhijit Mazumdar, William Tahaney, Jamal Hill, Yun Zhang, Sumankalai Ramachandran, Jitesh Kawedia, et al. "Abstract IA017: Targeting the mTOR pathway for the prevention of triple-negative breast cancer." Cancer Prevention Research 16, no. 1_Supplement (January 1, 2023): IA017. http://dx.doi.org/10.1158/1940-6215.precprev22-ia017.
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Abstract Phase III cancer prevention clinical trials have shown that breast cancer prevention is feasible using anti-estrogen drugs. However, these drugs have not been widely accepted because of concerns about toxicity. In addition, anti-estrogen drugs do not prevent estrogen-negative breast cancers, including the most aggressive form of breast cancer, triple-negative breast cancer (TNBC), that does not express the estrogen receptor (ER), progesterone receptor, or the human epidermal growth factor receptor 2 (HER2). Our laboratory is focused on identifying growth-regulatory molecules that are essential for the growth of TNBCs. For this study, we identified mTOR as an essential growth-regulatory molecule that is highly expressed in TNBCs. We then investigated whether the mTOR inhibitor everolimus can prevent mammary tumors in transgenic mouse models including 4 models of TNBC and one model of ER-negative/HER2-positive breast cancer. Everolimus treatment significantly delayed mammary tumor formation but with a varying degree in all five mouse models. Everolimus treatment for up to 1 year was well tolerated with no observable toxicity. These results suggest that mTOR inhibitors may be promising drugs for the prevention of ER-negative and triple-negative breast cancers in women at risk of these aggressive breast cancers. Grant support: This research was supported by an NCI-PREVENT contract to P. Brown and A. Mazumdar (HHSN261201500018I/HHSN26100006). Citation Format: Powel H. Brown, Abhijit Mazumdar, William Tahaney, Jamal Hill, Yun Zhang, Sumankalai Ramachandran, Jitesh Kawedia, Jing Qian, Alejandra Contreras, Michelle Savage, Lana Vornik. Targeting the mTOR pathway for the prevention of triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr IA017.
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Arvidson, Lisa, Reginaldo Prioli, Samuel Jensen, Michael J. Smith, Katie O. White, Richard A. Heil-Chapdelaine, Chi-Chou Huang, Tuan H. Phan, Hideki Sasaki, and Melinda L. Angus-Hill. "Abstract 4701: Spatial resolution of tumor and immune cell lineages in the hypoxic microenvironment of pancreatic ductal adenocarcinoma (PDAC)." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4701. http://dx.doi.org/10.1158/1538-7445.am2023-4701.
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Abstract Understanding how the tumor microenvironment (TME) evolves during tumorigenesis and therapeutic response is crucial to developing personalized treatments with the goal of improving cancer therapy. With robust and comprehensive multiplexed imaging technologies, immune biomarker antibodies can be used to interrogate immune cell lineages and structures. When combined with specific oncology biomarker antibodies, this approach can capture the immune response within the TME in a variety of neoplasms. The Cell DIVETM Multiplex Imaging Solution allows probing and imaging of dozens of biomarkers on a whole single tissue section using an iterative staining and dye inactivation workflow. The broad portfolio of robust IHC-validated antibodies from Cell Signaling Technology (CST) enables the detection of key proteins in the TME, allowing immune cell detection and phenotyping in tissue. Here, we demonstrate multiplexed Cell DIVE imaging using a novel CST panel to probe pancreatic ductal adenocarcinoma (PDAC). These biomarker antibodies define the immune cell landscape in the hypoxic tumor. Development of the antibody panel required minimal optimization, enabled the identification of complex cell types and revealed their cell-to-cell interactions within the tumor microenvironment. The availability of cell type specific biomarkers, combined with the ability to interrogate using multiplexed tissue imaging, provides unprecedented and novel insights and spatial resolution of immune cell populations with many cell types in the TME. Citation Format: Lisa Arvidson, Reginaldo Prioli, Samuel Jensen, Michael J. Smith, Katie O. White, Richard A. Heil-Chapdelaine, Chi-Chou Huang, Tuan H. Phan, Hideki Sasaki, Melinda L. Angus-Hill. Spatial resolution of tumor and immune cell lineages in the hypoxic microenvironment of pancreatic ductal adenocarcinoma (PDAC). [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 4701.
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Arvidson, Lisa, Reginaldo Prioli, Samuel Jensen, James B. Hoying, Michael W. Golway, Michael J. Smith, Katie O. White, et al. "Abstract 4698: Reproducibility in spatial biology: reducing variables to improve the reliability of insight generation." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4698. http://dx.doi.org/10.1158/1538-7445.am2023-4698.
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Abstract There is an ongoing crisis in reproducibility in scientific studies, and studies in spatial biology are no exception. Cell DIVETM Multiplex imaging solution (Leica Microsystems) provides reliable workflow solutions to minimize variability from study to study. Cell DIVE allows probing and imaging of dozens of biomarkers on a whole tissue section with an iterative staining and dye inactivation workflow. At its core, Cell DIVE is designed to provide methods reproducibility, from tissue preparation, antigen retrieval, and sample imaging and slide storage. Cell DIVE is designed to work with directly conjugated primary antibodies, another source of variability. However, conjugated antibodies from Cell Signaling Technology (CST) are rigorously validated using stringent acceptance criteria to reduce variability. In addition, the use of recombinant antibodies, the consistent conjugate brightness and antibody degree-of-labeling reduce lot to lot variability, ensuring reliable conjugated antibodies for spatial biology studies. High resolution imaging results are obtained by consistent round to round imaging, consistent calibration and corrections, and reduction of human error using the BAB 200 liquid handling solution (Advanced Solutions Life Sciences). We present here, an iterative biomarker study using adjacent tissue sections probed with distinct lots of CST antibody panels, imaged in temporally separated batches using a Cell DIVE imager fitted with a BAB200 liquid handler. Following robust analysis (segmentation, phenotyping and statistical analysis), we report the reproducibility findings across parameters. Methods and results reproducibility in spatial biology is essential for reliable insight generation, giving confidence in the quality of future studies aimed at improving patient outcomes. Citation Format: Lisa Arvidson, Reginaldo Prioli, Samuel Jensen, James B. Hoying, Michael W. Golway, Michael J. Smith, Katie O. White, Richard A. Heil-Chapdelaine, Chi-Chou Huang, Tuan H. Phan, Hideki Sasaki, Melinda Angus-Hill. Reproducibility in spatial biology: reducing variables to improve the reliability of insight generation. [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 4698.
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McQueeney, Kelley E., Patrick Bhola, Sarah J. Hill, and Anthony Letai. "Abstract 4309: Early apoptotic measurements of patient-derived organoids predict patient response to therapy." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4309. http://dx.doi.org/10.1158/1538-7445.am2023-4309.
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Abstract The use of imperfect models and ex vivo culture systems to try to predict patient drug response represents an enormous bottle neck in cancer treatment. Nonetheless, determining how effective an approved drug will be for an individual cancer patient, as well as identifying novel compounds that may be beneficial to a specific population often requires the use of primary tumor cells. Patient-derived organoids represent an intermediate between primary tumor cells, whose limited supply may hinder reliable drug testing, and cell lines, which often do not reflect what happens in vivo. Herein, we describe the development of a novel assay platform, termed 3D-DBP (3D dynamic BH3 profiling), to detect early apoptotic measurements in ovarian cancer patient-derived organoids and present evidence that this method can be used to predict patient response to therapy. We have optimized the use of patient-derived organoids from 16 individual tumors in a microscopy-based imaging assay. We image the BH3 peptide-induced release of cytochrome c from mitochondria, which indicates permeabilization of the outer mitochondrial membrane, in intact organoids. The less cytochrome c retained in each organoid, the more primed that organoid is for apoptosis. By comparing results of drug-treated and untreated cells, we can identify drugs that cause a significant increase in apoptotic priming in organoids. In the 16 patient-derived organoids investigated this 3D DBP technique was an effective means of predicting patient response to carboplatin therapy. In summary, we have not only created a means of visualizing drug response in intact organoids, but also have demonstrated its clinical utility. Citation Format: Kelley E. McQueeney, Patrick Bhola, Sarah J. Hill, Anthony Letai. Early apoptotic measurements of patient-derived organoids predict patient response to therapy. [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 4309.
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Gadde, Manasa, Elizabeth Schwabe, Kshithija Mulam, Lindsay Hill, and Christopher Bulow. "Abstract 1682: Bridging gaps in treatment resistance 2D models with the incorporation of 3D models." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1682. http://dx.doi.org/10.1158/1538-7445.am2023-1682.
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Abstract Introduction: 3D cellular models have become of increasing interest in anti-cancer drug discovery as a bridge between clinical models and traditional in vitro methods. An important component of this research is the comparison of drug-to-cell interactions and morphological characteristics between cells in mono-layer culture and the cells in 3D spheroids. Materials and Methods:The ResCu system is a novel long term, physiologically relevant culture system that avoids the need for passaging. It propagates tumoroids in a microenvironment that resembleshuman tissue. Cells with KRAS G12C mutation were cultured in the ResCu system for three months, during which they were constantly exposed to G12C inhibitors (G12Ci) for the evolution of resistant cell populations. Cells were also cultured in traditional 2D cultures and exposed to G12Ci. Transcriptomics was performed to determine resistant networks and identify different resistant subclones in each group. Results: We applied the ResCu system to model clinical resistance. We captured 95% of clinically identified on-target and pathway bypass resistance changes, and in the 2D system, only a fraction of mechanisms were discovered. Additionally, we noticed certain cell populations could tolerate higher doses of the G12Ci after resistance evolution in ResCu compared to 2D. A few had similar responses suggesting that the origin of the cell line plays a role in the microenvironment's impact on cellular response. Conclusion: By comparatively analyzing resistance evolution data for KRAS G12Ci in traditional 2D and ResCu, we were able to collect physiologically relevant data that can more confidently be applied to clinical studies than mono-layer cell culture data alone. Citation Format: Manasa Gadde, Elizabeth Schwabe, Kshithija Mulam, Lindsay Hill, Christopher Bulow. Bridging gaps in treatment resistance 2D models with the incorporation of 3D 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 1682.
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Smith, Michael J., Chi-Chou Huang, Tuan H. Phan, Hideki Sasaki, Katie O. White, Richard A. Heil-Chapdelaine, and Melinda Angus-Hill. "Abstract 2871: Spatial landscape of the tumor microenvironment in pancreatic ductal adenocarcinoma using multiplexed imaging and AI based analysis." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2871. http://dx.doi.org/10.1158/1538-7445.am2023-2871.
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Abstract Pancreatic tumors are highly heterogenous, often with more aggressive regions that are responsible for invasion and metastasis. These aggressive pancreatic ductal adenocarcinoma (PDAC) cells undergo epithelial to mesenchymal transition and create subregions in the tumor that evade treatments and provide a critical support niche for continued tumor growth and metastasis. Conventional chemotherapy plus radiation, or in advanced disease chemotherapy plus targeted drug therapy can lengthen patient survival. However, even in patients with local disease, the 5-year survival rate remains at around 40%, demonstrating that there is need for improved conventional and immune therapies for all pancreatic cancer patients. In this study, dozens of biomarkers have been used to probe tumor heterogeneity in pancreatic ductal adenocarcinoma (PDAC) tissue. We rely on the published finding that hypoxia gene expression is consistent in PDAC, regardless of tumor location, whether primary tumor or metastasis. With the spatial biology solution, Cell DIVETM and proprietary Spatial AI analytics software, dozens of biomarkers can be used to computationally reduce tumor heterogeneity, and to spatially define cells in the microenvironment within hypoxic and normoxic regions of PDAC, and in normal pancreas. We found that these hypoxic PDAC regions are devoid of immune cells in general, with the appearance of spatially co-localized populations of cell types consistent with tumor desmoplasia and inflammation. Taken together, multiplexed whole slide imaging and analysis enables spatially resolved whole tissue analysis of the tumor microenvironment, including new insights into spatial biology in the hypoxic PDAC environment. Citation Format: Michael J. Smith, Chi-Chou Huang, Tuan H. Phan, Hideki Sasaki, Katie O. White, Richard A. Heil-Chapdelaine, Melinda Angus-Hill. Spatial landscape of the tumor microenvironment in pancreatic ductal adenocarcinoma using multiplexed imaging and AI based analysis [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 2871.
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Dillon, Medbh A., Lisa Arvidson, Cole G. Phalen, Julian R. Ishibashi, John B. Johanneson, Zachary J. Thomson, Peiyao A. Zhao, et al. "Abstract 5331: Spatial resolution of immune cell lineages in the tumor microenvironment of plasma cell dyscrasias." Cancer Research 84, no. 6_Supplement (March 22, 2024): 5331. http://dx.doi.org/10.1158/1538-7445.am2024-5331.
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Abstract Plasma cell dyscrasias (PCDs) are diseases of the hematologic system, with Multiple Myeloma as the most common disease. Less common PCDs include primary and secondary extramedullary plasmacytomas (EMP), which occur in soft tissues. EMPs are typically solitary and infrequent, often localized in the upper aerodigestive and gastrointestinal tracts, lung, and lymph nodes among other organs, and can convert to Multiple Myeloma. Secondary extramedullary plasmacytomas are often noted in advanced disease following multiple rounds of therapy and are commonly associated with poor prognosis. Studies aimed at gaining a better understanding of soft tissue EMPs, whether solitary plasmacytomas with undiagnosed multiple myeloma or in the context of recurrent or metastatic EMP disease, are limited. In this study, we employ a comprehensive approach using multiple modalities, including dissociated CITE-seq, spatial transcriptomics, and multiplexed spatial immuno-fluorescence imaging to interrogate the tumor and immune landscape in EMP disease. Importantly, the use of the same biomarker antibodies across these modalities provides a cross-data-framework for a deep contextual understanding of the immune and tumor cell organization and cell-to-cell signaling in EMP. Ultimately, this study provides new insights into patient-to-patient and tumor location variability, tumor and immune cell microenvironment heterogeneity, and possible future therapeutic strategies for EMP. Citation Format: Medbh A. Dillon, Lisa Arvidson, Cole G. Phalen, Julian R. Ishibashi, John B. Johanneson, Zachary J. Thomson, Peiyao A. Zhao, Jocelin Malone, Mackenzie S. Kopp, Matthew Norton, Gabriella Spang, Susan A. Ludmann, Adam K. Savage, Claire E. Gustafson, Marla Glass, Emma L. Kuan, Tao Peng, Lucas T. Graybuck, Xiao-jun Li, Troy R. Torgerson, Peter J. Skene, Ananda W. Goldrath, Samuel Jensen, Stephanie Anover-Sombke, Melinda L. Angus-Hill. Spatial resolution of immune cell lineages in the tumor microenvironment of plasma cell dyscrasias [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 5331.
