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Ashis Sengupta. "Abhijit Sen, <i>Rabindranath Tagore’s Theatre: From Page to Stage</i>." Asiatic: IIUM Journal of English Language and Literature 16, no. 1 (June 24, 2022): 190–94. http://dx.doi.org/10.31436/asiatic.v16i1.2503.
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Chakravartty, Gargi. "Shahin Akhtar and Mousumi Bhowmik (eds.), Janana Mahfil (Selected Writings of Bengali Muslim Women Writers 1904-1938). Calcutta: Stree. 1998. 316 pages. Rs. 220. Abhijit Sen and Abhijit Bhattacharya (eds.), Swarnakumari Devi's Collection of Essays (Bengali). Calcutta: Bikalpa Publication. 1998. 229 pages. Rs. 75." Indian Journal of Gender Studies 8, no. 2 (September 2001): 330–32. http://dx.doi.org/10.1177/097152150100800212.
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Chakravarty, Gargi. "Book Reviews : Sambuddha Chakravarty, Andare Antare: Unish Shatake Bangali Bhadramahila. Calcutta: Stree Prakashan, 1995. 274 pages. Rs. 150. Abhijit Sen and Jasodhara Bagchi (eds.), Shatavarshe Ashalata Sen. School of Women's Studies, Jadavpur University: Stree Prakashan, 1995. 95 pages. Rs. 65." Indian Journal of Gender Studies 4, no. 2 (September 1997): 281–84. http://dx.doi.org/10.1177/097152159700400210.
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Abraham, Joseph. "Abject Poverty and Multiple Deprivations in Rural India Based on SECC 2011 in Comparison with NSSO and NFHS: Summary Findings Analyzed." IRA-International Journal of Management & Social Sciences (ISSN 2455-2267) 6, no. 1 (February 10, 2017): 67. http://dx.doi.org/10.21013/jmss.v6.n1.p10.
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<em>This paper analyzes latest findings from the recently completed Socio Economic and Caste Census 2011(SECC2011), by focusing on rural abject poverty and multi-dimensionality of it by the pre-set seven deprivation parameters across rural India .As per schema of SECC2011 for analyzing the various facets of multi-dimensional poverty, firstly one set of households will be excluded on the basis of 13 automatic exclusion parameters, and subsequently another set of households will be automatically included on the basis of five parameters and finally the remaining set would be subjected to verifications by seven deprivations. Thereby, the SECC 2011 had set in motion an effort to capture some specifics of multidimensional poverty as desired by the Ministry of Rural Development (MoRD) in the Government of India. It is surmised here that the union of automatically included and deprived households will provide a base line of the number of poor through a multi-dimensional mode. The intersection of automatically included households with the seven deprivations variables will also identify the socio economic characteristics of the abjectly poor. Besides presenting the above analysis of SECC data, an attempt is made to compare these findings with those based on the unidimensional National Sample Survey (NSSO) poverty ratios ( by S.Tendulker 2009, C Rangarajan 2012) and multi-dimensional (R. Radhakrishna et al 2010) NFHS data based studies. A separate set of multi-dimensional poverty numbers were arrived at in the past for three Five Year Plans (1992-97, 1997- 02, 2002-07) through the Below Poverty Line (BPL) Censuses that were under taken by the Ministry of Rural Development (MoRD) to identify the poor households through the State/UT Governments. These later estimates of poor households were never permitted to exceed the official poverty ratio worked out by the Planning Commission for respective State/UT governments. The concepts used to arrive at these poor households will be briefly reviewed here as a prelude to explaining the modes operandi of identifying multi dimensional poverty via SECC 2011. A committee was set in up in February 2013 under the Chairmanship of Abhijit Sen , then Planning Commission Member, to examine the SECC indicators for data analysis, to recommend appropriate methodologies for determining classes of beneficiaries for different rural development programmes. Some of the recommendations of the committee would also be put to scrutiny. </em>
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Dr. Dilip Bhatt. "Application of Rasa Theory in Ravindranath Tagore’s The Waterfall." International Peer Reviewed E Journal of English Language & Literature Studies - ISSN: 2583-5963 1, no. 2 (December 10, 2019): 1–7. http://dx.doi.org/10.58213/ell.v1i2.9.
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Veer Rasa or Heroic has its roots in the higher kind of people, splendour, enormity, goodness,power, liveliness, and the ability to take action. Attention to detail and a strong desire forsuccess can be seen in this character's demeanour. Strength and endurance are two traits thatoften indicate a person's potential for heroism. In other words, when faced with danger orperil, one is firm and does not budge. A strong sense of persistence supports this firmness.The dynamic energy or the spirit of veer is what keeps them both going. The traits offirmness and patience are sustained by a positive outlook and energy. The focus of this paperis on the play's intensity and heroism. When an engineer named Bibhuti offers to build a damon the river, the King of Uttarkut accepts. Thus, the villagers' livelihoods are impacted: theirfishing, farming, and community activities are all disrupted by the disaster. Baba Dhananjaybegins a non-violent revolt at this critical juncture. The public's movement grows strongerand more rebellious over time. Abhijit, the king's son, also succeeds in bursting the dam bysacrificing himself. The Muktadhara River has been restored to its natural state. This paperalso discusses issues related to the human-machine conflict.
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Putri, Indah Merdeka, and Ali Muhyidin. "Cambodian and Thai Political Actors Interest in Preah Vihear Temple Border Conflict in 2008-2011." Jurnal Politik 4, no. 2 (March 31, 2019): 215. http://dx.doi.org/10.7454/jp.v3i2.73.
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This paper examines how domestic interest of political actors in particular country may spark conflict and create reconciliation with other country. The case of the Preah Vihear border temple dispute between Cambodia and Thailand in 2008-2011 shows that distinctive political interest within each country has made the the relation of both countries in up and down situation, in term of escalating conflict or initiating reconciliation, in that period of time. By discussing the interest of Cambodia’s political actor represented by Prime Minister Hun Sen with the Cambodian's People Party (CPP) and Thailand’s elites represented by Prime Minister Abhisit Vejjajiva with the Democracy Party (PD) and, later, by Yingluck Shinawatra with the Pheu Thai Party, the article argues that Preah Vihear conflict has been used by these political actors for their domestic political gains. Based on this study, it can be concluded that a border conflict can be basically influenced by political actor interest to maintain or gain domestic power. By underlining the domestic political actor interest, this study gives a different dimension compare to other studies at the same topic that tend to explain the conflict by using descriptive or chronological approach.
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Dozmorov, Mikhail, Maggie Marshall, Narmeen Rashid, Jacqueline Grible, Aaron D. Valentine, Amy Olex, Kavita Murthy, et al. "Abstract P1-13-23: Carboplatin resistance-associated changes in the 3D chromatin landscape of a triple-negative breast cancer Patient-Derived Xenograft." Cancer Research 83, no. 5_Supplement (March 1, 2023): P1–13–23—P1–13–23. http://dx.doi.org/10.1158/1538-7445.sabcs22-p1-13-23.
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Abstract Changes in the three-dimensional (3D) structure of the genome are an emerging hallmark of cancer. Cancer-associated copy number variants and single nucleotide polymorphisms promote rewiring of chromatin loops, disruption of topologically associating domains (TADs), active/inactive chromatin state switching, leading to oncogene expression and silencing of tumor suppressors. However, little is known about 3D changes during cancer progression to a chemotherapy-resistant state. We integrated chromatin conformation capture (Hi-C), RNA-seq, and whole-genome sequencing obtained from triple-negative breast cancer patient-derived xenograft primary tumors (UCD52) and carboplatin-resistant samples and found increased short-range (< 2Mb) interactions, chromatin looping, formation of topologically associating domains (TAD), chromatin state switching into a more active state, and amplification of ATP-binding cassette (ABC) transporters. Transcriptome changes suggested the role of long-noncoding RNAs in carboplatin resistance. Rewiring of the 3D genome was associated with TP53, TP63, BATF, FOS-JUN family of transcription factors and led to activation of aggressiveness-, metastasis- and other cancer-related pathways. Integrative analysis highlighted increased ribosome biogenesis and oxidative phosphorylation, suggesting the role of mitochondrial energy metabolism. Our results suggest that 3D genome remodeling may be a key mechanism underlying carboplatin resistance. Citation Format: Mikhail Dozmorov, Maggie Marshall, Narmeen Rashid, Jacqueline Grible, Aaron D. Valentine, Amy Olex, Kavita Murthy, Abhijit Chakraborty, Joaquin Reyna, Daniela Salgado Figueroa, Da-Inn Lee, Brittany Baur, Sushmita Roy, Ferhat Ay, Chuck Harrell. Carboplatin resistance-associated changes in the 3D chromatin landscape of a triple-negative breast cancer Patient-Derived Xenograft [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-23.
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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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Szabo, Elizabeth, Emily Blackburn, Alexander Radecki, Abhijit Rath, and Christopher Heinen. "Abstract 5615: Functional analysis of variants of uncertain significance in the MSH6 mismatch repair gene." Cancer Research 84, no. 6_Supplement (March 22, 2024): 5615. http://dx.doi.org/10.1158/1538-7445.am2024-5615.