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Xiao, Weikun, Chae-Young Eun, Xinyu Zhang, Charlene DeKalb, Mahsa Pahlavan, Bayan Mahgoub, Hanaa Knaneh, Alireza Sohrabi, Stephanie K. Seidlits, and Reginald Hill. "Abstract 1567: Increased extracellular matrix stiffness induces hypersecretion of chemoresistance-promoting cancer associated fibroblast-derived exosomes in pancreatic cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1567. http://dx.doi.org/10.1158/1538-7445.am2022-1567.
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Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer with few effective treatments. Despite recent advances in in other cancers, the five-year survival rate of PDAC is still only 10%, with most patients succumbing to their disease within the first year. One of the main factors responsible for this poor outcome is the development of chemoresistance in nearly all clinical cases. While the intrinsic factors that facilitate chemoresistance in the tumor cells have been studied extensively, fewer studies have elucidated how the complex and unique microenvironment surrounding the tumor affects therapeutic responses. The abundant stromal cells and the stiff desmoplastic microenvironment constitute more than 90% of the primary tumor bulk. However, there is a lack of high-throughput, easily tunable models to recapitulate this complex microenvironment, in order to identify a critical cell-extrinsic factors that could drive acquired chemoresistance in PDAC cells. To address this issue, we have developed a Matrigel-based, orthogonally tunable 3-dimensional (3D) culture system to co-culture mouse derived PDAC organoids and host-matching cancer-associated fibroblasts (CAFs). Using this system, we found that matrix-activated CAFs readily remodel the desmoplastic matrix through lysol-oxidase dependent crosslinking. Moreover, our novel system demonstrates how collagen-I and matrix stiffness affect chemoresistance via the hypersecretion CAF-derived exosomes. Interestingly, our data show that it is CAF-derived exosomes, not the organoid-derived exosomes, that are most important in regulation of proliferation and chemoresistance. Lastly, we identified key cell surface integrins for collagen-I as therapeutic targets to prevent desmoplastic matrix-mediated chemo-resistance in PDAC. Our study provides insights into how matrix composition and stiffness affect therapeutic outcome in PDAC. Moving forward, therapies aimed at interrupting how PDAC cells and stomal cells sense the matrix microenvironment could be utilized to eventually overcome matrix-mediated chemoresistance in PDAC. Citation Format: Weikun Xiao, Chae-Young Eun, Xinyu Zhang, Charlene DeKalb, Mahsa Pahlavan, Bayan Mahgoub, Hanaa Knaneh, Alireza Sohrabi, Stephanie K. Seidlits, Reginald Hill. Increased extracellular matrix stiffness induces hypersecretion of chemoresistance-promoting cancer associated fibroblast-derived exosomes in pancreatic cancer [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 1567.
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Hill, Kristen S., Evan R. Roberts, Xue Wang, John M. Koomen, Jane L. Messina, Jamie K. Teer, Youngchul Kim, Jie Wu, Charles E. Chalfant, and Minjung Kim. "Abstract PR13: PTPN11 plays oncogenic roles and is a therapeutic target for BRAF wild-type melanomas." Cancer Research 80, no. 19_Supplement (October 1, 2020): PR13. http://dx.doi.org/10.1158/1538-7445.mel2019-pr13.
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Abstract Melanoma is one of the most highly mutated cancer types, harboring numerous alterations with unknown significance. To identify functional drivers of melanoma, we searched for cross-species conserved mutations utilizing a mouse melanoma model driven by loss of PTEN and CDKN2A, and identified mutations in Kras, Erbb3, and Ptpn11. PTPN11 encodes the SHP2 protein tyrosine phosphatase (PTP) that activates the RAS/RAF/MAPK pathway. Although PTPN11 is an oncogene in leukemia, lung, and breast cancers, its roles in melanoma are not clear. In this study, we found that PTPN11 is frequently activated in human melanoma specimens and cell lines and is required for full RAS/RAF/MAPK signaling activation in BRAF wild-type (either NRAS mutant or wild-type) melanoma cells. PTPN11 played oncogenic roles in melanoma by driving anchorage-independent colony formation and tumor growth. In Pten and Cdkn2a null mice, tet-inducible and melanocyte-specific PTPN11E76K expression significantly enhanced melanoma tumorigenesis. Melanoma cells derived from this mouse model showed doxycycline-dependent tumor growth in nude mice. Silencing PTPN11E76K expression by doxycycline withdrawal caused regression of established tumors by induction of apoptosis and senescence and suppression of proliferation. Moreover, the PTPN11 inhibitor (SHP099) also caused regression of NRASQ61K-mutant melanoma. Using a quantitative tyrosine phospho-proteomics approach, we identified GSK3α/β as one of the key substrates that were differentially tyrosine-phosphorylated in these experiments modulating PTPN11. This study demonstrates that PTPN11 plays oncogenic roles in melanoma and regulates RAS and GSK3α/β signaling pathways. This study also identifies PTPN11 as a novel and actionable therapeutic target for BRAF wild-type melanoma. This abstract is also being presented as Poster A14. Citation Format: Kristen S. Hill, Evan R. Roberts, Xue Wang, John M. Koomen, Jane L. Messina, Jamie K. Teer, Youngchul Kim, Jie Wu, Charles E. Chalfant, Minjung Kim. PTPN11 plays oncogenic roles and is a therapeutic target for BRAF wild-type melanomas [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR13.
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Pahlavan, Mahsa, Weikun Xiao, Flora Eun, Chang-Il Hwang, and Reginald Hill. "Abstract PO-123: Development of a 3D biomimetic metastatic liver niche model for pancreatic cancer." Cancer Research 81, no. 22_Supplement (November 15, 2021): PO—123—PO—123. http://dx.doi.org/10.1158/1538-7445.panca21-po-123.
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Abstract Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer death in the United States with a 5-year survival rate of only 7%. Early diagnosis is very difficult and thus 53% of PDAC patients are diagnosed after metastasis has already occurred with liver being the most frequently affected site. Therefore, it is urgent to understand the mechanism that leads to PDAC metastasis in liver in order to develop potential therapeutics. Research shows that environment that comprises the metastatic niche has unique features that facilitate tumor growth and chemoresistance. Differences between the tumor microenvironment (TME) of the primary site and the metastatic site may be a key reason why metastatic tumors are highly resistant to standard treatment. However, most current models only recreate the primary tumor environment, while a proper model which recapitulates the key features of the metastatic niche to study liver metastasis (LM) is still missing. To address this problem, we aim to design a biomimetic model that specifically recapitulates the liver premetastatic niche (PMN). Our 3D model accomplishes this by using 1) a collagen rich extracellular matrix (ECM) that mimics the metastatic site, 2) LM-derived fibroblasts, 3) and LM organoids derived from a mouse model of PDAC. Our preliminary results showed that primary PDAC organoids require CAFs derived from primary PDACs to exhibit chemoresistance. In contrast, LM organoids did not require primary CAFs to exhibit the same level of chemoresistance. This suggests that there are cell intrinsic factors that promote chemoresistance in LM organoid in addition to possible cell extrinsic factors from the PMN. In this research we investigate the role of LM-derived CAFs and PDAC-derived exosomes in liver PMN development and study their effect on growth and chemoresistance of LM organoids. Results of this research will help us to develop strategies specifically tailored to overcome the factors which promote chemoresistance in the PMN. Citation Format: Mahsa Pahlavan, Weikun Xiao, Flora Eun, Chang-Il Hwang, Reginald Hill. Development of a 3D biomimetic metastatic liver niche model for pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-123.
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Pahlavanneshan, Mahsa, Weikun Xiao, Chae Young Eun, Chang-Il Hwang, and Reginald Hill. "Abstract 3513: Developing a 3D biomimetic liver metastatic niche model for pancreatic cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 3513. http://dx.doi.org/10.1158/1538-7445.am2023-3513.
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Abstract Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer death in the Unites States with a 5-year survival rate of only 11%. Early diagnosis is very difficult and thus 53% of patients are diagnosed after metastasis has already occurred, with the liver being the most frequently affected site. Both primary tumors and metastases have highly fibrotic stroma. Thus, stromal targeting agents have the potential to benefit patients, even those with metastatic disease. However, in addition to different resident fibroblasts, a study based on a rapid autopsy program of metastatic PDAC patients showed that tumor ECM density is actually lower at sites of liver metastasis compared to the primary tumor. These results highlight some of the differences between the microenvironment of the liver metastatic niche (LMN) compared to that of the primary tumor. Thus, to best help patients, models which recapitulate the LMN are needed. We developed a 3D biomimetic model to co-culture PDAC organoids and host matching primary CAFs to recapitulate the desmoplastic environment of primary PDAC. Our preliminary results show that primary site derived CAFs induce organoid growth, chemoresistance, and ECM remodeling when co-cultured with PDAC organoids. Utilizing paired organoids which metastasized to the liver (LM organoids), we tested if primary site derived CAFs would have the same effect on LMs. Interestingly, we observed that while LM organoids were intrinsically more drug resistant, co-culture with primary site derived CAFs had no effect on chemoresistance or ECM remodeling. Next, we utilized a metastasis associated fibroblast (MAF) liver cell line to investigate the role of MAFs in tumor growth, chemoresistance, and ECM remodeling. Our results show that primary and metastatic organoids use different mechanism to induce ECM stiffness triggered by fibroblast activation and remodeling in their resident fibroblasts. Citation Format: Mahsa Pahlavanneshan, Weikun Xiao, Chae Young Eun, Chang-Il Hwang, Reginald Hill. Developing a 3D biomimetic liver metastatic niche model for pancreatic cancer [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 3513.
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Mahgoub, Bayan, Weikun Xiao, and Reginald Hill. "Abstract 2349: Investigating the effect of ECM stiffness on macrophage-derived exosome secretion and PDAC organoid progression." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2349. http://dx.doi.org/10.1158/1538-7445.am2023-2349.
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Abstract Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of only 11%. Current treatments that mostly target the cancer cells themselves, have not been able to significantly improve survival rates, meaning there is an urgent need for novel therapies. PDAC is unique among solid tumors because it exhibits extensive desmoplasia that is characterized by an abundance of extracellular matrix (ECM) components. In recent years, an increasing body of work has shown that cancer tissue is stiffer than normal tissue by a factor of 3 or more. This change in ECM stiffness has been shown to play an important role in affecting cell to cell communication as well as cancer progression and chemoresistance. However, how ECM stiffness affects macrophages, an important immune component of the pancreatic tumor microenvironment (TME), and macrophage-derived exosome secretion is still understudied. Preliminary studies have shown that macrophages are highly sensitive to the mechanical environment. How cell-cell information transfer through exosomes may regulate this process in the PDAC tumor microenvironment (TME) needs to be explored. Elucidating these potential changes can provide us with insights on how stiffness affects therapeutic outcome in PDAC. Our previous studies utilizing a biomimetic model that allows us to tune stiffness, showed that increased stiffness resulted in significantly higher exosome secretion from fibroblasts. Based on this finding, we hypothesize that increasing stiffness will result in hypersecretion of macrophage-derived exosomes that increases the chemoresistance of PDAC. 2D culture of macrophages on varying stiffness plates was used to study these changes in vitro. We then examined how changes in ECM stiffness affected the function and polarization of tumor associated macrophages, as well as elucidating how exosome hypersecretion and uptake, regulate these “stiffness enhanced” macrophages’ ability to affect PDAC progression. Understanding how macrophage-derived exosome signaling changes due to ECM stiffness may provide us with insights needed to develop novel therapies. Citation Format: Bayan Mahgoub, Weikun Xiao, Reginald Hill. Investigating the effect of ECM stiffness on macrophage-derived exosome secretion and PDAC organoid progression [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 2349.
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Lajmi, Luke, Wishrawana S. Ratnayake, Khandker M. Khalid, Sloan Breedy, Aaron Todman, Tracess Smalley, Christopher A. Apostolatos, Robert Hill, and Mildred Acevedo-Duncan. "Abstract 4382: PKC-ι/ζ signaling is crucial for apoptosis/pyroptosis inhibition and invasiveness of glioblastoma cells through upregulation of β-catenin, PDK1/Akt1 and Smad cascades via 14-3-3." Cancer Research 84, no. 6_Supplement (March 22, 2024): 4382. http://dx.doi.org/10.1158/1538-7445.am2024-4382.
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Abstract Glioblastoma (GB) is an aggressive form of brain cancer derived from astrocytes. Poor predictability of patient outcomes has limited the development of current therapeutic treatments of GB mainly due to the development of drug resistance. Comparative over-expression of atypical protein kinase C-iota and zeta (aPKC-ι/ζ) in GB cells and tissue samples were previously reported. This study establishes the downstream effects of PKC-ι/ζ attenuation on key cellular signaling which governs apoptosis, pyroptosis, survival, proliferation and epithelial-mesenchymal transition (EMT). Our data suggested that aPKC knockdown of expression induces apoptosis and works as an antecedent of pyroptosis. Data also suggested that involvement of Akt1 and PDK1 in aPKC maturation process weakened due to aPKC attenuation. aPKC attenuation downregulated Ras/Erk1 and canonical β-catenin pathways which resulted in reduced transcriptional activities of Stat3, c-Myc, c-Jun and β-catenin. In addition SNAIL1, SLUG, and PRRX1 were diminished that have been known to stimulate EMT. Proteins 14-3-3 and Smad2/3 acted as molecular adaptors between these pathways. A PKC-ι specific inhibitor 5-amino-1-(2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)-1H-imidazole-4-carboxamide (ICA-1S) and a PKC-ζ specific inhibitor 8-hydroxy-1,3,6-naphthalenetrisulfonic acid (ζ-Stat) were used to conduct in-vivo experiments using mouse models. Intravenous and oral administration of ICA-1S resulted in the reduction of tumor growth by approximately 30% in athymic nude mice for U-87 xenografts. Taken together, these results suggest that not only do aPKCs play a central role in GB progression, invasiveness, and cell survival, but that effective therapeutics can be developed to specifically target oncogenic aPKCs. Citation Format: Luke Lajmi, Wishrawana S. Ratnayake, Khandker M. Khalid, Sloan Breedy, Aaron Todman, Tracess Smalley, Christopher A. Apostolatos, Robert Hill, Mildred Acevedo-Duncan. PKC-ι/ζ signaling is crucial for apoptosis/pyroptosis inhibition and invasiveness of glioblastoma cells through upregulation of β-catenin, PDK1/Akt1 and Smad cascades via 14-3-3 [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 4382.
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Mayekar, Manasi, Deborah Caswell, Natalie Vokes, Emily K. Law, Wei Wu, William Hill, Eva Gronroos, et al. "Abstract 2197: Targeted cancer therapy induces APOBEC fueling the evolution of drug resistance." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2197. http://dx.doi.org/10.1158/1538-7445.am2022-2197.
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Abstract Introduction: Increasing our understanding of drivers of mutagenesis in lung cancer is critical in our efforts to prevent tumor reoccurrence and resistance. Results: Using the multi-region TRACERx lung cancer study, we uncovered that APOBEC3B is significantly upregulated when compared with other APOBEC family members in EGFR driven lung cancer and identified subclonal enrichment of APOBEC mutational signatures. To model APOBEC mutagenesis in lung cancer, several novel EGFR mutant mouse models containing a human APOBEC3B transgene were generated. Using these models, it was uncovered that APOBEC3B expression is detrimental at tumor initiation when expressed continuously in a p53 wildtype background. This detrimental effect is likely due to elevated chromosomal instability, which was observed to increase significantly with APOBEC3B expression in an EGFR mutant TP53 deficient mouse model. Induction of subclonal expression of APOBEC3B in an EGFR mutant mouse model with tyrosine kinase inhibitor (TKI) therapy resulted in a significant increase in resistant tumor development. Significant downregulation of the base excision repair gene uracil-DNA glycosylase (UNG) was also observed in APOBEC3B expressing mice, which paralleled findings in patient tumors and cell lines treated with TKI therapy. Finally, a mouse mutational signature was identified in APOBEC3B expressing cell lines, reinforcing the idea that APOBEC driven mutagenesis contributes to TKI resistance. Conclusion: This study demonstrates a unique principle by which targeted therapy induces changes within tumors ideal for APOBEC driven tumor evolution, fueling therapy resistance. Citation Format: Manasi Mayekar, Deborah Caswell, Natalie Vokes, Emily K. Law, Wei Wu, William Hill, Eva Gronroos, Andrew Rowan, Maise Al Bakir, Clare Weeden, Caroline E. McCoach, Collin M. Blakely, Nuri Alpay Temiz, Ai Nagano, Daniel L. Kerr, Julia K. Rotow, Oriol Pich, Franziska Haderk, Michelle Dietzen, Carlos Martinez Ruiz, Bruna Almeida, Lauren Cech, Beatrice Gini, Joanna Przewrocka, Chris Moore, Miguel Murillo, Bjorn Bakker, Brandon Rule, Cameron Durfee, Shigeki Nanj, Lisa Tan, Lindsay K. Larson, Prokopios P. Argyris, William L. Brown, Johnny Yu, Carlos Gomez, Philippe Gui, Rachel I. Vogel, Elizabeth A. Yu, Nicholas J. Thomas, Subramanian Venkatesan, Sebastijan Hobor, Su Kit Chew, Nicholas McGranahan, Nnennaya Kanu, Eliezer M. Van Allen, Julian Downward, Reuben S. Harris, Trever Bivona, Charles Swanton. Targeted cancer therapy induces APOBEC fueling the evolution of drug resistance [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 2197.
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Moyer, Cassandra L., Abhijit Mazumdar, Jamal Hill, Martin E. Sanders, and Powel Brown. "Abstract P4-01-14: The RXR agonist, IRX4204, increases the anti-tumor activity of HER2-targeted therapies in HER2-amplified breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): P4–01–14—P4–01–14. http://dx.doi.org/10.1158/1538-7445.sabcs21-p4-01-14.
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Abstract Background: HER2 targeted monoclonal antibodies and tyrosine kinase inhibitors (TKI) are effective treatments for HER2-amplified primary tumors. However, the challenge persists that primary and acquired resistance to anti-HER2 therapy is common, and that anti-HER2 targeted therapies fail to achieve a cure in the metastatic setting. There is a critical need for safe and effective therapies that can overcome anti-HER2 drug resistance and eliminate breast cancer metastases. Here, we present data demonstrating the activity of IRX4204, a highly specific agonist of the nuclear retinoid X receptor (RXR), to inhibit the growth of HER2-amplified breast cancer cell lines alone and in combination with current anti-HER2 therapies. Methods: In vitro cell growth assays were conducted to evaluate the efficacy of IRX4204 alone and in combination with trastuzumab, tucatinib, neratinib or T-DM1, using a panel of breast cancer cell lines expressing various levels of HER2. A calculated coefficient of drug interaction (CDI) and isobologram analysis was used to assess the additive, synergistic or antagonistic effects of IRX4204 with each anti-HER2 targeted therapy. Results: IRX4204 treatment alone inhibited the growth of HER2-overexpressing cell lines, SkBr3, AU565, HCC1419 and ZR75-1 in vitro, but not the growth of HER2-normal cell lines MCF7, MDA-MB-231, or HCC1143. When combined with trastuzumab, tucatinib, neratinib or T-DM1, additive or synergistic effects were observed in all of the drug-sensitive cell lines. Moreover, IRX4204 in combination with neratinib or tucatinib inhibited the growth of a TKI-resistant breast cancer cell line (HCC1954). Conclusion: These data demonstrate a novel use of an RXR agonist, IRX4204, to inhibit the growth of HER2-amplified breast cancer cell lines and to enhance the activity of anti-HER2 therapy in vitro. These results also demonstrate that IRX4204 can overcome anti-HER2 resistance to inhibit the growth of HER2-positive cells. These data demonstrate that IRX4204 can enhance the anti-cancer activity of anti-HER2 therapies even in TKI-resistant cells. In vivo experiments and mechanistic studies are ongoing. Citation Format: Cassandra L Moyer, Abhijit Mazumdar, Jamal Hill, Martin E Sanders, Powel Brown. The RXR agonist, IRX4204, increases the anti-tumor activity of HER2-targeted therapies in HER2-amplified breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-01-14.
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Kaninjing, Ernest, Gladys Asiedu, Kaitlin Van Voorhis, Mary Ellen Young, Ebenezer Erefah, Emmanuel Agboola, Folakemi Odedina, et al. "Abstract 1310: Social determinants of migrant health factors impacting prostate cancer care and survivorship among sub-Saharan African immigrant men diagnosed with prostate cancer." Cancer Research 84, no. 6_Supplement (March 22, 2024): 1310. http://dx.doi.org/10.1158/1538-7445.am2024-1310.
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Abstract Background: Sub-Saharan African Immigrants (SSAI) represent one of the fastest-growing segments of the immigrant population in the United States (US). Between 2010 and 2018, the SSAI population in the US increased by 53%, significantly outpacing the 12% growth rate for the overall foreign-born population in the US during that time frame. Despite these growing numbers, little is published about the extent to which SSAIs adapt to health behaviors more common in the US or remain immersed in the values, beliefs and practices reflective of their country of origin. Importantly, no study has comprehensively examined the Social Determinants of Health (SDOH) among this population relative to their migration experiences and their influence on health-seeking behaviors and decision-making regarding prostate cancer care and treatment options. Methods: This qualitative study employed grounded theory and the social determinants of migrant heath framework to better understand the needs of SSAI prostate cancer survivors in the United States and how to effectively support these survivors. In-depth interviews were conducted with 8 survivors who live in the states of Florida and Minnesota. Findings: Some participants reported limited access to care and financial challenges paying for drugs. In terms of coping with diagnosis and treatment, most of the participants relied on their faith, a positive outlook about survivorship and support of family members. Some participants relied on the coaching and support of a loved one who experienced prostate cancer in the past. Erectile dysfunction severely impacted the sexual life of most participants as they experienced difficulty getting an erection. Conclusion: Participants expressed the benefit of belonging to support groups with other survivors for social and emotional support. As the number of immigrants from sub-Saharan continue to rise, so too will the demand for culturally tailored care to address and reduce disparities in survivorship among this sub-population. Citation Format: Ernest Kaninjing, Gladys Asiedu, Kaitlin Van Voorhis, Mary Ellen Young, Ebenezer Erefah, Emmanuel Agboola, Folakemi Odedina, Roxana Dronca, Kimlin Ashing, Solomon Rotimi, Che Ngufor, Arnola Merriweather, John McCall, Anthony Hill. Social determinants of migrant health factors impacting prostate cancer care and survivorship among sub-Saharan African immigrant men diagnosed with prostate 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 1310.
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Chiang, Chun-Te, Danielle Hixon, Nevart Mooradian, Pratiksha Kshetri, Scott Valena, Roy Lau, Charlie Ambrose, Michael Doche, Reginald Hill, and Shannon M. Mumenthaler. "Abstract A017: Exploring the interplay between macrophage subtypes and colorectal cancer cell growth." Cancer Immunology Research 11, no. 12_Supplement (December 1, 2023): A017. http://dx.doi.org/10.1158/2326-6074.tumimm23-a017.
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Abstract Tumor-associated macrophages, a major stromal component within the tumor microenvironment (TME), play diverse roles in tumor progression and response to therapy. Although their tumor infiltration is linked to unfavorable prognoses in various cancer types, their specific involvement in colorectal cancer (CRC) remains a subject of debate. Within the TME, macrophages can adopt pro-inflammatory (M1) or immune-suppressive (M2) phenotypes in response to signals. In this study, we aimed to investigate the intricate interplay between CRC cells and macrophages under different tumor microenvironmental stresses, shedding light on the impact of macrophage phenotype and function on tumor cell behavior. We characterized signaling pathways and macrophage markers in the THP-1 monocytic cell line, differentiating THP-1 cells into M0 macrophages and polarizing them into M1 and M2 phenotypes using distinct inducers, LPS+IFNγ or IL4+IL13, respectively. Treatment with M1 and M2 inducers resulted in the induction of p-STAT1 and p-STAT6 signaling, as well as metabolic markers like IDO and TGM2, respectively, in THP-1 cells. Subsequently, we collected conditioned media (CM) from M0, M1, and M2 macrophages and assessed their impact on colon cancer cell proliferation. Consistent with previous studies, M1 CM demonstrated a suppressive effect on the growth of several CRC cell lines, whereas M0 or M2 CM did not elicit a change. Interestingly, we found a few CRC lines where the M1 CM did not reduce cell growth, suggesting that the response to M1 macrophages may be influenced by tumor cell-intrinsic factors. To gain further insights, a high-content imaging-based workflow was utilized for physical co-cultures of macrophage subtypes and CRC cells. Furthermore, we validated our findings using patient-derived tumor organoids to examine the interaction between macrophages and CRC in a more physiologically relevant context. Overall, our systematic exploration provides valuable insights into the complex interplay between macrophage subtypes and the progression of colon cancer. It emphasizes the influence of the tumor immune microenvironment on cancer cell behavior across diverse intrinsic cellular factors. Citation Format: Chun-Te Chiang, Danielle Hixon, Nevart Mooradian, Pratiksha Kshetri, Scott Valena, Roy Lau, Charlie Ambrose, Michael Doche, Reginald Hill, Shannon M. Mumenthaler. Exploring the interplay between macrophage subtypes and colorectal cancer cell growth [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A017.
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KITLV, Redactie. "Book Reviews." New West Indian Guide / Nieuwe West-Indische Gids 71, no. 3-4 (January 1, 1997): 317–91. http://dx.doi.org/10.1163/13822373-90002612.