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Abstract Lynch syndrome (LS) is a hereditary condition that increases patients’ lifetime risk of cancer, primarily colorectal cancer. LS is caused by germline mutations in mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2. Identification and classification of these mutations is important in LS diagnosis for guiding treatment plans and preventative care for patients’ and their families. However, the consequences of some variants in these genes are not immediately obvious, granting them classification as variants of uncertain significance (VUS). Laboratory functional analysis to determine whether these variants disrupt MMR function in human cells can provide important evidence for understanding the pathogenicity of VUS and reclassifying them. Half of known variants in the MMR gene MSH6 are VUS and, thus, the goal of my project is to provide evidence for a subset of these variants to help provide evidence for reclassification for these variants. We are calibrating and validating functional assays for MSH6 variants, using known MSH6 pathogenic and benign controls. We will then test MSH6 VUS identified in patients as reported in the InSiGHT database, ClinVar database, and current literature. We are using CRISPR gene editing to recreate these variants in the endogenous MSH6 loci in human embryonic stem cells (hESC). Using these edited hESC lines we are examining the impact of the variants on RNA and protein stability, repair of DNA microsatellites, which is a hallmark of normal MMR function, and induction of the MMR-dependent DNA damage response. With this compilation of data, we will convert the results into a quantitative Odds of Pathogenicity value. This Odds of Pathogenicity score can be used by expert variant interpretation committees to help readily reclassify these variants and provide a clearer diagnosis for these suspected Lynch syndrome patients. Citation Format: Elizabeth Szabo, Emily Blackburn, Alexander Radecki, Abhijit Rath, Christopher Heinen. Functional analysis of variants of uncertain significance in the MSH6 mismatch repair gene [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 5615.
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Xiao, Lanbo, Abhijit Parolia, Yuanyuan Qiao, Pushpinder Bawa Pushpinder, Sanjana Eyunni, Rahul Mannan, Sandra E. Carson, et al. "Abstract 5469: Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5469. http://dx.doi.org/10.1158/1538-7445.am2022-5469.
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Abstract The switch/sucrose non-fermentable (SWI/SNF) complex plays a crucial role in chromatin remodeling and is recurrently altered in over 20% of human cancers. Here, we developed a proteolysis targeting chimera (PROTAC) degrader of ATPase subunits of the SWI/SNF complex, SMARCA2 and SMARCA4. Intriguingly, we found androgen receptor (AR)/forkhead box A1 (FOXA1)-positive prostate cancer to be exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to benign prostate as well as other cancer cell lines, including those with inactivating SMARCA4 mutations. Mechanistically, SWI/SNF inhibition rapidly compacts the cis-regulatory elements that are bound and activated by transcription factors that drive cancer proliferation, namely AR, FOXA1, ERG, and MYC. This ensues in chromatin untethering of these oncogenic drivers, chemical decommissioning of their core enhancer circuitry, and attenuation of downstream gene programs. Furthermore, we found SWI/SNF inhibition to disrupt super-enhancer and promoter DNA looping interactions that wire supra-physiologic expression of the AR, FOXA1, and MYC oncogenes, thereby tempering their expression in cancer cells. Monotherapy with the SMARCA2/4 degrader induced potent inhibition of tumor growth in cell line-derived xenograft models of prostate cancer and remarkably synergized with AR antagonists, inducing disease remission in models of castration-resistant prostate cancer. We also found the combinatorial treatment to significantly inhibit the growth of enzalutamide resistant disease using in vitro as well as patient-derived xenograft models. Notably, no major toxicities were seen in mice upon prolonged treatment with the SMARCA2/4 degrader, including no indications of thrombocytopenia, gastrointestinal goblet cell depletion, or germ cell degeneration. Taken together, these results suggest that impeding enhancer accessibility through SWI/SNF ATPase inactivation represents a novel therapeutic approach in enhancer addicted human cancers. Citation Format: Lanbo Xiao, Abhijit Parolia, Yuanyuan Qiao, Pushpinder Bawa Pushpinder, Sanjana Eyunni, Rahul Mannan, Sandra E. Carson, Yu Chang, Xiaoju Wang, Yuping Zhang, Josh Vo, Steven Kregel, Stephanie A. Simko, Andrew D. Delekta, Mustapha Jaber, Heng Zheng, Ingrid Apel, Lisa McMurry, Fengyun Su, Rui Wang, Sylvia Wang, Sanjita Sasmal, Leena K. Satyam, Subhendu Mukherjee, Chandrasekhar AbbinenI, Kiran Aithal, Mital S. Bhakta, Jay Ghurye, Xuhong Cao, Nora M. Navone, Alexey Nesvizhskii, Rohit Mehra, Ulka Vaishampayan, Marco Blanchette, Yuzhuo Wang, Susanta Samajdar, Murali Ramachandra, Arul M. Chinnaiyan. Targeting SWI/SNF ATPases in enhancer-addicted prostate 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 5469.
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Travers, Kevin, Nathan Wilson, and Abhijit Kale. "Abstract 255: Isolation of unaltered sub-populations of immune cells using magnetic levitation." Cancer Research 83, no. 7_Supplement (April 4, 2023): 255. http://dx.doi.org/10.1158/1538-7445.am2023-255.
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Abstract The analysis and characterization of subsets of immune cells from heterogeneous samples, such as peripheral blood mononuclear cells (PBMCs), requires isolation and enrichment. Common methods for this enrichment step include fluorescence activated cell sorting and positive or negative selection with magnetic beads. However, these methods alter native cell phenotypes during the enrichment process by the application of pressure, binding of antibodies, extensive manipulation and centrifugation, among other perturbations. This results in altered gene expression, generating molecular profiles that are not representative of true biological significance. These alterations are prevented by using magnetic levitation cell isolation and enrichment. The LeviCellTM platform performs hands-free cell enrichment by utilizing magnetic fields to levitate viable, healthy cells away from dead cells and debris. Unlike other single cell separation methods, the enriched target cells are not subject to mechanical force, labeling, or staining to achieve viability enrichment. This results in a single cell suspension that is ready for immediate downstream analysis, producing molecular profiles free of isolation-induced gene expression artifacts. We have developed reagents to extend the benefits of this technology to the immuno-oncology research market. These new reagents are used to target the enrichment of all T cells, the CD4+ or CD8+ subsets of T cells, or all B cells, with other target populations in development. In all cases, unwanted cells are captured within the levitation chamber, depleting them from the sample. These reagents leverage the magnetic field across the levitation chamber. Specifically-tagged, unwanted cells are pulled to the edges of the levitation chamber while the target cells undergo viable cell enrichment. The end result is a cell population that has been enriched and at higher viability. We have seen consistent depletion rates of >98%, resulting in a final targeted population with 90% or higher purity in most cases. Here we demonstrate the performance of the LeviCell platform in the enrichment of targeted cell populations relevant to the immuno-oncology research community. Citation Format: Kevin Travers, Nathan Wilson, Abhijit Kale. Isolation of unaltered sub-populations of immune cells using magnetic levitation [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 255.
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Qian, Jing, William Tahaney, Yanxia Ma, Abhijit Mazumdar, and Powel Brown. "Abstract P5-12-08: The role of a novel phosphatase NUDT5 in triple-negative breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): P5–12–08—P5–12–08. http://dx.doi.org/10.1158/1538-7445.sabcs21-p5-12-08.
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Abstract Background: 281,550 new cases of invasive breast cancer will be diagnosed in US this year. 15% of these patients will be diagnosed with triple-negative breast cancers (TNBCs), which is the most aggressive subtype of breast cancer. Non-specific chemotherapy remains the current standard of care for TNBCs, due to the lack of targeted therapy. We hypothesized that phosphatases are potential new drug targets for TNBCs and performed a whole phosphatase microarray analysis using TNBCs vs. estrogen receptor (ER)-positive breast cancers. NUDT5, the enzyme hydrolyzes 8-oxo-dGDP and ADP-ribose, is among the most highly expressed phosphatases in TNBCs. The goal of these studies is to investigate NUDT5 dependency and mechanism in TNBC development.Methods: In this study, we have obtained NUDT5 mRNA expression level from publicly available TCGA, METABRIC, and the CCLE datasets, and compared NUDT5 mRNA level in TNBC vs. ER-positive breast cancer. Next, we examined the association of overall survival with NUDT5 expression level dichotomized by median mRNA expression in breast cancer patients. We then engineered doxycycline-inducible NUDT5 knockdown and knockout systems in TNBC cell lines, and characterized cell growth features over 7 days with or without NUDT5 depletion. Growth inhibition effect is also confirmed by NUDT5 inhibitor. After 72 hours of doxycycline induction, cell growth was determined by cell count over 7 days. Using these TNBC cellular models, we also determined molecular phenotypes after NUDT5 depletion by immunofluorescent microscopy for 8-oxo-dGDP and γH2AX. ImageXpress Automated Cell Imaging System and CellReporterXpress were applied for image processing and data quantification. Results: NUDT5 RNA is highly overexpressed in TNBCs as compared to ER-positive breast cancers and normal breast tissue. Survival analyses indicated that increasing NUDT5 level is significantly correlated with worse clinical outcomes of breast cancer patients. NUDT5 protein is highly expressed in TNBC cell lines, compared to ER-positive breast cancer cell lines. NUDT5 knockdown or knockout both significantly inhibits the growth of TNBC cell lines. Loss of NUDT5 induced the oxidative DNA lesion 8-oxoG level in the nucleus, as well as the ratio of γH2AX-positive cells. The inhibitor of NUDT5 also suppressed TNBC cell growth in vitro. Conclusions: Our results showed that the level of NUDT5 negatively correlates with TNBC patient survival. NUDT5 is required for the TNBC cells growth and tolerance to endogenous DNA damage agents. Our findings have revealed the essential function of NUDT5, and will provide critical insights for the future development of NUDT5 inhibitors for the treatment of TNBC patients. This work was supported by Charles Cain Endowment (PB). Citation Format: Jing Qian, William Tahaney, Yanxia Ma, Abhijit Mazumdar, Powel Brown. The role of a novel phosphatase NUDT5 in triple-negative 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 P5-12-08.