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-Leslie G. Desmangles, Joan Dayan, Haiti, history, and the Gods. Berkeley: University of California Press, 1995. xxiii + 339 pp.-Barry Chevannes, James T. Houk, Spirits, blood, and drums: The Orisha religion in Trinidad. Philadelphia: Temple University Press, 1995. xvi + 238 pp.-Barry Chevannes, Walter F. Pitts, Jr., Old ship of Zion: The Afro-Baptist ritual in the African Diaspora. New York: Oxford University Press, 1993. xvi + 199 pp.-Robert J. Stewart, Lewin L. Williams, Caribbean theology. New York: Peter Lang, 1994. xiii + 231 pp.-Robert J. Stewart, Barry Chevannes, Rastafari and other African-Caribbean worldviews. London: Macmillan, 1995. xxv + 282 pp.-Michael Aceto, Maureen Warner-Lewis, Yoruba songs of Trinidad. London: Karnak House, 1994. 158 pp.''Trinidad Yoruba: From mother tongue to memory. Tuscaloosa: University of Alabama Press, 1996. xviii + 279 pp.-Erika Bourguignon, Nicola H. Götz, Obeah - Hexerei in der Karibik - zwischen Macht und Ohnmacht. Frankfurt am Main: Peter Lang, 1995. 256 pp.-John Murphy, Hernando Calvo Ospina, Salsa! Havana heat: Bronx Beat. London: Latin America Bureau, 1995. viii + 151 pp.-Donald R. Hill, Stephen Stuempfle, The steelband movement: The forging of a national art in Trinidad and Tobago. Philadelphia: University of Pennsylvania Press, 1995. xx + 289 pp.-Hilary McD. Beckles, Jay R. Mandle ,Caribbean Hoops: The development of West Indian basketball. Langhorne PA: Gordon and Breach, 1994. ix + 121 pp., Joan D. Mandle (eds)-Edmund Burke, III, Lewis R. Gordon ,Fanon: A critical reader. Oxford: Blackwell, 1996. xxi + 344 pp., T. Denean Sharpley-Whiting, Renée T. White (eds)-Keith Alan Sprouse, Ikenna Dieke, The primordial image: African, Afro-American, and Caribbean Mythopoetic text. New York: Peter Lang, 1993. xiv + 434 pp.-Keith Alan Sprouse, Wimal Dissanayake ,Self and colonial desire: Travel writings of V.S. Naipaul. New York : Peter Lang, 1993. vii + 160 pp., Carmen Wickramagamage (eds)-Yannick Tarrieu, Moira Ferguson, Jamaica Kincaid: Where the land meets the body: Charlottesville: University Press of Virginia, 1994. xiii + 205 pp.-Neil L. Whitehead, Vera Lawrence Hyatt ,Race, discourse, and the origin of the Americas: A new world view. Washington DC: Smithsonian Institution Press, 1995. xiii + 302 pp., Rex Nettleford (eds)-Neil L. Whitehead, Patricia Seed, Ceremonies of possession in Europe's conquest of the new world, 1492-1640. Cambridge: Cambridge University Press, 1995. viii + 199 pp.-Livio Sansone, Michiel Baud ,Etnicidad como estrategia en America Latina y en el Caribe. Arij Ouweneel & Patricio Silva. Quito: Ediciones Abya-Yala, 1996. 214 pp., Kees Koonings, Gert Oostindie (eds)-D.C. Griffith, Linda Basch ,Nations unbound: Transnational projects, postcolonial predicaments, and deterritorialized nation-states. Langhorne PA: Gordon and Breach, 1994. vii + 344 pp., Nina Glick Schiller, Cristina Szanton Blanc (eds)-John Stiles, Richard D.E. Burton ,French and West Indian: Martinique, Guadeloupe and French Guiana today. Charlottesville: University Press of Virginia; London: Macmillan Caribbean, 1995. xii + 202 pp., Fred Réno (eds)-Frank F. Taylor, Dennis J. Gayle ,Tourism marketing and management in the Caribbean. New York: Routledge, 1993. xxvi + 270 pp., Jonathan N. Goodrich (eds)-Ivelaw L. Griffith, John La Guerre, Structural adjustment: Public policy and administration in the Caribbean. St. Augustine: School of continuing studies, University of the West Indies, 1994. vii + 258 pp.-Luis Martínez-Fernández, Kelvin A. Santiago-Valles, 'Subject People' and colonial discourses: Economic transformation and social disorder in Puerto Rico, 1898-1947. Albany: State University of New York Press, 1994. xiii + 304 pp.-Alicia Pousada, Bonnie Urciuoli, Exposing prejudice: Puerto Rican experiences of language, race, and class. Boulder: Westview Press, 1996. xiv + 222 pp.-David A.B. Murray, Ian Lumsden, Machos, Maricones, and Gays: Cuba and homosexuality. Philadelphia: Temple University Press, 1996. xxvii + 263 pp.-Robert Fatton, Jr., Georges A. Fauriol, Haitian frustrations: Dilemmas for U.S. policy. Washington DC: Center for strategic & international studies, 1995. xii + 236 pp.-Leni Ashmore Sorensen, David Barry Gaspar ,More than Chattel: Black women and slavery in the Americas. Bloomington: Indiana University Press, 1996. xi + 341 pp., Darlene Clark Hine (eds)-A. Lynn Bolles, Verene Shepherd ,Engendering history: Caribbean women in historical perspective. Kingston: Ian Randle; London: James Currey, 1995. xxii + 406 pp., Bridget Brereton, Barbara Bailey (eds)-Bridget Brereton, Mary Turner, From chattel slaves to wage slaves: The dynamics of labour bargaining in the Americas. Kingston: Ian Randle; Bloomington: Indiana University Press; London: James Currey, 1995. x + 310 pp.-Carl E. Swanson, Duncan Crewe, Yellow Jack and the worm: British Naval administration in the West Indies, 1739-1748. Liverpool: Liverpool University Press, 1993. x + 321 pp.-Jerome Egger, Wim Hoogbergen, Het Kamp van Broos en Kaliko: De geschiedenis van een Afro-Surinaamse familie. Amsterdam: Prometheus, 1996. 213 pp.-Ellen Klinkers, Lila Gobardhan-Rambocus ,De erfenis van de slavernij. Paramaribo: Anton de Kom Universiteit, 1995. 297 pp., Maurits S. Hassankhan, Jerry L. Egger (eds)-Kevin K. Birth, Sylvia Moodie-Kublalsingh, The Cocoa Panyols of Trinidad: An oral record. London & New York: British Academic Press, 1994. xiii + 242 pp.-David R. Watters, C.N. Dubelaar, The Petroglyphs of the Lesser Antilles, the Virgin Islands and Trinidad. Amsterdam: Foundation for scientific research in the Caribbean region, 1995. vii + 492 pp.-Suzannah England, Mitchell W. Marken, Pottery from Spanish shipwrecks, 1500-1800. Gainesville: University Press of Florida, 1994. xvi + 264 pp.
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Lane, Alan. "Ronan Toolis & Christopher Bowles . The lost Dark Age kingdom of Rheged: the discovery of a royal stronghold at Trusty's Hill, Galloway. 2016. vi+169 pages, several colour and b&w illustrations. Oxford & Philadelphia (PA): Oxbow; 978-1-78570-311-9 hardback £30." Antiquity 91, no. 358 (August 2017): 1114–15. http://dx.doi.org/10.15184/aqy.2017.114.
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Dijkstra, Krijn K., Roberto Vendramin, Robert E. Hynds, David R. Pearce, Despoina Karagianni, Felipe Gálvez-Cancino, Oriol Pich, et al. "Abstract 692: Patient-derived co-cultures of TRACERx lung cancer organoids and autologous T-cells reveal heterogeneity in immune evasion between cancer subclones." Cancer Research 82, no. 12_Supplement (June 15, 2022): 692. http://dx.doi.org/10.1158/1538-7445.am2022-692.
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Abstract Introduction: Intra-tumor heterogeneity (ITH) is a major driver of treatment resistance. ITH also affects anti-tumor immunity, with immune cell infiltration, neo-antigen expression and T cell receptor (TCR) profiles differing between separate regions of an individual tumor. However, the extent to which separate tumor subclones differ in their capacity for immune evasion, the tumor-intrinsic mechanisms underlying any such heterogeneity, and its impact on cancer immunosurveillance remain largely unexplored. We have previously developed personalized models of anti-tumor immunity, based on co-cultures of cancer organoids and autologous T-cells. These co-culture systems can be used to evaluate the efficacy of cancer immunosurveillance at the level of an individual patient. Approach: Here, we leverage the multi-region TRACERx lung cancer evolution study to generate a patient-derived study platform that allows the evaluation of T-cell responses to individual cancer subclones. We generated libraries of >20 separate non-small cell lung cancer (NSCLC) organoid lines, based on isolating individual (clonal) organoids established from multiple spatially separated tumor regions. Each organoid subline was co-cultured with autologous tumor infiltrating lymphocytes (TIL) to evaluate how they differ in their capacity to elicit a T-cell response. Results: Our data reveal heterogeneity between individual clonal organoid sublines in their capacity to stimulate TIL. The proportion of TIL being activated by a particular subclone, as measured by 4-1BB (CD137) expression, ranged from 5 to 42%. These differences could not be explained by differences in MHC class I or PD-L1 expression. We are currently using DNA, RNA and TCR sequencing to characterize ‘immune evading’ and ‘non-immune evading’ sublines. Data will be updated on emerging subclonal immune evasion mechanisms inferred through DNA/RNA/TCR sequencing. Conclusion: Individual cancer subclones show differences in the degree of immune evasion. This patient-derived study platform allows moving beyond descriptive analyses of the heterogeneity of anti-tumor immunity, allowing fine-grained functional studies of how ITH affects cancer immunosurveillance. Citation Format: Krijn K. Dijkstra, Roberto Vendramin, Robert E. Hynds, David R. Pearce, Despoina Karagianni, Felipe Gálvez-Cancino, Oriol Pich, Mark S. Hill, Vittorio Barbè, Andrew Rowan, Selvaraju Veeriah, Cristina Naceur-Lombardelli, Antonia Toncheva, Supreet Bola, Mariam Jamal-Hanjani, Crispin Hiley, Kevin Litchfield, James Reading, Sergio A. Quezada, Charles Swanton, TRACERx consortium. Patient-derived co-cultures of TRACERx lung cancer organoids and autologous T-cells reveal heterogeneity in immune evasion between cancer subclones [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 692.
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Mazumdar, Abhijit, Jamal Hill, William Tahaney, Yanxia Ma, Alejandro Contreras, Shizuko Sei, Altaf Mohammed, and Powel Brown. "Abstract 715: Targeting the mTOR pathway for the prevention of er-negative breast cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 715. http://dx.doi.org/10.1158/1538-7445.am2022-715.
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Abstract Background: Triple-Negative breast cancer (TNBC) is an aggressive cancer that lacks expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. These cancers have a poor prognosis and are treated predominantly with chemotherapy. Therefore, we are working to find preventive therapies for these potentially lethal cancers. Dysregulation of PI3K-mTOR pathway is commonly associated with TNBC and other ER-negative breast cancers. We hypothesized that targeting mTOR may prevent development of ER-negative breast cancers and in this study tested whether the mTOR inhibitor, everolimus, prevents cancer in several mouse models of ER-negative breast cancer. Methods: MMTV-erbB2 mice were purchased from the Jackson Laboratory. C3(1)/SV40TAg and BRCA1co/co;MMTV-Cre;p53+/- were generated through breeding. P53-null and p53-mutant mammary gland mice were generated by transplanting p53-null or p53-mutant mammary glands into cleared fat pads of p53-wild type mice. The mice were treated with either control or everolimus (5mg/kg), administered by oral gavage daily (5X/week). All mice develop palpable mammary tumors within 8-12 months. Mice were observed daily for tumor formation and drug toxicity. The percentage of tumor free mice was recorded, and time to tumor development was visualized using Kaplan-Meier curves and analyzed using the generalized Wilcoxon test. Results: Treatment with everolimus significantly increased median survival of all mouse models. Everolimus treatment was also able to completely prevent mammary tumor formation in 27% of C3(1)/SV40Tag mice and 44% p53-mutant mammary gland mice. In p53-null mammary gland mice, 46% of control mice had developed tumors after 420 days, compared to 7% of everolimus treated mice. Long term treatment of everolimus was associated with mild toxicity that includes slight weight loss (<10%) and skin changes (matted hair, skin erythema). Conclusions: Everolimus significantly delayed mammary tumorigenesis in all five breast cancer mouse models. Our results suggest that everolimus is a promising cancer preventive drug for ER-negative tumors, and that further studies of everolimus in combination with other targeted therapies are warranted. In the future, clinical trials of the everolimus should be considered for the prevention of breast cancer in high-risk patients. Supported by NCI PREVENT Cancer Preclinical Drug Development Program (HHSN-2612015000-18I (PB). Citation Format: Abhijit Mazumdar, Jamal Hill, William Tahaney, Yanxia Ma, Alejandro Contreras, Shizuko Sei, Altaf Mohammed, Powel Brown. Targeting the mTOR pathway for the prevention of er-negative breast cancer [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 715.
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Torres, Keila E., Charlotte N. Hill, Dario Rocha, Elmer Fernández, Ignacio A. Wichmann, Gareth I. Owen, and Alejandro H. Corvalan. "Abstract 2517: Characterization of the immune microenvironment of Epstein-Barr virus associated gastric cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2517. http://dx.doi.org/10.1158/1538-7445.am2022-2517.
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Abstract Consistent with better clinical outcome, Epstein-Barr Virus associated gastric cancer (EBVaGC) displays a particular expression pattern of immunological genes and is highly infiltrated by effector immune cells. To decipher potential mechanisms linking tumor infiltrating lymphocytes (TILs) with an expression of immune-related genes in EBVaGC we utilized RNAseq gene expression data from The Cancer Genome Atlas (TCGA) Stomach Adenocarcinoma (STAD) dataset and performed cellular deconvolution analyses by a mixed approach including two complementary approaches (MIXTURE and xCell). In accordance with previous studies, we observed an increase in CD8+ cells and Interferon activity. Further analysis by gene set variation analysis (GSVA) showed an increased exhausted CD8+ signature accompanied by a higher intratumoral Treg signature. Accordingly, an enrichment in both stimulatory and inhibitory immune checkpoint levels on EBVaGC tumors was observed. We next performed differential expression analysis comparing EBVaGC to other STAD subtypes (CIN, GS, HM-SNV, HM-indel) individually. As a result, from this approach, we generated a list of unique EBVaGC-specific genes that was used to construct EBVaGC-specific cell-cell interaction networks. To infer cell-cell interactions underlying the specific tumor immune microenvironment, we implemented the NicheNetR algorithm by including only differentially expressed ligands and targets from the list of EBVaGC genes obtaining a ligand-interaction matrix from which we constructed a EBVaGC-like gene signature. Functional annotation of this ligand-target network showed ligands and targets principally involved in chemotaxis, T-cell apoptosis, and cellular responses to bacterial infection. This signature correlated with better survival not only in EBVaGC but also in other TCGA cohorts such as colon adenocarcinoma and kidney renal clear cell carcinoma. Our findings identified an increase in exhausted CD8+ signature, high intratumoral Treg signature and enrichment in inhibitory immune checkpoint transcripts. We herein propose a new EBVaGC-like gene expression signature that correlates with better survival in multiple cancer types. In-vitro and in-vivo assays will be required for functional validation of these findings as well as clinical trials to confirm the role of our novel EBVaGC-like gene signature in a precision oncology setting. Grant Support: ANID/FONDECYT/POSTDOCTORADO/3201028, CONICYT-FONDAP 15130011, FONDECYT 1191928 & 1180241, IMII P09/016-F, CONICET and Universidad Católica de Córdoba 80020180100029CC, grant 33620180100993CB from the Universidad Nacional de Córdoba. Citation Format: Keila E. Torres, Charlotte N. Hill, Dario Rocha, Elmer Fernández, Ignacio A. Wichmann, Gareth I. Owen, Alejandro H. Corvalan. Characterization of the immune microenvironment of Epstein-Barr virus associated gastric cancer [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 2517.
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Shi, Gongping, Sayantan Banerjee, Xin Li, Gajendra Jogdand, Yongmei Zhao, Kunio Nagashima, Thorkell Andresson, Jyoti Shetty, Bao Tran, and Yinling Hu. "Abstract 1355: Lipid-rich foamy macrophages along with CD4 T cell-derived signaling drive aberrant lipid metabolism and are a cause of lung cancer development." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1355. http://dx.doi.org/10.1158/1538-7445.am2022-1355.
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Abstract Previously we reported that bone marrow-derived macrophages are required for lung squamous cell carcinoma development in kinase-dead Ikkα knockin (KA/KA) mice. The KA/KA lungs display strikingly enlarged sizes, sustained inflammation with increased expression of multiple cytokines and chemokines and marked infiltrating macrophages and T cells, and tissue damage, which look like a “burning hill”. To determine a critical event for the pathogenesis of the lung disease and SCC development, in this study, we found that these F4/80+CD11b+CSF1R+ monocyte-derived macrophages isolated from KA/KA lungs showed enlarged sizes carrying many lipid droplets and highly expressed the genes that encode proteins involved in lipid metabolism compared to WT. To determine whether the lung lipid concentrations regulate foamy macrophage development, we incubated Raw macrophages with WT or KA/KA lung extract, respectively, and found that KA/KA lung extracts induced lipid droplets and elevated lipid levels and pathways for lipid metabolism compared to WT lung extracts. Furthermore, we found that cytokines including IL-4, IL-6, IL-33, and IFNb, promoted lipid metabolism in Raw macrophages incubated with WT lung extracts, and also stimulated lipid metabolism in human lung SCC SW900 cells. These results suggest that these cytokines, which were highly expressed in KA/KA lungs, contribute to aberrant lipid metabolism. Because IL-4, which is produced by Th2 T cells, promoted lipid metabolism in macrophages and lung SCC cells, we further showed that KA/KA lung CD4 T cells stimulated lipid gene expression in Raw macrophages compared to WT lung CD4 T cells. Depleting CD4 T cells indeed significantly decreased foamy macrophage formation in the lungs of KA/KA mice. Importantly, treatment with a lipid inhibitor reduced IL-4-mediated lipid metabolism in Raw macrophages and human lung SCC SW900 cells, as well as this treatment attenuated lung foamy macrophage numbers and dampened lung SCC development in irradiated KA/KA mice with KA/KA bone marrow transplants. These findings highlight that the interplay between CD4 T cells, macrophages, cytokines, and epithelial cells contribute to a series of biological events in a landscape scale, which promote lung disease and lung SCC development through aberrant lipid metabolism. Citation Format: Gongping Shi, Sayantan Banerjee, Xin Li, Gajendra Jogdand, Yongmei Zhao, Kunio Nagashima, Thorkell Andresson, Jyoti Shetty, Bao Tran, Yinling Hu. Lipid-rich foamy macrophages along with CD4 T cell-derived signaling drive aberrant lipid metabolism and are a cause of lung cancer development [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 1355.
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Higgins, Taylor-Jade, Jayesh Sharma, Elizabeth R. Zhang-Velten, Sarah Elliott, Junjie Ma, Jun Chen, Gabriele Schiattarella, et al. "Abstract 3584: Early and non-invasive detection of radiation-induced cardiotoxicity in pre-clinical and clinical models." Cancer Research 83, no. 7_Supplement (April 4, 2023): 3584. http://dx.doi.org/10.1158/1538-7445.am2023-3584.
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Abstract Background: Nearly half of all patients receive radiation therapy as a component of their cancer care. Despite the efficacy of radiation therapy as a cancer treatment, cardiotoxicity is a major concern in patients receiving chest radiotherapy. There are currently no standardized approaches for early detection of radiation-induced cardiotoxicity as a stage that offers potential for early intervention. In this study, we employ hyperpolarized 13C- pyruvate magnetic resonance spectroscopy to non-invasively characterize early metabolic changes in the heart in response to radiation. Methods: We established a pre-clinical model of radiation induced heart disease (RIHD) by performing whole heart irradiation (8Gy x 5) in rats. Echocardiography was used characterize mechanical changes in the heart following radiation. To non-invasively detect myocardial mitochondrial dysfunction following cardiac irradiation in vivo, we employed hyperpolarized 13C- pyruvate magnetic resonance spectroscopy (MRS) to track the fate of pyruvate, an intermediate of glucose metabolism, as it is metabolized in the heart. Hyperpolarized 13C- pyruvate MRS was also employed in a patient who received thoracic radiation for treatment of thymoma to non-invasively study changes in glucose metabolism in response to radiation. Results: We identified evidence of early cardiac mitochondrial dysfunction prior to onset of mechanical changes in the heart. Following cardiac irradiation, due to mitochondrial dysfunction, pyruvate was preferentially metabolized to lactate in the cytoplasm (as opposed to bicarbonate in the mitochondria in non-irradiated hearts). The ratio of products of 13C- pyruvate metabolism in the mitochondria and cytoplasm as ascertained by hyperpolarized 13C- pyruvate MRS served as a biomarker for metabolic dysfunction in the heart both in a pre-clinical rat model and in a patient who received thoracic radiation. Conclusions: We have developed a non-invasive approach for detection of cardiac mitochondrial dysfunction, which may serve as a biomarker for early detection of radiation-induced cardiotoxicity, and shown feasibility in a human patient. Clinical adoption of this approach may enable early identification of patients who are at high risk for future cardiac complications and may benefit from mitigation strategies. Citation Format: Taylor-Jade Higgins, Jayesh Sharma, Elizabeth R. Zhang-Velten, Sarah Elliott, Junjie Ma, Jun Chen, Gabriele Schiattarella, Chantal Vidal, Nan Jiang, Daniel Daou, Joseph Hill, Thomas Gillette, Craig Malloy, Vlad Zaha, Jae Mo Park, Prasanna Alluri. Early and non-invasive detection of radiation-induced cardiotoxicity in pre-clinical and clinical 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 3584.
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Breedy, Sloan, Wishrawana S. Ratnayake, Luke Lajmi, Robert Hill, and Mildred Acevedo-Duncan. "Abstract 2555: 14-3-3 and Smad2/3 are key mediators of atypical-PKCs in neuroblastoma progression." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2555. http://dx.doi.org/10.1158/1538-7445.am2023-2555.
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Abstract Neuroblastoma (NB) is a cancer that develops in the neuroblasts. It is the most common cancer in children under the age of 1 year, accounting for approximately 6% of all cancers. The prognosis of NB is linked to both age and degree of cell differentiation. This results in a range of survival rates for patients, with outcomes ranging from recurrence and mortality to high survival rates and tumor regression. Our previous work indicated that PKC-ι promotes cell proliferation in NB cells through the PKC-ι/Cdk7/Cdk2 cascade. We report on two atypical protein kinase inhibitors as potential therapeutic candidates against BE(2)-C and BE(2)-M17 cells: a PKC-ι-specific 5-amino-1-2,3-dihydroxy-4-(methylcyclopentyl)-1H-imidazole-4-carboxamide (ICA-1S) and a PKC-ζ specific 8-hydroxy-1,3,6-naphthalenetrisulfonic acid (ζ-Stat). In the current study, we report the effects of aPKC inhibition on 14-3-3-centered signaling in NB progression. To this end we utilized various techniques such as western blotting, Flowcytometry, scratch assays and invasion assays. These assays were employed to assess the downstream implications of aPKCs and 14-3-3 attenuation on signaling pathways regulating proliferation, cell cycle regulation, apoptosis, and metastasis. Both compounds induced apoptosis and retarded the epithelial-mesenchymal transition (EMT) of NB cells. Proteins 14-3-3 and Smad2/3 acted as central regulators of aPKC-driven progression in BE(2)-C and BE(2)-M17 cells in relation to the Akt1/NF-κB and TGF-β pathways. We demonstrate the downstream effects of aPKC attenuation on aPKC phosphorylation, the Akt1/NF-κB pathway, the Cdk7/Cdk2 pathway and EMT in relation to 14-3-3 and Smad2/3. We have analyzed the expression of EMT markers including Vimentin, a mesenchymal marker that is a hallmark of cancer metastasis. Data indicates that aPKCs upregulate Akt1/NF-κB and TGF-β pathways in NB cells through an association with 14-3-3 and Smad2/3 that can be diminished by aPKC inhibitors. In summary, both inhibitors appear to be promising potential neuroblastoma therapeutics and merit further research. Citation Format: Sloan Breedy, Wishrawana S. Ratnayake, Luke Lajmi, Robert Hill, Mildred Acevedo-Duncan. 14-3-3 and Smad2/3 are key mediators of atypical-PKCs in neuroblastoma progression [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 2555.
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Kwant, Kathryn Strobel, Sony S. Rocha, Timothy Yu, Katrina Stephenson, Raphaela Rose Banzon, Sydney Vollhardt, Golzar Hemmati, et al. "Abstract 2861: TriTAC-XR: An extended-release T cell engager platform designed to minimize cytokine release syndrome." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2861. http://dx.doi.org/10.1158/1538-7445.am2022-2861.
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Abstract CD3-targeted T cell engagers are potent anti-tumor therapies, but their development often requires management of cytokine release syndrome (CRS). One strategy to reduce CRS is subcutaneous dosing, which is hypothesized to mitigate CRS by reducing the maximum drug concentration (Cmax) and preserve efficacy by maintaining the same minimum drug concentration (Cmin) as intravenous dosing. Although promising for mitigating CRS, this approach is limited by its increased immunogenicity risks. A T cell engager designed to be dosed intravenously but engineered to mimic the PK properties of subcutaneous dosing could alleviate CRS without increasing immunogenicity. Here we describe TriTAC-XR, a platform of T cell engager prodrugs designed to become slowly activated in systemic circulation. This extended-release mechanism results in a slow build-up of circulating active drug and minimizes the Cmax/Cmin ratio, similar to subcutaneous dosing. TriTAC-XR prodrugs were engineered by adding a peptide mask and protease-cleavable linker to the N-terminus of a TriTAC, a constitutively active and half-life extended T cell engager. The mask binds to the anti-CD3ε domain and inhibits T cell binding. Upon cleavage by systemic proteases, active T cell engager is released. In vitro, TriTAC-XR has markedly reduced binding to recombinant CD3ε protein and to primary T cells as well as reduced potency in functional T cell-dependent cellular cytotoxicity (TDCC) assays compared to its unmasked active drug. In cynomolgus monkeys, TriTAC-XRs targeting multiple tumor antigens resulted in a gradual build-up of active drug during the first week post dose and significantly lower Cmax/Cmin ratios than comparable constitutively active TriTACs. Modeling based on these PK data predicts that TriTAC-XR dosed intravenously will result in a slower build-up of active drug and smaller Cmax/Cmin ratios than TriTAC dosed intravenously or subcutaneously. Cytokine release and target cell depletion in cynomolgus monkeys were used to compare the therapeutic index of TriTAC-XR to TriTAC. A single dose of FLT3-targeting TriTAC-XR resulted in 100-fold protection in cytokine release and similar FLT3 expressing cell depletion when compared to an equivalent FLT3-targeting TriTAC. Similarly, repeat dosing of a TriTAC-XR targeting B cells resulted in complete B cell depletion with substantially lower cytokines than a comparable TriTAC. TriTAC-XR is expected to improve the safety of T cell engagers by reducing CRS and may increase clinical dosing convenience by enabling higher doses that will extend dosing intervals. Citation Format: Kathryn Strobel Kwant, Sony S. Rocha, Timothy Yu, Katrina Stephenson, Raphaela Rose Banzon, Sydney Vollhardt, Golzar Hemmati, Evan Callihan, Wade H. Aaron, Subramanian Thothathri, Jessica O'Rear, Eric Bragg, Willis Kwong, Hubert Situ, Avneel Hundal, Stephen Yu, Taggra Jackson, Kevin Carlin, Yinghua Xiao, Maria Rosalyn Dayao, Linh To, Nick Bergo, Kevin Wright, Richard Austin, Holger Wesche, Bryan Lemon, S. Jack Lin. TriTAC-XR: An extended-release T cell engager platform designed to minimize cytokine release syndrome [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 2861.
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Rocha, Sony S., Regina Lin, Maria R. Dayao, Raphaela Rose Banzon, Subramanian Thothathri, Kevin J. Wright, Wade Aaron, et al. "Abstract 2928: TROP2 ProTriTAC™, a protease-activated T cell engager prodrug targeting TROP2 for the treatment of solid tumors." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2928. http://dx.doi.org/10.1158/1538-7445.am2023-2928.