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Dasgupta, Abhijit, Grant Duclos, Ricardo Miragaia, Brychan Manry, Etai Jacob, Natasha Markuzon, and Asaf Rotem. "Abstract 3520: A scalable single cell RNA-seq pipeline leveraging machine learning and high-quality references for cell-type prediction." Cancer Research 84, no. 6_Supplement (March 22, 2024): 3520. http://dx.doi.org/10.1158/1538-7445.am2024-3520.
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Abstract Single cell RNA-seq (scRNA-seq) technology transformed our understanding of biology at the cell level. Inferring cell types provide insights into the relative abundance of, and genomic differences between, different cell types. Current methods leverage known cell type markers and genomic similarity measures to attribute cell types to groups of cells. We present a scalable machine learning-based pipeline that can leverage high quality reference annotation data to infer cell types quickly for multiple scRNA-seq experimental samples. This pipeline leverages two machine learning technologies: variational autoencoders (VAE) to create a low-dimensional representation of the reference transcriptome; and, supervised learning methods that use this representation to learn cell types from the reference data. This pipeline can quickly score new experimental data using GPU-enabled computing platforms and provide probabilities of a cell being each cell type present in the reference data. This novel pipeline is evaluated using 5 public reference data sets. We evaluate whether VAE-based representations benefit supervised learning, compared to PCA and t-SNE. We next evaluate different supervised learning methods for predictive performance. Finally, we compare the pipeline’s performance with commonly-used cell type prediction algorithms (Seurat, scANVI). We find that using a VAE is generally better than both PCA and t-SNE for feature generation to predict cell type. Using the VAE representation, there is no significant difference in accuracy between logistic regression and other supervised learning algorithms. Finally, using logistic regression as the learning machine, this pipeline is as accurate as Seurat and better than scANVI, while running about 2-5x faster than Seurat. Table 1 Balanced accuracy (%) from leave-one-subject-out cross-validation across 5 public data sets. Intervals are the range of the metric across the cross-validation folds. Algorithm PBMC (10X) HLCA Eraslan snRNA Blueprint Breast Blueprint Lung Our pipeline 92 (87-95) 92 (88-93) 93 (90-97) 89 (80-96) 97 (95-99) Seurat 96 (95-97) 90 (94-98) 94 (93-97) 96 (87-98) 98 (94-99) scANVI 91 (84-95) 72 (78-86) 92 (88-96) 94 (80-97) 88 (86-100) Citation Format: Abhijit Dasgupta, Grant Duclos, Ricardo Miragaia, Brychan Manry, Etai Jacob, Natasha Markuzon, Asaf Rotem. A scalable single cell RNA-seq pipeline leveraging machine learning and high-quality references for cell-type prediction [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 3520.
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luo, Jie, Abhijit Prolia, Yuanyuan Qiao, Jean Tian, Rahul Mannan, Somnath Mahapatra, Zhixiang Chen, Rithvik Seri, Shaomeng Wang, and Arul Chinnaiyan. "Abstract 6048: Targeting AR positive prostate cancer cells by the novel P300/CBP oral available PROTAC degrader." Cancer Research 84, no. 6_Supplement (March 22, 2024): 6048. http://dx.doi.org/10.1158/1538-7445.am2024-6048.
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Abstract Background The Androgen Receptor (AR) serves as the core lineage-specific transcription factor for prostatic epithelial cells. Targeting AR is currently the most promising therapeutic strategy. However, the inevitable development of acquired resistance to anti-androgen treatments underscores the urgent need to devise new therapeutic strategies. Recent studies have revealed that in prostate cancer cells, AR is hijacked by oncogenic transcription factors, such as FOXA1 and HOXB13, which promiscuously bind to distinct enhancer sites, driving the progression of prostate cancer. This process leads to the formation of a substantially rewired AR cancer specific enhanceosome, requiring a variety of coregulators to exhibit oncogenic driver characteristics, which can be potential therapeutic targets for prostate cancer. Histone acetyltransferases (HATs) P300 and CBP are paralogs which play dominant roles in orchestrating high-order chromatin structures and transcription factor complexes by acetylating histone proteins at multiple residuals. Although accumulating evidence suggests that P300/CBP function as AR coregulator and targeting P300/CBP can markedly suppress AR-positive prostate cancer cell growth, including growth of castration-resistant prostate cancer (CRPC), most of the P300/CBP inhibitors have performed poorly in clinical trials. Methods We developed a novel P300/CBP dual oral available PROTAC degrader, namely CBPD-409. The on-target effects of CBPD-409 were assessed by quantitative proteomics (TMT-mass spectrometry) in prostate cancer cell lines. The RNA-seq analysis was conducted to investigate CBPD-409 effects on global transcriptome in prostate cancer cells. The cytotoxicity of CBPD-409 in multiple prostate cancer cell lines was examined by cell-titer-glo and incucyte assays. Conclusion In multiple cell lines, CBPD-409 exhibits remarked potency to degrade both P300 and CBP proteins in time and does dependent manner, without evident off-target effects. By employing CBPD-409, we demonstrate that degrading P300/CBP preferentially suppress AR+ prostate cancer cell growth. The global transcriptomic profiling in CBPD-409 treated prostate cancer cells revealed that loss of P300/CBP results in remarkedly downregulation of AR, Myc, FOXA1 and ERG signaling. Assessment of CBPD-409 cytotoxicity in a panel prostate cancer cell lines suggests that AR positive prostate cancer cells display highest sensitivity to CBPD-409. Citation Format: Jie luo, Abhijit Prolia, Yuanyuan Qiao, Jean Tian, Rahul Mannan, Somnath Mahapatra, Zhixiang Chen, Rithvik Seri, Shaomeng Wang, Arul Chinnaiyan. Targeting AR positive prostate cancer cells by the novel P300/CBP oral available PROTAC degrader [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 6048.
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Lin, Fanching, Renee Clift, Steven Horton, Matt Guest, Alain Noncovich, Abhijit Bhat, Sanjana Ballal, et al. "Abstract 6019: Biodistribution, molecular imaging and efficacy evaluation of a novel GPC3-targeted radiopharmaceutical therapy for hepatocellular carcinoma." Cancer Research 84, no. 6_Supplement (March 22, 2024): 6019. http://dx.doi.org/10.1158/1538-7445.am2024-6019.
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Abstract Introduction: Glypican-3 (GPC3) is a membrane-anchored oncofetal protein with minimal expression in normal tissues. Significant upregulation of GPC3 protein has been observed in the majority of hepatocellular carcinomas (HCC), and is associated with poor prognosis. The differential expression of GPC3 between tumor and normal tissues provides an opportunity for targeted radiopharmaceutical therapy (RPT) to treat HCC, a leading cause for cancer-related deaths worldwide. Methods: The novel RPT agent RYZ-GPC3 comprises a small macrocyclic peptide binder with high affinity to GPC3 linked with a tetraxetan moiety capable of chelating a variety of radioisotopes. The affinity of peptide binders to GPC3 was determined by surface plasma resonance (SPR) and radioligand binding assays. Cellular internalization was radiometrically measured at multiple time points. Non-human primate (NHP) PET imaging was performed with 64Cu. In vivo biodistribution, monotherapy and combination treatments with 177Lu or 225Ac were performed in HCC xenografts. Human imaging was conducted in HCC patients with 68Ga PET/CT. Results: The novel agent is a highly potent (KD=0.7 nM) and selective peptide binder to GPC3 of human, mouse, canine and NHP origins, and is compatible with multiple radiometal isotopes. In vivo biodistribution study of [177Lu]Lu-RYZ-GPC3 in HCC xenografts showed sustained tumor uptake of 16.6, 16.4, and 8.8 %ID/g at 24, 48, and 96 hours with fast renal clearance, resulting in favorable tumor/kidney ratios of 3.6, 10.2, and 13.0, respectively. Minimal or no uptake was observed in other normal tissues. PET imaging in NHP confirmed absence of on-target uptake by liver or other organs, and fast renal clearance. As monotherapy, durable (>60 days) tumor regression (TGI>100%) was achieved with 177Lu (111 MBq)- and 225Ac (0.111 MBq)-labeled RYZ-GPC3. At 10x lower injected activity, 177Lu- and 225Ac-labeled RYZ-GPC3 significantly improved anti-tumor effect of lenvatinib in multiple HCC models. Furthermore, PET/CT imaging in a 70-year-old patient with histologically proven HCC demonstrated distinct and avid [68Ga]Ga-RYZ-GPC3 tumor uptake. Conclusion: Preclinical data and preliminary human imaging demonstrate the potential of the novel binder as a theranostic agent for the treatment of patients with GPC3+ HCC. Citation Format: Fanching Lin, Renee Clift, Steven Horton, Matt Guest, Alain Noncovich, Abhijit Bhat, Sanjana Ballal, Chandrasekhar Bal, Kathryn Shah, Anna Karmann, Gary Li. Biodistribution, molecular imaging and efficacy evaluation of a novel GPC3-targeted radiopharmaceutical therapy for hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6019.