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Abstract Tumor-associated calcium signal transducer 2 (Trop2) is a cell surface glycoprotein that promotes cell renewal, proliferation and tumorigenesis. Trop2 is homogenously overexpressed in numerous solid tumor types, including breast, head and neck, prostate, bladder, and non-small cell carcinoma; however, Trop2 is also expressed in several normal tissues, including skin, respiratory tract, and female reproductive organs. Although Trop2-targeted antibody drug conjugates (ADCs) have demonstrated clinical activity, with regulatory approvals in subsets of breast and bladder cancers, their broader utility is still hampered by off-target payload-mediated toxicities. To address this issue, and to avoid on-target off-tumor toxicities, we developed a Trop2-targeting ProTriTAC™ (Protease-activated Tri-specific T cell Activating Construct), a T cell engager prodrug which is engineered to be preferentially activated in tumor tissue. ProTriTACs consists of three humanized antibody-derived binding domains on a single polypeptide chain: anti-albumin for half-life extension, anti-CD3 for T cell engagement, and anti-target antigen for tumor cell engagement. The anti-albumin domain, bearing a masking moiety and a protease-cleavable linker, keeps the prodrug inert by inhibiting binding of the adjacent anti-CD3 domain to T cells. Cleavage of the linker by tumor-associated proteases removes the anti-albumin domain along with the masking moiety to reveal a potent active drug that directs T cell killing within the tumor. As designed, in vitro binding and functional assays show that the protease-activated T cell engager has >1000-fold improved binding to primary human T cells and ~100-fold improved T cell killing compared to its intact masked prodrug. In immunodeficient mice reconstituted with human T cells, anti-Trop2 ProTriTAC demonstrated robust anti-tumor activity in multiple xenograft tumor models, including HCC70 (breast), CAL27 (head and neck), and HPAFII (pancreatic), with complete tumor regression as low as 30 μg/kg. To determine the potential toxicity and toxicokinetic characteristics of anti-Trop2 ProTriTAC, an intra-animal dose escalation was conducted in cynomolgus monkeys until individual maximum tolerated dose (MTD). The starting dose was 20 μg/kg with weekly 3-fold dose escalations until MTD. The one-month study revealed that anti-Trop2 ProTriTAC was tolerated at the 180 μg/kg dose level, but not at the next higher dose level of 540 μg/kg. Toxicokinetics, gross pathology, histopathology, and cytokine data will be presented. The preclinical activity in rodent tumor models, coupled to its tolerability in cynomolgus monkeys, support the development of anti-Trop2 ProTriTAC as a therapeutic in a broad range of Trop2-expressing solid tumors. Citation Format: Sony S. Rocha, Regina Lin, Maria R. Dayao, Raphaela Rose Banzon, Subramanian Thothathri, Kevin J. Wright, Wade Aaron, Yinghua Xiao, Nick Bergo, Linh To, Mabel Bush, Manasi Barath, Timothy Yu, Willis Kwong, Hubert Situ, Eric Bragg, Jessica O'Rear, Kevin Carlin, Stephen Yu, Maritza Solorio, Bryan Lemon, Richard Austin, Holger Wesche, S. Jack Lin. TROP2 ProTriTAC™, a protease-activated T cell engager prodrug targeting TROP2 for the treatment of solid tumors [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 2928.
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Scott, Nina, Myra Ruka, and Amy R. Jones. "Abstract 5278: Cancer WHIRI research: Improving the early cancer pathway for indigenous NZ peoples." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5278. http://dx.doi.org/10.1158/1538-7445.am2022-5278.
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Abstract Background: Māori, Indigenous peoples of New Zealand (NZ) are twice as likely to die after a diagnosis of cancer compared to non-Māori. Cancer pathways are not designed for Māori health gain and are not pandemic resilient. Māori receive delayed poorer quality treatment and those with comorbidities are undertreated [1]. Existing inequities from time of referral to cancer services through to treatment were exacerbated by the COVID-19 response in Aotearoa NZ. Coordination of care is crucial for Māori patients and whānau (family), but poorly developed along this early part of the cancer pathway. In addition, care quality is not well monitored, and the current pathway is vulnerable to changes created by pandemic conditions. Aims: This study seeks to co-design, implement and evaluate a holistic cultural and clinical cancer service that is patient and whānau centred; the Whānau Hauora Integrated Response Initiative (WHIRI) programme. This comprehensive, pandemic resilient, racism-free, hauora (wellbeing) enhancing and responsive model of care will be designed for the early part of the secondary care cancer pathway. Design and Method: The WHIRI programme includes navigation, a holistic whānau/family hauora assessment tool, proactive management by a team of clinicians and a team responsible for making systems changes. WHIRI was launched mid-pandemic (early 2020) for kaumātua (elderly Māori) with long-term conditions and ran for 3 months. During COVID we found that WHIRI had the potential to change hospital systems and improve experiences for patients and whānau. WHIRI ensures the provision of best-practice timely treatment for Māori patients and could make large gains in closing the survival gap between Māori and non-Māori in the short- to medium-term, leading to reductions in Māori cancer deaths. We plan to redesign WHIRI into a cancer programme that functions effectively in all COVID levels using qualitative Kaupapa Māori methodology. Key to this methodology is partnerships with patients, whānau, cancer clinicians, Māori navigators and The Cancer Control Agency New Zealand. We will present our methods and co-design model of cancer care. We will outline the potential to expand the model nationally with reach from primary care all the way through to palliative care. It will also provide a platform for future research to measure the impact of WHIRI on cancer and whānau care. 1. Hill S, Sarfati D, Blakely T, Robson B, Purdie G, Chen J, et al. Survival disparities in Indigenous and non-Indigenous New Zealanders with colon cancer: the role of patient comorbidity, treatment and health service Citation Format: Nina Scott, Myra Ruka, Amy R. Jones. Cancer WHIRI research: Improving the early cancer pathway for indigenous NZ peoples [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 5278.
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Elgamal, Ola A., Sandip Vibhute, Sydney Fobare, Abeera Mehmood, Mariah L. Johnson, Jean Truxall, Emily Stahl, et al. "Abstract 1060: Introducing a novel DHODH inhibitor with superior in vivo activity as monotherapy or in novel combination regimen with immunotherapy for hematological malignancies." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1060. http://dx.doi.org/10.1158/1538-7445.am2022-1060.
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Abstract Acute myeloid leukemia (AML) is characterized by the uncontrolled expansion of un-differentiated hematopoietic progenitor myeloblasts. AML treatment is very challenging owing to its complex heterogeneity resulting in a dismal 5-year overall survival rate particularly in elderly patients unfit for standard induction chemotherapy. The expansion of AML requires the availability of sufficient nucleotides supporting the anabolic processes required for AML growth thus, targeting nucleotide biosynthesis can halt AML progression. Indeed, targeting dihydroorotate dehydrogenase (DHODH), a critical rate-limiting step in the de novo pyrimidine synthesis pathway not only induced cytotoxicity but has been shown to promote blast differentiation in a HOXA9/MEIS1 over-expressing model. We sought to develop a DHODH inhibitor that had superior properties to those reported for AML therapy. Compound 41 (cmpd 41) demonstrates sub-nanomolar 50% inhibitory concentration for DHODH biochemical activity and potent in vitro activity across several AML cell lines and primary AML cells independent of mutational subtype, including mutated TP53. Cmpd 41 also demonstrated superior in vivo anti-leukemic activity in multiple AML xenograft models as monotherapy and demonstrated synergy with a hypomethylating agent, decitabine in TP53 mutated AML. Given the heterogeneity of AML and frequent emergence of resistant clones, we aimed to investigate ways to enhance response to DHODH inhibitors through combination. After in vitro treatment of AML cell lines and primary patient samples with DHODH inhibitors, we observed an increase in CD38 surface expression suggesting synergy with CD38 targeting monoclonal antibody (mAb) immunotherapies. Indeed, we are the first to report synergy between DHODH inhibitors and anti-CD38 mAb in AML which emphasizes the synergy between this promising novel class of agents with immunotherapies via recruiting innate immunity. Consequently, given the relevance of CD38 mAb therapy to multiple myeloma (MM), we extended these studies to MM and remarkably found that cmpd 41 was highly efficacious as a monotherapy and in combination with CD38 mAb, resulted in complete tumor regression in a subcutaneous MM xenograft model. In summary, we introduce a best in class DHODH inhibitor with a data-driven combination strategy for both AML and MM. Our studies suggest a highly synergistic combination strategy involving immunotherapy for AML and other hematologic malignancies. Citation Format: Ola A. Elgamal, Sandip Vibhute, Sydney Fobare, Abeera Mehmood, Mariah L. Johnson, Jean Truxall, Emily Stahl, Bridget Carmichael, Shelley J. Orwick, Ramasamy Santhanam, Kasey Hill, Susheela Tridandapani, Christopher C. Coss, Alice S. Mims, Karilyn T. Larkin, Mitch A. Phelps, Sharyn D. Baker, Alex Sparreboom, Thomas E. Goodwin, Gerard Hilinski, Chad E. Bennett, Erin Hertlein, John C. Byrd. Introducing a novel DHODH inhibitor with superior in vivo activity as monotherapy or in novel combination regimen with immunotherapy for hematological malignancies [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 1060.
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Bichoo, Raouef Ahmed, Mohammed Bilal Elahi, Dorin Dumitru, Naila Bint Ihsan, Eiman Khalifa, Masuma Sarker, Tapan K. Mahapatra, Brendan Paul Wooler, Peter Kneeshaw, and Kartikae Grover. "Abstract P1-01-06: Predictor of sentinel node positivity in screen-detected invasive breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): P1–01–06—P1–01–06. http://dx.doi.org/10.1158/1538-7445.sabcs21-p1-01-06.
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Abstract Introduction: Sentinel lymph node biopsy represents the standard of care for staging axilla in breast cancer patients who are clinically node negative. ACOSOG Z11 trial results questioned the importance of low burden nodal disease. Results from the SOUND trial on omission of axillary surgery in selected patients with early stage breast cancer are still awaited. Breast screening programs aim to detect cancers at an early stage and are expected to have low burden of nodal disease. The aim of our study was to determine predictors of sentinel node biopsy positivity in invasive breast cancers detected on screening mammography. Methods: This retrospective study included patients with node negative invasive breast cancer detected on screening mammogram performed between April 2018 and March 2020 and subsequently underwent curative surgery including sentinel node biopsy at breast care unit of Castle Hill Hospital, Cottingham, U.K. We looked at patient’s clinical, radiological and pre-operative pathological features and correlated them with histological results of sentinel node biopsy. Statistical analysis of the data was performed using SPSS version 22 and p-value of 0.05 was considered significant. Results: We identified 304 patients who met inclusion criteria. The mean age of these patients was 62.71 ± 7.2 years (range 47-78 years). Majority (88%) of women were postmenopausal. Overall, the sentinel node positivity rate was 11.76%. Women over the age of 55 years were less likely to be node positive compared to younger women (9.9% vs 22%, p=0.016). Tumours less than 10mm in size had node positive rate of 5.5% compared to tumour larger than 21mm (25%, p = 0.000). In comparison to grade 2and grade 3 tumours, grade 1 tumours had lower node positivity rate, (5% vs 14.4%) but the difference did not reach statistical significance (p= 0.073). All women with tubular and mucinous histological subtypes (n=13) were node negative. All women with grade 1 tumours less than 10mm in size (n=48) had a negative sentinel node biopsy compared to women with grade 2 tumors more than 20mm (9/32=28% positivity rate) and p-value of 0.000. There was no association between oestrogen, progesterone and HER2 receptor status with sentinel lymph node positivity rate. Conclusion: In selected screen detected patients including those above the age of 55 years, having grade 1 cancer, and less than 10 mm size on pre-treatment imaging, there might be scope for omission of axillary surgery. Citation Format: Raouef Ahmed Bichoo, Mohammed Bilal Elahi, Dorin Dumitru, Naila Bint Ihsan, Eiman Khalifa, Masuma Sarker, Tapan K Mahapatra, Brendan Paul Wooler, Peter Kneeshaw, Kartikae Grover. Predictor of sentinel node positivity in screen-detected invasive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-01-06.
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Veenstra, David L., Nathaniel Hendrix, Chantal M. Dolan, Kathryn Fisher, Deepa Lalla, Nina Hill, and Beverly Moy. "Abstract P3-16-01: Population effectiveness model of the consequences of recurrence after trastuzumab emtansine (T-DM1) treatment among U.S. patients with high-risk HER2+ early-stage breast cancer (ESBC)." Cancer Research 82, no. 4_Supplement (February 15, 2022): P3–16–01—P3–16–01. http://dx.doi.org/10.1158/1538-7445.sabcs21-p3-16-01.
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Abstract Background: To estimate the long-term consequences of disease recurrence following treatment with adjuvant T-DM1 among U.S. patients with high-risk HER2+ ESBC who did not achieve pathologic complete response (pCR) after neoadjuvant therapy. Methods: A Markov model was used to simulate local/regional and distant recurrence with 10 years of follow-up. This corresponds to the estimated number of U.S. patients with incident high-risk HER2+ ESBC in 2021 (n = 10,000), which was derived from SEER population-based estimates, the NEOSPHERE trial and expert clinical opinion. The probability of recurrence was based on the T-DM1 arm in the KATHERINE trial and long-term results from the HERA trial. We assumed that 80% of patients with any recurrence experience distant recurrence, while the remainder have local/regional recurrence. SEER data and literature review were used to estimate probabilities of survival, distant recurrence secondary to local/regional recurrence, and direct medical costs. We estimated indirect costs were equal to 15% of direct medical costs. Model outcomes included: recurrences, breast cancer-related deaths, non-breast cancer-related deaths, direct medical costs, and indirect costs (all undiscounted). Results were compared to a scenario in which there was no recurrence to estimate population impact. All outcomes were also projected over 10 annual incident cohorts, each with 10 years of follow-up. Results: We estimated the 2021 U.S. patient cohort would experience 2,279 recurrences, including 1,834 distant, and 1,559 breast cancer-related deaths over 10 years, resulting in 7,744 lost years of life and $632 million in additional spending, including $549 million in direct medical costs. Projection to 10 years of incident cohorts would lead to approximately 23,000 recurrences, 16,000 deaths, 77,000 lost years of life and $6 billion in direct medical costs. Conclusions: Patients with HER2+ ESBC who do not achieve pCR after neoadjuvant therapy are at ongoing risk of recurrence despite the effectiveness of treatment with T-DM1. There is substantial clinical and economic value in further reducing the recurrence risk among this population. Findings for 2021 Cohort Projected over 10 YearsWith recurrenceNo recurrenceDifferenceLocal/regional recurrences4450445Distant recurrence1,83401,834Breast cancer deaths1,55901,559Non-breast cancer deaths416457-41Direct costs$573M$24M$549MIndirect costs$86M$3.6M$82MLife years90,24997,993-7,744Costs$659M$27M$632M Citation Format: David L Veenstra, Nathaniel Hendrix, Chantal M Dolan, Kathryn Fisher, Deepa Lalla, Nina Hill, Beverly Moy. Population effectiveness model of the consequences of recurrence after trastuzumab emtansine (T-DM1) treatment among U.S. patients with high-risk HER2+ early-stage breast cancer (ESBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-16-01.