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Kar, Debamitra. "Liberating the River: Land and Politics in Tagore’s Plays." Gitanjali & Beyond 2, no. 1 (November 24, 2018): 51–65. http://dx.doi.org/10.14297/gnb.2.1.51-65.
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In matters of development and progress, it has always been a question of the acquisition of land. As history shows, control over land—extendable to different metaphors—and its resources has been instrumental in the development and destruction of human civilisation. Tagore’s Muktadhara dwells on the principle of identifying how the manipulation of a river-course could change the destiny of two neighbouring states and establish the rule of one man over others. So, in the character of Abhijeet, a typical Tagore-protagonist, one who breaks the dam to put an end to the authoritarian regime, a prototype of modern day environmental activists could be seen. The text goes beyond a mere pantheistic and humanist quest for the freedom of man as Tagore politicises the concept of land into a geopolitical space, and relates it to the imperialist policies and hegemonic propaganda that he experienced personally in his travels across Europe, Japan and America during this time.
From Muktadhara (1922) to Raktakarabi (1924), Tagore seems to continue with this politics of land. If the former text represents the appropriation of nature for political benefit, the latter shows how industrialisation destroys the agricultural base, forces migration, and how these steps would be the only logical progress of the economy that advocates rampant capital accumulation. Interestingly, a play set in a mine uses a theme song about ‘pous’—a month of cultivation and opulence. The essays written by Tagore during this period, like his Introduction to Elmhirst’s ‘The Robbery of the Soil’, also reveal his vision of a sustained and inclusive human development.
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Lanier, Amanda, Abhijit Mazumdar, William Tahaney, and Powel Brown. "Abstract P2-16-01: The Kinesin-like protein Kif11 is essential for the Survival of TP53-mutant Triple Negative Breast Cancer Cells." Cancer Research 83, no. 5_Supplement (March 1, 2023): P2–16–01—P2–16–01. http://dx.doi.org/10.1158/1538-7445.sabcs22-p2-16-01.
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Abstract Background: Breast cancer is the most commonly diagnosed non-cutaneous malignancy in American women and one of the leading causes of cancer deaths. Breast cancer can be divided into several subtypes, the most aggressive of which is Triple-Negative Breast Cancer (TNBC), a disease with few targeted therapies. TP53 mutations are found in 80% or more of TNBCs. However, direct targeting of mutant TP53 has been difficult. To identify drugs that can specifically induce the death of TP53-mutant breast cancers, we conducted a drug screen in TP53-mutant and TP53-wild type breast cancer cells. Through this combined in silico and in vitro drug screen, we discovered that TP53 mutant TNBC cells have an increased sensitivity to KIF11 inhibition as compared to TP53 wild-type cells. Hypothesis: We hypothesize that TP53 mutational status confers sensitivity of triple-negative breast cancer cells to KIF11 inhibition. Methods: We obtained data on TP53 mutational status, KIF11 mRNA expression levels, and clinical characteristics from publicly-available TCGA, METABRIC, and CCLE datasets. To demonstrate the effect of KIF11 inhibition on cell growth, we treated TP53 mutant and wild-type breast cancer cell lines with the small molecule KIF11 inhibitor SB-743921 and KIF11 siRNAs. Cell counts were obtained through staining with DAPI or Hoechst nuclear stains and imaging on the MetaXPress PICO instrument. To determine protein expression of p53 and Kif11 across various cell lines, western blotting was performed. We then investigated the biological mechanisms of growth inhibition by DRAQ7 staining and flow cytometry analysis following Annexin V-PI staining. Results: Using cell growth assays we demonstrated that TP53 mutant cells are more sensitive to KIF11 inhibition. We next utilized cell lines in which TP53 mutations had been introduced into TP53 wild-type cells to show that overexpression of a TP53 mutant gene can sensitize cells to KIF11 inhibition. Using assays of proliferation and apoptosis, we showed that TP53 mutant breast cancer cells treated with a KIF11 inhibitor undergo cell death. Using publicly-available datasets of breast cancers, we showed that KIF11 is upregulated in TNBCs and TP53 mutant cancers, and that high expression of KIF11 in breast cancer is correlated with poorer clinical prognosis. Conclusions: Our results show that the Kif11 protein is essential for the survival of TP53 mutant TNBC cells. Inhibitors of Kif11 induce death of TP53 mutant TNBCs and thus, this kinesin-like protein involved in cell spindle mechanics is a potential target for the treatment of these aggressive cancers. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Numbers TL1TR003169 and UL1TR003167. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was also supported by the John Charles Cain Endowment. Citation Format: Amanda Lanier, Abhijit Mazumdar, William Tahaney, Powel Brown. The Kinesin-like protein Kif11 is essential for the Survival of TP53-mutant Triple Negative Breast Cancer Cells [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-16-01.
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Gill, Jaidip, Abhijit Dasgupta, Brychan Manry, and Natasha Markuzon. "Abstract 4927: Combining single-cell ATAC and RNA sequencing for supervised cell annotation." Cancer Research 84, no. 6_Supplement (March 22, 2024): 4927. http://dx.doi.org/10.1158/1538-7445.am2024-4927.
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Abstract Background: Analysis of samples at the single-cell level offers insights into cellular heterogeneity and cell function. Cell type annotation is the first critical step for performing such an analysis. While current methods primarily utilize single-cell RNA sequencing (scRNA-seq) for annotation, several studies have demonstrated improved classification accuracy by combining scRNA-seq with transposase-accessible chromatin sequencing (ATAC-seq) using unsupervised methods. However, the utility of ATAC-seq features for supervised cell-type annotation has not been explored. Aims/Objectives: The objective of this study was to evaluate the relative performance of supervised cell-type classification using scRNA-seq alone vs. in multimodal combination with ATAC-seq; and how these data interplay with choice of classification and dimensionality reduction methods. Methods: A peripheral-blood mononuclear cell multi-omic dataset from a single, healthy female donor wasanalysed in this study. Ground truth annotations were generated using unsupervised annotation with the weighted nearest neighbour clustering method. Two dimensionality reduction methods (principal component analysis (PCA), single-cell Variational Inference (scVI) autoencoder) and four classification models (logistic regression, random forest, support vector machine (SVM)) were implemented and performance metrics (F1 score, precision, and recall) were compared over 10 bootstrap samples. Results: ATAC-seq features improved annotation quality and prediction confidence when using scVI embeddings, independent of the classifier. The best-performing model (SVM with scVI embeddings) showed an increase from a median macro F1 score of 0.907 (IQR = [0.902, 0.910]) using scRNA-seq alone to 0.946 (IQR = [0.940, 0.949], p <0.05) with ATAC-seq added. For PCA embeddings, improvements in macro F1 score were insignificant. All cell types (B, T, monocytes, natural killer and dendritic cells) showed significant improvements when using ATAC-seq with scVI embeddings. CD4 T effector memory cells showed the largest gain in F1 score (0.112, p <0.01), whilst type-2 conventional dendritic cells showed the smallest improvement (0.006, p <0.05). Prediction confidence was improved in B cells, monocytes, natural killer cells, CD4 and CD8 naïve cells, CD4 T central memory cells and CD8 T effector memory cells. Improvements in F1 scores were lost when only classifying major cell types rather than subtypes. Conclusions: Employing ATAC-seq embeddings with scVI autoencoder enhances supervised annotation quality over scRNA-only methods. Further studies should explore the use of ATAC to improve the annotation of highly heterogeneous tissues such as tumours. Citation Format: Jaidip Gill, Abhijit Dasgupta, Brychan Manry, Natasha Markuzon. Combining single-cell ATAC and RNA sequencing for supervised cell annotation [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 4927.
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Qian, Jing, and Powel Brown. "Abstract P4-08-07: Inhibition of the NUDT5 phosphatase suppresses the growth of triple-negative breast cancers." Cancer Research 83, no. 5_Supplement (March 1, 2023): P4–08–07—P4–08–07. http://dx.doi.org/10.1158/1538-7445.sabcs22-p4-08-07.
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Abstract Inhibition of the NUDT5 Phosphatase Suppresses the Growth of Triple-negative Breast Cancers Jing Qian1, Yanxia Ma1, Abhijit Mazumdar1, Cassandra Moyer1, Brent D. G. Page3, William Tahaney2, Jamal Hill1, Darian Coleman1, Powel. H. Brown1, 2 1 Department of Clinical Cancer Prevention, UT MD Anderson Cancer Center, Houston, TX 2 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 3 Faculty of Pharmaceutical Sciences, University of British Columbia, Canada, Vancouver BC Background: 281,550 new cases of invasive breast cancer will be diagnosed in US this year. 15% of these patients will be diagnosed with triple-negative breast cancers (TNBCs), which is the most aggressive subtype of breast cancer. Non-specific chemotherapy remains the current standard of care for TNBCs, due to the lack of targeted therapy. We have previously conducted a whole phosphatase RNA microarray analysis of TNBCs compared to estrogen receptor (ER)-positive breast cancers. These studies identified phosphatases that were either over-expressed or under-expressed in TNBCs as compared to ER-positive breast cancers. In this study, we investigated one of the highly expressed phosphatases NUDT5, which hydrolyzes 8-oxo-dGDP and ADP-ribose, as a potential new target for the treatment of TNBCs. Hypothesis: NUDT5 is a critical phosphatase that is necessary for the growth of triple-negative breast cancers. Methods: We obtained NUDT5 mRNA expression levels from publicly-available TCGA, METABRIC, and the CCLE datasets, and compared NUDT5 mRNA level in TNBCs versus ER-positive breast cancers. To demonstrate the effect of NUDT5 inhibition on cell growth, we used siRNA, shRNA, sgRNA, and the small molecule inhibitor TH5427 on various ER-positive cell lines and TNBC cell lines. Cell number was counted on Day 1, 3, 5 and 7. We then investigated the biological mechanisms of growth inhibition by Annexin V-PI, DRAQ7,and BrdU proliferation assays. We studied the effect of NUDT5 loss on oxidative stress and DNA damage pathways by measuring 8-oxoG level and γH2AX positivity in the nucleus. Using nude mouse xenograft models, we also investigated the effect of TH5427 on TNBC growth in vivo. Results: NUDT5 mRNA was highly overexpressed in TNBCs as compared to ER-positive breast cancers in several publically-available datasets. NUDT5 loss significantly inhibited the growth of the TNBC cell lines MDAMB231 and MDAMB436, but not the ER-positive cell lines MCF7 and MDAMB361. NUDT5 inhibition via siRNA or TH5427 did not induce apoptosis or cell death, but did suppress growth as assessed by BrdU incorporation.. In the nucleus, loss of NUDT5 induces the accumulation of the oxidative DNA marker, 8-oxoG, and the DNA damage marker, γH2AX, in TNBCs cells, indicating that loss of NUDT5 induces oxidative DNA damage response. In the MDAMB231 xenograft models, the inhibitor of NUDT5 suppressed TNBC tumor growth in mice. Conclusions: Our results showed NUDT5 is highly expressed in TNBCs as compared to ER-positive tumors. inhibition of NUDT5 suppresses the growth of TNBC but not of ER-positive breast cancer cells. NUDT5 loss also induces oxidative DNA damage, with increased 8-oxoG and γH2AX positivity. These results demonstrate that NUDT5 is essential for the growth of TNBC cells and suggest that NUDT5 is a promising new target for the treatment of these aggressive breast cancers. This work was supported by Charles Cain Endowment (PB). Citation Format: Jing Qian, Powel Brown. Inhibition of the NUDT5 phosphatase suppresses the growth of triple-negative breast cancers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-07.
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Eyunni, Sanjana, Abhijit Parolia, Eleanor Young, James Matthew George, Rahul Mannan, Sandra E. Carson, Yuping Zhang, et al. "Abstract 1433: FOXA1 alterations distinctively drive prostate tumorigenesis or therapy resistance in mice." Cancer Research 84, no. 6_Supplement (March 22, 2024): 1433. http://dx.doi.org/10.1158/1538-7445.am2024-1433.
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Abstract Androgen receptor (AR) signaling is critical for survival of prostate cancer (PCa) cells, thus making androgen deprivation therapy (ADT; e.g., castration) as the mainstay for treatment. Notably, oncogenic functions of AR rely on chromatin-binding regulatory proteins, which includes a pioneer transcription factor called FOXA1. FOXA1 de-compacts chromatin to enable AR’s binding to the DNA and expression of it's target genes. Recently, our lab found FOXA1 alterations to recur within three distinct structural classes in over 35% of metastatic castration resistant PCa (mCRPC) in Caucasian men. Subsequent studies found FOXA1 mutations to be prevalent in over 40% of primary PCa in Chinese men, positioning FOXA1 as a principal oncogene in this disease. Yet, hitherto, no studies have defined the pathobiology of FOXA1 alterations in mouse models. Here, we have developed the first-in-field transgenic mice with conditional overexpression of FOXA1 mutants in the prostate luminal epithelia. We found truncal FOXA1 Class1 mutants to initiate luminal hyperplasia in a monogenic model, or hyperproliferative prostate adenocarcinoma in a compound Trp53-deficient genetic background. Mechanistically, Class1 mutants concurrently upregulate the AR and mTORC1/2 pathways to drive transformation, with this being the first report of FOXA1-driven PCa formation in mice. In contrast, FOXA1 Class2 mutants—which are acquired in mCRPC—do not drive prostate luminal transformation. Instead, single-cell multi-omics (RNA+ATAC) profiling of Class2-mutant mouse prostate tissue uncovered extensive transcriptional remodeling of epithelial cells into a luminal stem-like cell fate, leading to a dramatic 15-20-fold expansion of the progenitor population vs control tissue. These luminal stem cells are similar to the Club/Hillock cells detected in the human prostate that have been implicated in driving resistance to ADT. Consistently, we found Class2-mutant prostates to show minimal atrophy upon castration, with immunohistological assessment uncovering a higher density of Ki67+ luminal epithelial cells relative to wild type and Class1 tissues. Class2-mutant organoids also showed higher subcutaneous grafting ability in mice in limiting dilution assays. Mechanistically, we found the cistromically-dominant Class2 mutants to pioneer over 40,000 neo-enhancer elements harboring motifs of stemness-associated transcription factors, which in turn instruct the ADT-resistant luminal progenitor gene program. Altogether, findings from our mouse models uncover FOXA1’s versatility as a driver oncogene that, depending on the mutation type, either activates enhancer-wired luminal tumorigenesis (Class1-initiating event) or therapy resistance-associated stemness (Class2-promoting alteration) gene programs in the mouse prostate tissue. Citation Format: Sanjana Eyunni, Abhijit Parolia, Eleanor Young, James Matthew George, Rahul Mannan, Sandra E. Carson, Yuping Zhang, Jean Tien, Mustapha Jaber, Jie Luo, Matthew Pang, Rohit Mehra, Xuhong Cao, Fengyun Su, Rui Wang, Marcin Cieslik, Dong Kee Lee, Jianming Xu, Arul M. Chinnaiyan. FOXA1 alterations distinctively drive prostate tumorigenesis or therapy resistance in mice [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 1433.
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Lanier, Amanda L., William Tahaney, Jing Qian, Cassandra Moyer, Yanxia Ma, Banu Arun, Abhijit Mazumdar, and Powel H. Brown. "Abstract 522: TP53mutations promote death of breast cancer cells following Kif11 inhibition." Cancer Research 84, no. 6_Supplement (March 22, 2024): 522. http://dx.doi.org/10.1158/1538-7445.am2024-522.
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Abstract Background: Triple-Negative Breast Cancer (TNBC) comprises 15-20% of breast cancer diagnoses. These aggressive breast cancers are characterized by their lack of expression of the estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), and progesterone receptor (PR), resulting in few targeted therapy options for TNBC patients. While 85-90% of TNBCs contain mutations in TP53, mutant p53 is challenging to target directly. Instead, we aim to identify other survival pathways critical for the growth and survival of TP53 mutant cells. Through a combined in vitro and in silico drug screen, we identified the Kif11 inhibitor SB-743921 as more effective in TP53 mutant compared to wild-type breast cancer cells. Hypothesis: We hypothesized that Kif11 inhibition causes TP53 mutant cells to undergo cell death due to failure of activation of p53-mediated cell cycle checkpoints. Methods: Clinical data from the TCGA and METABRIC cohorts was obtained from cBioPortal. Expression and survival analyses were performed using GraphPad Prism. Cell growth assays were conducted by seeding cells, treating under designated conditions, then staining with Hoechst 33342 for cell counting on the ImageXpress Pico. Cell death was determined by staining with Annexin V and PI or DAPI Staining followed by flow cytometry analysis. Cell cycle analysis was conducted following synchronization with Lovastatin and Mevalonate release followed by imaging analysis of cell lines expressing the Fast FUCCI reporter or PI staining and flow cytometry analysis. Immunofluorescence imaging was conducted by staining with anti-alpha-tubulin-AlexaFluor488 and DAPI and imaging on the Nikon TI2 or ImageXPress PICO. In vitro expression experiments were carried out through qPCR and western blotting. Results: KIF11 is most highly expressed in TP53 mutant and triple-negative tumors and high expression of KIF11 is associated with poorer overall survival. In breast cancer cell lines, Kif11 inhibition leads to a cell cycle block in both TP53 mutant and wild-type cells, but TP53 mutant cells then die following this cell cycle block. Furthermore, Kif11 inhibition causes mitotic dysfunction, including monopolar spindle formation and multinucleated cells in TP53 mutants. Introduction of a TP53 mutation into TP53 wild-type cells also induces cell death following Kif11 inhibition. Conclusions: KIF11 is highly expressed in aggressive breast cancers and is associated with poorer prognosis. Using the small molecule inhibitor SB-74321 that has been tested in phase I/II clinical trials with favorable tolerability, we found that Kif11 inhibition results in mitotic dysfunction and death of TP53 mutant breast cancer cells due to mitotic catastrophe. These results suggest that Kif11 is a promising target for the treatment of TP53 mutant TNBCs. Citation Format: Amanda L. Lanier, William Tahaney, Jing Qian, Cassandra Moyer, Yanxia Ma, Banu Arun, Abhijit Mazumdar, Powel H. Brown. TP53mutations promote death of breast cancer cells following Kif11 inhibition [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 522.