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Pathak, Lekhika, Tutumoni Baishya, Partha Saikia, Nihar Ranjan Das, Sailen Baishya, Rupam Das, Pragya Dutta, et al. "Abstract 2772: The development of immunotherapy agents from the indigenous herbal plants and microbes used by the tantric practitioner of Vedic Jiva Upakara Cikitsha Tantra (Vedic altruism-based medicine system) of Assam, India." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2772. http://dx.doi.org/10.1158/1538-7445.am2023-2772.
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Abstract The ancient India's indigenous tantric community had its unique medicinal philosophy as well as clinical practice, distinct from Ayurveda. One such tantric community was Assam's Vedic Jiva Upakarvada practitioners (1). These practitioners developed an unique health care practice in the silk village of Sualkuchi, and the adjoining area, a part of the Vedic Silk Road (the North-South Silk Road stretching from Tibet to South East Asia via India's Assam state). We have been systematically studying the medical practice of these healing practitioners for the last two decades (1). These practitioners used more than 36 different plant-derived products, as well as soil, plus fecal and urine products rich in diverse microbial communities. They postulated that these agents contain good nigudah (1), microscopic life forms that can activate Avatar Kosha in our body (1). Using our pre-clinical in vitro as well as mouse model of cancer stem cells (2-4), we have screened 12 out of 36 plants, as well as microbial-rich soil of a sacred hill area frequented by tantric practitioners to collect herbal plants, animal feces and soils (the Suad muni ashram area of Sualkuchi). Here we report our preliminary results of the screening of these ingredients for their potential immunotherapy uses. Method: These herbal plants/soils/animal feces items were dissolved in the RPMI culture media using a traditional method using water, as well as special plant-derived juices. The conditioned RPMI culture media was then used to culture CSCs of tumor stemness defense (TSD) phenotype (2). Results: Our preliminary results show that while some of the agents induce apoptosis of TSD, other agents are capable of inducing TSD phenotypes to CSCs of diverse tumors including oral cancer (SCC-25 cell line), breast cancer (MCF-7) and colon cancer cell line (LOVO). Conclusion: The traditional healer used products may have unique anti-cancer including immuno-activating properties that need further exploration. We are now using our mouse models to find out if some of these agents including unique microbes present in these agents may transform cold tumors into hot or immunogenic tumors. 1. https://www.biorxiv.org/content/10.1101/2020.11.14.382572v1.full.pdf 2.PMID: 36248858 3. PMID: 28884113. 3. PMID: 31387932. 4. PMID: 31266772 Citation Format: Lekhika Pathak, Tutumoni Baishya, Partha Saikia, Nihar Ranjan Das, Sailen Baishya, Rupam Das, Pragya Dutta, Chayanika Das, Mallika Maral, Gakul Das, Bikul Das. The development of immunotherapy agents from the indigenous herbal plants and microbes used by the tantric practitioner of Vedic Jiva Upakara Cikitsha Tantra (Vedic altruism-based medicine system) of Assam, India [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 2772.
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Lucas, Olivia, Sophie Ward, Rija Zaidi, Mark Hill, Emilia Lim, Haoran Zhai, Abigail Bunkum, et al. "Abstract 4277: Measuring proliferation rates of distinct tumour clones using single-cell DNA sequencing." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4277. http://dx.doi.org/10.1158/1538-7445.am2023-4277.
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Abstract Background: Tumour proliferation rate is a key phenotypic feature of cancer, with higher rates linked to poorer clinical outcomes. Thus far, proliferation rates have been measured using pathological or experimental techniques on bulk tumour samples. However, while tumours are heterogeneous compositions of distinct clones with varying levels of fitness, measuring the proliferation of individual clones has not been possible to date. We hypothesise that enabling the identification of the most proliferative clones would reveal genomic hallmarks of aggressive clones, or the prediction of their potential phenotype, e.g., metastatic potential. Methods: We have developed SPRINTER (Single-cell Proliferation Rate Inference in Neoplasms Through Evolutionary Routes), a novel computational method to measure proliferation rates in individual tumour clones using single-cell whole-genome DNA sequencing. To assess the accuracy and power of SPRINTER, we have also developed an experimental approach to DNA sequence >18,000 single cells, accurately separated in different DNA-replication phases. We have sequenced and applied SPRINTER to >10,000 non-small cell lung cancer cells from longitudinal and metastatic tumour samples within the TRACERx study and PEACE autopsy programme. We have further analysed published data from >10,000 breast cancer cells. Results: We demonstrate that SPRINTER can accurately identify subpopulations of cells with different proliferation rates using relatively small numbers of cells, in contrast to previous preliminary approaches. While our estimates are concordant with previous bulk experimental studies (5-40%), we importantly have identified clonal heterogeneity in proliferation rates. Using bulk analysis, we have identified patterns of dissemination of tumour clones in non-small cell lung cancer. Integrating this with single-cell data, our results indicate that more widely disseminating tumour clones have higher proliferation rates, suggesting a link between proliferation and dissemination potential. We additionally find that clones are more proliferative in the metastatic versus the primary setting. Furthermore, we have identified high proliferation clones that may have a selective advantage in a breast tumour, and have inferred that they likely arose recently in cancer evolution. Conclusions: We have developed a novel method that enables accurate identification of proliferation rates of individual tumour clones using single-cell DNA sequencing data, allowing the investigation of genomic hallmarks in highly proliferative clones that might lead to higher fitness. Citation Format: Olivia Lucas, Sophie Ward, Rija Zaidi, Mark Hill, Emilia Lim, Haoran Zhai, Abigail Bunkum, Sonya Hessey, Michelle Dietzen, Andrew Rowan, Cristina Naceur-Lombardelli, Nnenna Kanu, Mariam Jamal-Hanjani, Charles Swanton, Simone Zaccaria. Measuring proliferation rates of distinct tumour clones using single-cell DNA sequencing. [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 4277.
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Lucas, Olivia, Sophia Ward, Rija Zaidi, Abigail Bunkum, Alexander M. Frankell, David A. Moore, Mark S. Hill, et al. "Abstract PR010: Linking proliferation rate to the evolution of single-cell primary and metastatic tumor clones." Cancer Research 84, no. 3_Supplement_2 (February 1, 2024): PR010. http://dx.doi.org/10.1158/1538-7445.canevol23-pr010.
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Abstract Proliferation is a key phenotypic feature of cancer, with higher rates associated with poorer clinical outcomes. Thus far, proliferation rates have been measured using pathological or experimental techniques on bulk tumor samples. However, tumors are heterogeneous compositions of distinct clones. Measuring the proliferation of individual clones has been unfeasible to date since proliferation and clonal diversity cannot easily be measured for the same set of cells, but it is potentially important as it may allow the identification of clones that develop more aggressive phenotypes (e.g., metastatic potential or treatment resistance). We have developed SPRINTER, a novel algorithm that uses single-cell whole-genome DNA sequencing (scDNA-seq) data to enable the accurate identification of actively replicating cells in both the S and G2 phases of the cell cycle and their assignment to distinct tumor clones, thus providing a proxy to estimate clone-specific proliferation rates. To evaluate SPRINTER’s accuracy, we generated a ground truth dataset of 8,844 diploid and tetraploid cancer cells by coupling scDNA-seq with 5-Ethynyl-2-deoxyuridine (EdU) labeling, and demonstrated that SPRINTER can accurately distinguish clone proliferation rates in contrast to previous approaches. We further generated a longitudinal, primary-metastasis matched dataset of 23,001 cancer cells obtained from 5 samples from the primary tumor and 5 samples from distinct metastases from a patient with non-small cell lung cancer, allowing us to integrate analyses of proliferation and cancer evolution through the metastatic disease course. We revealed widespread heterogeneity in clone proliferation rates both between and within samples, supported by multiple orthogonal analyses including Ki-67 pathology, nuclei microscopy imaging, and patient clinical imaging, with high proliferation seen in fast-growing metastatic lesions. We demonstrated an association between clones with high proliferation and increased metastatic potential, as well as increased shedding of circulating tumor DNA. We further illustrated SPRINTER’s broad applicability on previous datasets of 42,009 breast cancer cells and 19,905 ovarian cancer cells, revealing an association between high proliferation and increased rates of different genetic variants. In conclusion, SPRINTER infers the proliferation rates of distinct tumor clones from scDNA-seq data, allowing the identification of clones with potentially aggressive phenotypes, such as metastatic potential. Citation Format: Olivia Lucas, Sophia Ward, Rija Zaidi, Abigail Bunkum, Alexander M. Frankell, David A. Moore, Mark S. Hill, Wing Kin Liu, Daniele Marinelli, Emilia L. Lim, Sonya Hessey, Cristina Naceur-Lombardelli, Andrew Rowan, Sukhveer Mann, Haoran Zhai, Michelle Dietzen, Boyue Ding, Gary Royle, Nicholas McGranahan, Mariam Jamal-Hanjani, Nnennaya Kanu, Charles Swanton, Simone Zaccaria. Linking proliferation rate to the evolution of single-cell primary and metastatic tumor clones [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr PR010.
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Evans, Edward James, Fabio Marongiu, Emilia Lim, Oriol Pich, Yonghua Zhuang, Dexiang Gao, William Hill, et al. "Abstract 3934: Smoking's influence on divergent paths to lung cancer." Cancer Research 84, no. 6_Supplement (March 22, 2024): 3934. http://dx.doi.org/10.1158/1538-7445.am2024-3934.
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Abstract Lung cancer is the leading cause of cancer mortality in the world. Many studies have highlighted how mutagens from cigarette smoke promote specific mutations such as G12 mutations in KRAS, contributing to clonal evolution that leads to lung cancer. Despite the indisputable correlation between smoking and lung cancer, people who have never smoked account for the 7th leading cause of cancer mortality. Given the differences in predominant exposures, we hypothesize that the clonal evolution between people with and without smoking histories are markedly different. Therefore, we analyzed lung samples from people with different cigarette smoking exposure to elucidate smoking’s effect on the somatic mutational landscape in the progression to lung cancer. To observe somatic mutations subjected to different exposures of smoking, we used a rare-mutation detection technique called DuplexSeq to analyze somatic variants from 200+ lung samples. We acquired DNA from cells from bronchoscopy brushings and lung punches of histologically normal tissue from people with and without lung cancer and who currently, formerly, or never smoked cigarettes. Through collaborations, we characterized mutations using bioinformatic pipelines, various databases, and statistical methods. In samples from people who smoke, we observe an enhancement of mutations with higher variant allele frequencies and pervasive positive selection acting on mutations in many cancer-associated genes. From our bronchoscopy brushings, NOTCH1 mutations show the most definitive increase of protein-altering variants, while NF1 and KRAS show a predominance of driver mutation in lung punches. Unexpectedly, people without lung cancer who never smoked had a notable presence of pathogenic mutations in PTEN and PIK3CA. Furthermore, multiple punches from the same individual highlight how expansions of mutations have stronger similarity within an individual than across individuals regardless of smoking status. This association points to the importance of the inherent lung microenvironment in influencing the mutational landscapes in lung cancer progression. Altogether, these results show how smoking increases the oncogenicity of observable mutations in the lung but does not preclude the presence of oncogenic clones, emphasizing the value of precision diagnoses and prevention. Ongoing research will be centered around functional assays to determine the impact of observed mutations on tissue function and longitudinal studies using mutational landscapes as a proxy for lung cancer risk. Citation Format: Edward James Evans, Fabio Marongiu, Emilia Lim, Oriol Pich, Yonghua Zhuang, Dexiang Gao, William Hill, Cian Murphy, Ryan Turner, Moumita Ghosh, York Miller, Mariam Jamal-Hanjani, Charles Swanton, James DeGregori. Smoking's influence on divergent paths to lung 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 3934.
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Ratcliffe, Laura, Rachel Pooley, Katherine Carr, Hamed Janbazacyabar, David Cobeta Lopez, Deborah Bruce, Sarah L. Martin, et al. "Abstract 5315: Bispecific antibody discovery platform for IND enabling studies: Case study of HER-2/NKG2D bispecific antibody." Cancer Research 84, no. 6_Supplement (March 22, 2024): 5315. http://dx.doi.org/10.1158/1538-7445.am2024-5315.
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Abstract There has been a surge in the number of therapeutic antibody modalities primarily attributable to the increasing array of antibody engineering platforms. Among these, the emergent class of bispecific antibodies has exhibited remarkable potential compared to conventional monoclonal antibodies, marked by their targeting precision, expanded therapeutic scope, and personalized medicine prospects. Presently, eight bispecific antibodies are approved, with over 100 in varying clinical trial phases. Using a bispecific targeting HER-2 and NKG2D, we outline a comprehensive end-to-end platform for bispecific antibody discovery and characterization, designed to facilitate the progression of novel bispecific antibodies through the antibody discovery pipeline. To secure the most optimal binders tailored to specific targets, our methodology capitalizes on an extensive repertoire of phage display libraries. This strategy is instrumental in the identification of antibody candidates with exceptional binding affinity, broad cross-species compatibility, and enhanced drug-like properties. From the anti-HER2 chimeric antigen receptor ML39 and anti-NKG2D Fab KYK2.0, we synthesized four distinct bispecific formats by fusing single-chain variable fragments (scFv) to immunoglobulin G (IgG) molecules. These formats varied in terms of valency and scFv positioning, allowing us to assess their impact on antibody expression, binding kinetics, and functional efficacy. Subsequently, the bispecific antibodies underwent comprehensive in vitro efficacy and safety characterization, employing multiple innovative technologies. Utilizing a distinctive label-free approach with the xCELLigence system, we elucidated the kinetics of immune cell-mediated target cell killing upon antigen-antibody complex recognition in specific cancer cells. Safety assessments, with a focus on on-target/off-tumor effects, were conducted using the Retrogenix platform. Furthermore, cytokine profiling was utilized to evaluate potential risks associated with enhanced cytokine levels, reinforcing the specificity and safety profile of the bispecific antibody. Finally, pertinent in vivo models, including peripheral blood mononuclear cells (PBMC) and immune cell transfer models, facilitated the translation of preclinical bispecific antibody evaluations into clinically relevant contexts. This comprehensive platform for bispecific antibody discovery and functional characterization serves as a robust foundation for supporting Investigational New Drug (IND) applications, thus facilitating the transition of novel bispecific antibodies from the pre-clinical to the clinical phase of the drug discovery process. Citation Format: Laura Ratcliffe, Rachel Pooley, Katherine Carr, Hamed Janbazacyabar, David Cobeta Lopez, Deborah Bruce, Sarah L. Martin, Matthew Benson, Jonathan White, Benita Quist, Sophie Vermond, Gemma Moiset, Sophie Hill, Renny Feldman, Paul Wan, Eva Oswald, Folkert Verkaar, Mark Aspinall-O'Dea, Julia Schueler, Namrata Jayanth. Bispecific antibody discovery platform for IND enabling studies: Case study of HER-2/NKG2D bispecific antibody [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 5315.