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Parolia, Abhijit, Lanbo Xiao, Yuanyuan Qiao, Pushpinder Bawa, Sanjana Eyunni, Eleanor Young, Rahul Mannan, et al. "Abstract 3592: Targeting SWI/SNF ATPases in enhancer-addicted human cancers." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3592. http://dx.doi.org/10.1158/1538-7445.am2022-3592.
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Abstract In mammalian cells, DNA is wrapped around histone octamers (collectively referred to as nucleosomes) which form a physical barrier to all DNA-based processes. The switch/sucrose non-fermentable (SWI/SNF) is a multi-subunit chromatin remodeling complex that uses energy from ATP hydrolysis to reposition or eject nucleosomes at non-coding regulatory elements, thereby enabling access to the underlying DNA for transcriptional activation. Notably, the SWI/SNF complex plays a crucial role in chromatin remodeling and is recurrently altered in over 20% of human cancers, with the revised complex in cancer cells enabling central oncogenic gene programs. Yet, no studies have assessed the therapeutic efficacy of complete SWI/SNF inactivation across human cancers. Here, we developed a proteolysis targeting chimera (PROTAC) degrader of ATPase subunits of the SWI/SNF complex, SMARCA2 and SMARCA4. In a panel with over 90 normal and cancer cell lines from 18 different lineages, we found MYC-driven multiple myeloma and androgen receptor (AR)/forkhead box A1 (FOXA1)-positive prostate and breast cancers to be preferentially sensitive to dual SMARCA2 and SMARCA4 degradation relative to benign prostate as well as other cancer cell lines, including cancer cell lines with inactivating SMARCA4 mutations. We found complete SWI/SNF ATPase degradation to instantaneously compact the cis-regulatory elements that are bound and activated by transcription factors that drive cancer proliferation, namely MYC, IRF4, TCF3, AR, FOXA1, and ERG. This ensued in parallel untethering of these oncogenic drivers from the chromatin, with subsequent chemical decommissioning of their core enhancer circuitry and attenuation of downstream gene programs. Furthermore, using chromatin conformation assays we found SWI/SNF inactivation to disrupt super-enhancer and promoter DNA looping interactions that wire supra-physiologic expression of the MYC, AR, ERG, IRF4, and TCF3 oncogenes themselves, thereby tempering their expression in cancer cells. Treatment with the SMARCA2/4 degrader alone induced potent inhibition of tumor growth in cell line-derived xenograft models of multiple myeloma, as well as prostate cancer, and synergized with AR antagonists, inducing disease remission in several drug-resistant disease models. Notably, no major toxicities were seen in mice upon prolonged treatment with the SMARCA2/4 degrader, including no indications of thrombocytopenia, gastrointestinal goblet cell depletion, or germ cell degeneration—all being major toxicities associated with the BRD4-targeting therapeutics. To our knowledge, this study is the first preclinical proof of concept that targeted obstruction of chromatin accessibility at non-coding regulatory elements can be a potent therapeutic strategy in enhancer-addicted tumors, warranting the safety and efficacy assessments of SWI/SNF inhibitors and degraders in human clinical trials. Citation Format: Abhijit Parolia, Lanbo Xiao, Yuanyuan Qiao, Pushpinder Bawa, Sanjana Eyunni, Eleanor Young, Rahul Mannan, Sandra E. Carson, Yu Chang, Yuping Zhang, James George, Mustapha Jaber, Fengyun Su, Rui Wang, Sanjita Sasmal, Leena Khare, Subhendu Mukerjee, Chandrasekhar AbbinenI, Kiran Aithal, Xuhong Cao, Yuzhuo Wang, Susanta Samajdar, Murali Ramachandra, Arul M. Chinnaiyan. Targeting SWI/SNF ATPases in enhancer-addicted human cancers [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 3592.
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Xiao, Lanbo, Tongchen He, Olaf Klingbeil, Young Eleanor, Xiaoli Wu, Yuanyuan Qiao, Abhijit Parolia, et al. "Abstract 6602: Targeting the SWI/SNF complex in POU2F-POU2AF transcription factor-driven malignancies." Cancer Research 84, no. 6_Supplement (March 22, 2024): 6602. http://dx.doi.org/10.1158/1538-7445.am2024-6602.
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Abstract Background: Small cell lung cancer (SCLC) is a rapidly progressing subtype of lung cancer with a high growth rate and early metastasis propensity, often resulting in a more advanced disease stage at diagnosis. A recent transcriptome analysis of human SCLC tumors revealed that SCLC could be characterized by the expression pattern of certain transcription factors (TFs), including ASCL1 (achaete-scute family bHLH transcription factor 1) and POU2F3 (POU domain class 2 transcription factor 3), exemplifying SCLC as a TF-driven malignancy. ASCL1-driven SCLC (SCLC-A) manifests a neuroendocrine phenotype, while POU2F3-driven SCLC (SCLC-P) is characterized as a tuft-cell-like variant. Recent studies revealed that POU domain class 2 transcription factors uniquely rely on coactivators to achieve their lineage-defining functions in the tuft cell and B cell lineages. In tuft-cell-like SCLC cells, the coactivators of POU2F3 (POU2AF2 and POU2AF3) endow POU2F3 with a critical transactivation domain by forming a master regulator complex, which supports enhancer-mediated cancer-promoting gene activation in SCLC-P cells. This indicates a potential therapeutic vulnerability of tuft-cell-like SCLC whereby strategies aimed at blocking POU2F3-POU2AF2/3 function may lead to clinical benefit. Methods: We conducted a domain-targeted CRISPR screen to identify druggable targets for SCLC-P, followed by pharmacological validation in preclinical SCLC models. Multi-omics techniques, including ATAC-seq, ChIP-seq, RNA-seq, and RIME, were employed to elucidate the SWI/SNF complex's regulatory influence on the POU2F-POU2AF axis. Results: Here we identified that the POU2F3 molecular subtype of SCLC (SCLC-P) exhibits an exquisite dependence on the activity of the SWI/SNF epigenetic complex. SCLC-P cell lines were sensitive to low nanomolar levels of a SWI/SNF ATPase degrader when compared to other molecular subtypes of SCLC. Co-factors of POU2F were found to interact with components of the SWI/SNF complex. The POU2F3 transcription factor complex is evicted from chromatin upon SWI/SNF ATPase degradation. A novel, orally bioavailable SWI/SNF ATPase PROTAC degrader demonstrated preferential efficacy in SCLC-P relative to the SCLC-A subtype. The SWI/SNF ATPase PROTAC degrader did not alter normal tuft cell numbers in lung or colon, nor did it exhibit toxicity in mice. B cell malignancies which displayed a dependency on the POU2F co-factor, POU2AF1, were also remarkably sensitive to SWI/SNF ATPase degradation. In a POU2AF1-dependent, disseminated murine model of multiple myeloma, AU-24118 had an enhanced survival benefit as compared to pomalidomide, an approved treatment for multiple myeloma. Conclusions: Taken together, our studies suggest that POU2F-POU2AF driven malignancies have an intrinsic dependence on the SWI/SNF complex representing a striking therapeutic vulnerability. Citation Format: Lanbo Xiao, Tongchen He, Olaf Klingbeil, Young Eleanor, Xiaoli Wu, Yuanyuan Qiao, Abhijit Parolia, Sanjana Eyunni, Rahul Mannan, Somnath Mahapatra, NamHoon Kim, Heng Zheng, Fengyun Su, Xuhong Cao, Susanta Samajdar, Murali Ramachandra, Christopher R. Vakoc, Arul M. Chinnaiyan. Targeting the SWI/SNF complex in POU2F-POU2AF transcription factor-driven malignancies [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 6602.
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Tahaney, William M., Jing Qian, Reid Powell, Cassandra L. Moyer, Yanxia Ma, Nghi Nguyen, Jamal Hill, et al. "Abstract GS1-09: Inhibition of GPX4 induces preferential death of p53-mutant triple-negative breast cancer cells." Cancer Research 82, no. 4_Supplement (February 15, 2022): GS1–09—GS1–09. http://dx.doi.org/10.1158/1538-7445.sabcs21-gs1-09.
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Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by lack of ER, PR, and Her2. Up to 85% of TNBCs have a p53 mutation as their oncogenic driver. TP53 is a tumor suppressor known as the “guardian of the genome” for its roles in regulating growth and death after genomic insult. Due to this high frequency of p53 mutations in TNBCs, targeting p53 mutants in a clinical setting is highly attractive. However, there are currently no FDA-approved drugs that can directly target p53 mutant TNBCs. We propose pathways exist that, when inhibited, will induce the specific death of p53-mutant breast cancer cells, but not p53-wild type breast cells. To investigate this hypothesis, we performed high-throughput drug screening to identify drugs that induce death in p53-mutant TNBCs. We then characterized the identified drugs for mechanism of death induction and in vivo drug effect. Methods: In vitro and in silico drug screens were conducted with small-molecule libraries of drugs with known protein targets, and screens were integrated and common drugs identified. P53-wild type and mutant cells were treated with identified drugs and stained with DAPI and DRAQ7 to identify growth-suppressive and death-inductive effects. One of these drugs, the GPX4 inhibitor ML-162, was selected for further study. Mechanism of death induction by ML-162 was determined with AnnexinV/PI, caspase cleavage, and ferroptosis assays. To confirm these results, GPX4 was knocked out and replicated the effect of ML-162. To determine the reliance of this phenotype on p53 mutational status, a series of inducible p53-mutant cell lines were created in ER+ and TNBC cell lines and then treated with small molecule inhibitors. ML-162 in vivo effect was demonstrated by treating p53-mutant TNBC xenografts in nude mice. Results: Integration of in vitro and in silico screens identified 6 common drugs, representing cell cycle inhibitors, cell division inhibitors, a proteasome inhibitor, and a peroxidase inhibitor. Identified drugs were demonstrated to reduce growth or induce death of p53-mutant TNBC cell lines. The GPX4 inhibitor ML-162 was further characterized, and found to induce death through ferroptosis, and not apoptosis or necroptosis. GPX4 knockout in p53-mutant TNBC cell lines induced ferroptosis and can be blocked with an anti-ferroptosis drug. Inducible p53-mutations in ER+ and TNBC cell lines were treated with ML-162. P53 mutations in TNBC, and not ER+, cell lines showed increased sensitivity to ML-162. To demonstrate in vivo effect of ML-162, TNBC cell line xenografts were grown in nude mice and treated with ML-162. This treatment significantly reduced tumor volume and also induced lipid peroxidation, a hallmark of ferroptosis. Conclusion: Our high-throughput screening demonstrated several of the identified drugs suppress growth or induce death preferentially in p53-mutant breast cancers. One of these drugs, ML-162, induces death of p53-mutant triple-negative breast cancer cells through induction of ferroptosis, both in vitro and in vivo. These studies provide the basic science foundation to further develop ferroptosis inducers for the targeted treatment of p53-mutant breast cancers. This work was funded by the John Charles Cain Endowment. Citation Format: William M Tahaney, Jing Qian, Reid Powell, Cassandra L Moyer, Yanxia Ma, Nghi Nguyen, Jamal Hill, Clifford Stephan, Abhijit Mazumdar, Peter JA Davies, Powel H Brown. Inhibition of GPX4 induces preferential death of p53-mutant triple-negative breast cancer cells [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 GS1-09.
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Cecchini, Michael, Mary Jo Pilat, Nataliya Uboha, Nilofer S. Azad, May Cho, Elizabeth J. Davis, Jordi Rodon Ahnert, et al. "Abstract B040: NCI 10129: A Phase 2 Study of the PARP inhibitor Olaparib (AZD2281) in IDH1 and IDH2 mutant advanced solid tumors." Molecular Cancer Therapeutics 22, no. 12_Supplement (December 1, 2023): B040. http://dx.doi.org/10.1158/1535-7163.targ-23-b040.
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Abstract Introduction: Cholangiocarcinoma (CCA) is a highly aggressive malignancy with mutations in Isocitrate dehydrogenase (IDH) identified in approximately 15% of patients. Neomorphic mutations in IDH 1/2 result in accumulation of the oncometabolite 2-hydroxyglutarate (2G), which has been implicated in tumor progression via inhibitory effects on alpha ketoglutarate. Moreover, the mutant IDH dependent accumulation of 2HG results in homologous recombination deficiency (HRD) and renders these cells exquisitely sensitive to Poly (ADP-Ribose) polymerase (PARP) inhibitors. NCI 10129 evaluated the efficacy of olaparib for IDH mutated solid tumors, and here we present the CCA cohort. Methods: NCI 10129 is a 3 arm, open label phase 2 clinical trial performed in the NCI National Clinical Trials Network evaluating olaparib 300 mg twice daily for IDH mutated solid tumors refractory to standard treatment. Patients with CCA were enrolled in 2 cohorts 1) IDHi pre-treated CCA and 2) IDHi untreated CCA. The primary endpoint was overall response rate (ORR) and secondary endpoints includes progression-free survival (PFS), and overall survival (OS). An exploratory analysis measured the impact of circulating 2HG levels, circulating tumor DNA, and tumor genomics on patient outcomes. Results: Thirty patients with CCA enrolled on NCI10129 (15 each IDHi pre-treated and IDHi treatment naïve), 18 patients received ≥ 2 prior systemic treatments, and 23 patients had IDH1 mutations and 7 patients IDH2 mutations. There were no objective responses seen in the first 15 CCA patients in either cohort and enrollment was closed. The median PFS was 2.4 months 95% CI (1.9 - 6.5) and median OS 12.9 months 95% CI (6.3 – not reached). The IDHi pre-treated cohort had improved median OS compared to IDHi treatment naïve (15.3 vs 7.3, P = 0.04). There were 8/30 (27%) patients with clinical benefit (CB) as defined by PFS > 6 months. Patients with CB had lower baseline mean D-2HG levels compared to those without CB (1.4 umol/L vs 5.9 umol/L, p = 0.02). Whole exome sequencing revealed the study population to be enriched for HRD by sum scores and HRD mutational signatures without alternative HRD mutations other than IDH1/2. No improvement in survival was noted based on HRD status. RNA sequencing Gene Set Enrichment Analysis revealed that cell cycle and interferon alpha pathways were activated in patients with CB (p < 0.01). Olaparib was tolerable with the majority of adverse events grade 1-2. Conclusion: Olaparib did not result in objective responses in IDH mutated CCA. However, a subgroup of patients did demonstrate prolonged PFS comparable to historical controls for refractory CCA as well that seen with targeted agents such as IDHi. Exploratory analysis revealed this subgroup to be enriched for lower baseline 2HG levels. Serial ctDNA analysis is ongoing and will be presented. Given the CB subgroup and OS data, additional clinical trials leveraging the HRD properties of IDH mutations is warranted. Future studies may benefit from DNA damage combination therapies thereby enhancing potency. Citation Format: Michael Cecchini, Mary Jo Pilat, Nataliya Uboha, Nilofer S Azad, May Cho, Elizabeth J Davis, Jordi Rodon Ahnert, Gabriel Tinoco, Geoff I Shapiro, Simon Khagi, Benjamin Powers, Roman Groisberg, Jan Drappatz, Li Chen, Biswajit Das, Xun Bao, Jing Li, Abhijit Patel, Monica Niger, Deborah Doroshow, Diane Durecki, Scott Boerner, Ranjit Bindra, Percy Ivy, Yu Shyr, Patricia LoRusso. NCI 10129: A Phase 2 Study of the PARP inhibitor Olaparib (AZD2281) in IDH1 and IDH2 mutant advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B040.
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Lanier, Amanda, William Tahaney, Jing Qian, Cassandra Moyer, Yanxia Ma, Banu Arun, Abhijit Mazumdar, and Powel Brown. "Abstract PO2-24-01: Kif11 Inhibition Preferentially Kills TP53-mutant Breast Cancer Cells." Cancer Research 84, no. 9_Supplement (May 2, 2024): PO2–24–01—PO2–24–01. http://dx.doi.org/10.1158/1538-7445.sabcs23-po2-24-01.
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Abstract Background Triple-Negative Breast Cancer (TNBC) makes up 15-20% of breast cancer diagnoses and is more common in younger women, those with BRCA mutations, and Black patients. Furthermore, TNBCs are defined by their lack of expression of the targetable receptors: estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), and progesterone receptor (PR), resulting in few targeted therapy options for TNBC patients. One potential therapeutic target in TNBC is mutant p53, since 85-90% of TNBCs harbor TP53 mutations. However, the mutant p53 protein is challenging to target directly. Therefore, we have sought to identify survival pathways critical to TP53 mutant cells. Through a combined in vitro and in silico drug screen, we identified that the Kif11 inhibitor SB-743921 differentially kills TP53 mutant breast cancer cells compared to TP53 wild-type cells. Hypothesis Based on this screening data, we hypothesized that Kif11 inhibition causes TP53 mutant cells to undergo mitotic catastrophe resulting in cell death due to failure of activation of p53-mediated cell cycle checkpoints. Methods Clinical data was obtained from cBioPortal from the TCGA and METABRIC cohorts. Expression data analysis and survival analyses were performed using GraphPad Prism. Cell growth assays were conducted by seeding cells in 96 well plates, treating under designated conditions, then staining with Hoechst 33342 for cell counting on the ImageXpress Pico. Cell death was determined by co-staining with Hoechst 33342 and DRAQ7 followed by imaging and analysis on the ImageXpress Pico and by Annexin V and Propidium Iodide Staining followed by flow cytometry analysis. Cell cycle analysis was conducted following synchronization with Lovastatin and Mevalonate release followed by collection of samples, fixation, PI staining, and flow cytometry analysis. Immunofluorescence imaging was conducted by staining with anti-alpha-tubulin-AlexaFluor488 and DAPI and imaging at 20x and 63x on the ImageXPress PICO. In vitro expression experiments were carried out through qPCR and western blotting. < Results In human breast cancers, KIF11 is more highly expressed in TP53 mutant, as compared to wild-type breast cancers, and in TNBCs, as compared to other breast cancer subtypes. Patients with tumors that had higher expression of Kif11 had poorer overall survival outcomes. Inhibition of Kif11 with the small molecule inhibitor SB-743921 induces greater death of TP53 mutant as compared to wild-type breast cancer cells. Kif11 inhibition leads to a cell cycle block in both TP53 mutant and wild-type cells, but TP53 mutant cells then die following this cell cycle block. Kif11 inhibition causes mitotic dysfunction, including monopolar spindle formation, in mutant and wild-type cells, but greater incidence of spindle abnormalities and multinucleated cells in TP53 mutants. Introduction of a TP53 mutation into TP53 wild-type cells also induces cell death following Kif11 inhibition. Conclusions The Kif11 mitotic kinesin is more highly expressed in TP53 mutant and triple-negative breast cancers than in TP53 wild-type breast cancers, and high expression is associated with poorer survival outcomes. In TP53 mutant cells, Kif11 inhibition results in mitotic dysfunction and cell death due to mitotic catastrophe. Acknowledgments Research reported in this publication was supported by the John Charles Cain Endowment and the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Numbers TL1TR003169 and UL1TR003167. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We would also like to thank the MDACC NORTH Campus Flow Cytometry and Cellular Imaging Core Facility for their assistance. Citation Format: Amanda Lanier, William Tahaney, Jing Qian, Cassandra Moyer, Yanxia Ma, Banu Arun, Abhijit Mazumdar, Powel Brown. Kif11 Inhibition Preferentially Kills TP53-mutant Breast Cancer Cells [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-24-01.