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Lin, Regina J., Sony S. Rocha, Maria R. Dayao, Subramanian Thothathri, Raphaela Rose Banzon, Kevin J. Wright, Wade Aaron, et al. "Abstract 2927: ITGB6 ProTriTAC™, a protease-activated T cell engager prodrug targeting Integrin-β6 for the treatment of solid tumors." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2927. http://dx.doi.org/10.1158/1538-7445.am2023-2927.
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Abstract Integrin-β6 (ITGB6) is a transmembrane protein that partners exclusively with the integrin-αV subunit to form the integrin-αVβ6 heterodimer. Due to its roles in tissue remodeling and cancer pathogenesis, therapeutic targeting of integrin-αVβ6 has been investigated for both fibrotic diseases and cancers. ITGB6 is homogenously overexpressed in numerous solid tumor types, including breast, head and neck, pancreatic, and non-small cell lung cancers. Additionally, its expression is an unfavorable prognostic marker in multiple cancers. However, past attempts to therapeutically target ITGB6 have been hindered by its expression in several normal tissues, including bladder, skin, lung, kidney, and muscle. For example, clinical testing of an integrin αVβ6-targeting monoclonal antibody was discontinued reportedly due to toxicity concerns. To reduce on-target/off-tumor toxicities from ITGB6 expression in normal tissues and to enable safe targeting of ITGB6 in solid tumors, we developed an ITGB6-targeting ProTriTAC™ (Protease-activated Tri-specific T cell Activating Construct), a T cell engager prodrug which is engineered to be preferentially activated in tumor tissue. ProTriTACs consists of three humanized antibody-derived binding domains on a single polypeptide chain: anti-albumin for half-life extension, anti-CD3 for T cell engagement, and anti-target antigen for tumor cell engagement. The anti-albumin domain, bearing a masking moiety and a protease-cleavable linker, keeps the prodrug inert by inhibiting binding of the adjacent anti-CD3 domain to T cells. Cleavage of the linker by tumor-associated proteases removes the anti-albumin domain along with the masking moiety to reveal a potent active drug that directs T cell killing within the tumor. As designed, in vitro binding and functional assays show that the protease-activated T cell engager has >1000-fold improved binding to human T cells and ~100-fold improved T cell killing compared to the intact masked prodrug. In immunodeficient mice reconstituted with human T cells, anti-ITGB6 ProTriTAC demonstrated robust anti-tumor activity in multiple ITGB6-expressing xenograft tumor models, including HCC70 (breast), CAL27 (head and neck), and HPAFII (pancreatic), with complete tumor regression as low as 30 μg/kg. To determine the potential toxicity and toxicokinetic characteristics of anti-ITGB6 ProTriTAC, an intra-animal dose escalation was conducted in cynomolgus monkeys. Starting at 20 μg/kg with weekly 3-fold dose escalations, anti-ITGB6 ProTriTAC was well tolerated up to 540 μg/kg, which was the highest dose tested. The preclinical activity in rodent tumor models, coupled to its tolerability in cynomolgus monkeys, support the development of anti-ITGB6 ProTriTAC as a therapeutic in a broad range of ITGB6-expressing solid tumors. Citation Format: Regina J. Lin, Sony S. Rocha, Maria R. Dayao, Subramanian Thothathri, Raphaela Rose Banzon, Kevin J. Wright, Wade Aaron, Yinghua Xiao, Nick Bergo, Linh To, Mabel Bush, Manasi Barath, Yi Yang, Timothy Yu, Willis Kwong, Hubert Situ, Eric Bragg, Jessica O'Rear, Kevin Carlin, Stephen Yu, Maritza Solorio, Bryan Lemon, Richard Austin, Holger Wesche, S. Jack Lin. ITGB6 ProTriTAC™, a protease-activated T cell engager prodrug targeting Integrin-β6 for the treatment of solid tumors [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 2927.
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Battaglia, Tracy A., Karen M. Freund, Jennifer S. Haas, and Stephenie C. Lemon. "Abstract A039: Translating research into practice: Results of a community-engaged, city-wide breast cancer patient navigation implementation study to reduce disparities." Cancer Epidemiology, Biomarkers & Prevention 32, no. 12_Supplement (December 1, 2023): A039. http://dx.doi.org/10.1158/1538-7755.disp23-a039.
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Abstract Introduction: Delays in accessing breast cancer care contribute to poor outcomes among women of color and those underinsured. Patient navigation is one of few proven interventions that overcome inequity in cancer care delivery, yet there is a need to address barriers to widespread implementation. Methods: Led by a city-wide coalition of multi-sector stakeholders, we conducted a Type 1 hybrid clinical effectiveness-implementation trial across five hospitals in Boston to test the impact of navigation on timely initiation of breast cancer treatment, while also exploring implementation outcomes including acceptability of and fidelity to an evidence-informed 11-step navigation protocol. A randomized cluster stepped wedge study design allowed for rolling out a multi-level navigation protocol iteratively in real life practices from 2019 through 2022. Hospital cancer registries sourced eligible cancer cases, while electronic medical record abstraction documented timely treatment, defined as within 60 or 90 days depending on the diagnosis. Odds ratios adjusted for time by calendar quarter and accounted for clustering by study site. Fidelity to protocol was measured using navigator documentation of interactions with patients and conducting social needs screenings. Key informant interviews and field observations were conducted to assess acceptability. Results: A total of 1,732 women with newly diagnosed breast cancer were included in the intent to treat analysis (553 historical control period, 1,179 intervention period). By study design, the majority of women were nonwhite (80%) and more than half were non-English speaking and on public health insurance. During the intervention period, 50% (n=587) had no documented evidence of receiving any contact from a navigator, 15% (n=181) had only one documented interaction with the navigator while 35% (n=407) were navigated and received social needs screens in accordance with study protocol. Compared with historical controls, navigated patients who received a social needs screen had twice the odds of receiving timely treatment (aOR 2.06, 95% CI 1.39, 3.06), those who had only one documented interaction with the navigator had 1.4 greater odds of timely treatment (aOR 1.44, 95% CI 1.08, 1.93) and those with no documented evidence of navigation were no more likely to receive timely treatment (aOR 1.42, 95% CI 0.81, 2.48. We found variability in how navigators identified patients, with significant disruption during the COVID pandemic. Navigators found navigation protocols and social needs screening acceptable, and patients reported feeling supported when asked about social needs. The study protocol formalized the navigation process within and across hospitals, yet tension for change in existing workflows and complexity in documentation served as barriers to adoption. Conclusions: Receipt of navigation is associated with more timely care among a diverse group of women at risk for poor outcomes. Despite stakeholder engagement, implementation of evidence-based breast cancer patient navigation remains suboptimal. Citation Format: Tracy A. Battaglia, Karen M. Freund, Jennifer S. Haas, Stephenie C. Lemon, Translating Research Into Practice (TRIP) Consortium. Translating research into practice: Results of a community-engaged, city-wide breast cancer patient navigation implementation study to reduce disparities [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 A039.
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Sharma, Jayesh, Elizabeth Zhang, Xuliang Wang, Junjie Ma, Jun Chen, Gabriele Schiattarella, Joseph Hill, et al. "Abstract 3659: Early in vivo detection of radiation-induced cardiotoxicity." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3659. http://dx.doi.org/10.1158/1538-7445.am2022-3659.
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Abstract Background: Radiation-Induced Heart Disease (RIHD) is a major source of morbidity and mortality in patients receiving thoracic radiation, which is a common treatment for malignancies like lung cancer. There is currently no standardized program for follow-up of RIHD in cancer survivors. Therefore, there is an acute need for developing detection of RIHD at a stage that offers potential for early intervention and reversibility. The gold standard for detection of global cardiac dysfunction is echocardiography. However, this current paradigm detects cardiac changes in metrics such as Left Ventricular Ejection Fraction (LVEF), which are relatively late manifestations in the pathology of cardiotoxicity, decreasing the possibility of reversing such damage. We sought to assess radiation-induced changes significantly earlier than the current standard of care by measuring the efficiency of the tricarboxylic acid cycle in cardiac mitochondria; we hypothesized that radiation leads to impaired mitochondrial function, causing increased conversion of pyruvate to lactate in the cytosol and decreased conversion in the mitochondria. In order to non-invasively measure this impairment, we utilized Magnetic Resonance Spectroscopy (MRS) to track the fate of hyperpolarized (HP) C-13 pyruvate. Methods: Sprague-Dawley rats underwent baseline and post treatment echocardiography and HP C-13 pyruvate MRS at multiple timepoints. Half of the animals underwent image-guided cardiac radiation with cone-beam CT, to a total dose of 40 Gy in 5 fractions, a paradigm similar to a common dose given to lung cancer patients. Results: In the cardiac radiation group, C-13 pyruvate MRS demonstrated a statistically significant decrease in cardiac function (determined by bicarbonate-to-lactate ratio in myocardial mitochondria) compared to pre-radiation baseline (p=0.02, one-tailed paired t-test) as early as 1 week post treatment. No significant decrease in this ratio was observed in the non-irradiated, age matched controls (p=0.95). Comparatively, no significant changes in LVEF or global longitudinal strain were observed in either the cardiac irradiation or control group of rats until 2 months post treatment. Conclusion: Radiation-induced myocardial mitochondrial dysfunction is an early event that can be characterized and detected in vivo by hyperpolarized C-13 pyruvate MRS within 1 week after radiation prior to onset of echocardiographic changes. For the first time, we have demonstrated feasibility of employing HP C-13 pyruvate MRS for detecting radiation-induced myocardial mitochondrial metabolic changes in a pre-clinical rat model. This technology has the potential to serve as a platform for building radiation-focused cardio-oncology programs for early detection and mitigation of radiation-induced cardiac injury in hundreds of thousands of patients receiving thoracic radiation annually. Citation Format: Jayesh Sharma, Elizabeth Zhang, Xuliang Wang, Junjie Ma, Jun Chen, Gabriele Schiattarella, Joseph Hill, Jaemo Park, Craig Malloy, Vlad Zaha, Prasanna Alluri. Early in vivo detection of radiation-induced cardiotoxicity [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 3659.
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Hill, Jonathan A., Kerry F. White, Matthew Rausch, Jou-Ku Chung, Amita Patnaik, Aung Naing, Daniel Morgensztern, et al. "Abstract 1137: Determination of a recommended Phase 2 dose (RP2D) for SRF388, a first-in-class IL-27-blocking antibody, in patients with advanced solid tumors." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1137. http://dx.doi.org/10.1158/1538-7445.am2022-1137.
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Abstract SRF388 is a first-in-class, anti-IL-27 antibody developed to enhance immune responses within the tumor microenvironment. Preclinical studies have demonstrated that IL-27 pathway blockade can inhibit tumor growth in mouse models of liver cancer and lung cancer metastases. There is also evidence that IL-27 pathway inhibition is accompanied by activation of the innate and adaptive arms of the immune system. An ongoing Phase I trial has shown good tolerability at all dose levels tested and preliminary monotherapy antitumor activity with SRF388 (NCT04374877). Here, we describe the preclinical and clinical data used to select a RP2D and characterize cytokine and chemokine changes observed in patients after treatment with SRF388. To guide selection of the RP2D, the relationship between maximal effective dose (MaxED), pharmacokinetics (PK), and whole blood inhibition of IL-27-mediated phosphorylation of STAT1 by SRF388 was evaluated in a mouse model of liver cancer. The concentration of SRF388 associated with optimal antitumor activity was ~20-fold above the concentration needed for complete inhibition (> 90%) of whole blood phosphorylated STAT1 (pSTAT1). These PK and activity relationships were also defined in patients during the dose-escalation phase of the trial and integrated with safety and efficacy data to select a monotherapy RP2D. In patients, PK were linear, no dose-limiting toxicities were reported, complete pSTAT1 inhibition was achieved throughout the first cycle at 0.3 mg/kg, and 1 patient experienced a confirmed partial response per RECIST version 1.1 at a dose of 10 mg/kg. In the MaxED mouse model, the area under the concentration versus time curve (AUC) associated with significant antitumor activity was 1720 day*μg/mL. In patients, the corresponding target AUC was achieved clinically at 10 mg/kg after a single dose of SRF388. Changes in the concentration of several serum cytokines and chemokines were observed after SRF388 treatment including an increase in IL-27, a phenomenon described for other anti-cytokine antibodies due to altered clearance of the cytokine-antibody complex. Changes in a subset of other serum cytokines/chemokines correlated with a reduction in target lesion size. Taken together, these data support the selection of a monotherapy RP2D of 10 mg/kg intravenously every 4 weeks for SRF388. These data highlight how complementary strategies utilizing preclinical and clinical biomarker evaluations can be employed to establish a monotherapy RP2D and assess biological activity of a first-in-class anti-cytokine antibody, SRF388, for patients with cancer. Citation Format: Jonathan A. Hill, Kerry F. White, Matthew Rausch, Jou-Ku Chung, Amita Patnaik, Aung Naing, Daniel Morgensztern, Charlene M. Mantia, Nizar M. Tannir, Lon S. Smith, Beth Bowers, Alex Alika, Lauren C. Harshman, Benjamin H. Lee. Determination of a recommended Phase 2 dose (RP2D) for SRF388, a first-in-class IL-27-blocking antibody, in patients with advanced solid tumors [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 1137.