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Moyer, Cassandra, Darian Coleman, Jamal Hill, Lana A. Vornik, Michelle Savage, Martin Sanders, Sei Shizuko, Altaf Mohammed, Powel Brown, and Abhijit Mazumdar. "Abstract PS07-07: The RXR agonist, IRX4204, delays the formation of Brca1 mutant mammary tumors via modulation of the anti-tumor immune response." Cancer Research 84, no. 9_Supplement (May 2, 2024): PS07–07—PS07–07. http://dx.doi.org/10.1158/1538-7445.sabcs23-ps07-07.
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Abstract Background: Women with germline BRCA1 mutations are at an increased risk for developing breast cancer in their lifetime, often at a young age with more aggressive tumors. At present, prophylactic bilateral mastectomy is the most effective strategy for reducing breast cancer risk. However, this invasive procedure is irreversible and associated with potential complications. We and others have found that PARP inhibitors can delay Brca1-mutant tumor formation in mice and could be beneficial for the prevention of breast cancer. However, currently available PARP inhibitors are associated with modest toxicities that may not be acceptable to women without cancer. Thus, there remains an urgent need for the development of safe and effective therapies for the prevention of breast cancer. Here, we present data demonstrating the activity of IRX4204, a minimally toxic and highly specific agonist of the nuclear retinoid X receptor (RXR), to delay the formation of mammary tumors in a Brca1-deficient mouse model. This inhibitory effect on tumor growth is due, in part, to the role of IRX4204 in stimulating the anti-tumor immune response. Methods: We used the established MMTV-Cre, conditional Brca1 gene knockout, p53 heterozygous loss mouse model (BRCA1co/co; MMTV-Cre+/+; p53+/-) and selected for mutant female pups using PCR genotyping. At 16 weeks of age, all mice were separated into 4 treatment groups (n=10 per group): (1) sesame oil control; (2) the novel RXR agonist, IRX-4204 (10mg/kg); (3) high-dose IRX4204 (20 mg/kg); and (4) the RXR agonist, 9-cis-UAB-30 (5 mg/kg). All treatments were given by oral gavage five days per week, and mice were observed daily for tumor formation and toxicity. At the study endpoint, tumors and normal mammary glands were collected for additional analyses. Immunohistochemical staining was used to quantify CD8a, Ki-67 and cleaved caspase 3 expression in Brca1-deficient tumors. Oil Red O staining was used to measure changes in lipid accumulation in Brca1-deficient cell lines treated with IRX4204. qPCR was used to quantify the changes in gene expression of lipid metabolism-associated genes upon treatment with IRX4204 in vitro. Results: Vehicle-treated Brca1-deficient mice had a median time-to-tumor formation (TTF) of 211 days, with 100% developing tumors by 330 days. Mice treated with UAB 5 mg/kg had an improved median TTF of 261 days, whereas mice treated with IRX4204 10mg/kg or 20mg/kg had a median TTF of 347 and 304 days, respectively (p < 0.01). In addition, 60% of mice treated with IRX4204 10 mg/kg remained tumor-free at 330 days. IRX4204-treated tumors showed an increased infiltration of CD8-positive T-cells over vehicle-treated tumors (p < 0.05). Treatment of Brca1-deficient cell lines with IRX4204 in vitro resulted in a significant increase in lipid accumulation accompanied by a 2-fold increase of Srebf1 expression (a key transcription factor that regulates lipid homeostasis) within 24 hours of treatment (p < 0.05). Conclusion: These data demonstrate a novel use of the RXR agonist, IRX4204, to delay the formation of Brca1-deficient mammary tumors. We have found that IRX4204 treatment modulates the tumor immune response through increased infiltration of cytotoxic CD8-positive T-cells in Brca1-deficient mammary tumors in vivo. We have also determined that IRX4204 modulates lipid metabolism in breast cancer cell lines in vitro. It is known that lipid-derived antigens can stimulate T-cell activity. Our findings suggest that RXR agonists may alter lipid antigen production to activate an anti-tumor response. Additional immune and lipidomic studies are on-going. This work was supported by NCI-PREVENT grant (to PB and AM HHSN26100008) and CFP Foundation (Odyssey Fellowship to CM). Citation Format: Cassandra Moyer, Darian Coleman, Jamal Hill, Lana A. Vornik, Michelle Savage, Martin Sanders, Sei Shizuko, Altaf Mohammed, Powel Brown, Abhijit Mazumdar. The RXR agonist, IRX4204, delays the formation of Brca1 mutant mammary tumors via modulation of the anti-tumor immune response [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS07-07.
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Tsimberidou, Apostolia M., Benigno C. Valdez, Bin Yuan, Yago Nieto, Mehmet Baysal, Abhijit Chakraborty, and Borje S. Andersson. "Abstract LB158: Synergistic cytotoxicity of histone deacetylase and poly-ADP ribose polymerase inhibitors and decitabine in pancreatic cancer cells: implications for novel therapy." Cancer Research 84, no. 7_Supplement (April 5, 2024): LB158. http://dx.doi.org/10.1158/1538-7445.am2024-lb158.
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Abstract Histone deacetylase inhibitors (HDACi) can modulate the acetylation status of proteins, influencing the genomic instability exhibited by cancer cells. Poly (ADP ribose) polymerase (PARP) inhibitors (PARPi) have a direct effect on protein poly (ADP-ribosyl)ation, which is important for DNA repair. Decitabine is a nucleoside cytidine analogue, which when phosphorylated gets incorporated into the growing DNA strand, inhibiting methylation and inducing DNA damage by inactivating and trapping DNA methyltransferase on the DNA, thereby activating transcriptionally silenced DNA loci. We explored various combinations of HDACi and PARPi +/- decitabine (hypomethylating agent) in pancreatic cancer cell lines BxPC-3 and PL45 (wild-type BRCA1 and BRCA2) and Capan-1 (mutated BRCA2). Colony formation and drug-mediated inhibition of cell proliferation in pancreatic cancer cell lines and comparison of the effects of each drug combination with the effect of the individual drugs are shown in Table. The combination of HDACi (panobinostat or vorinostat) with PARPi (talazoparib or olaparib) resulted in synergistic cytotoxicity in all cell lines tested. The addition of decitabine further increased the synergistic cytotoxicity noted with HDACi and PARPi, triggering apoptosis (evidenced by increased cleavage of caspase 3 and PARP1). The 3-drug combination treatments (vorinostat, talazoparib, and decitabine; vorinostat, olaparib, and decitabine; panobinostat, talazoparib, and decitabine; panobinostat, olaparib, and decitabine) induced more DNA damage (increased phosphorylation of histone 2AX) than the individual drugs and impaired the DNA repair pathways (decreased levels of ATM, BRCA1, and ATRX proteins). The 3-drug combinations also altered the epigenetic regulation of gene expression (NuRD complex subunits, reduced levels). This is the first study to demonstrate synergistic interactions between the aforementioned agents in pancreatic cancer cell lines and provides preclinical data to design individualized therapeutic approaches with the potential to improve pancreatic cancer treatment outcomes. Table. Colony formation and drug-mediated inhibition of cell proliferation in pancreatic cancer cell lines. Comparison of the effects of each drug combination with the effect of the individual drugs (Table shows the p-values for each comparison.) Colony formation BxPC-3 PL45 Capan-1 Pano SAHA TLZ Ola DAC Pano SAHA TLZ Ola DAC Pano SAHA TLZ Ola DAC Pano+TLZ 0.00048 0.0052 2.40E-06 2.70E-06 0.0051 0.021 Pano+Ola 0.0035 0.078 0.0011 0.00094 0.0016 0.022 SAHA+TLZ 1.80E-05 0.17 0.0029 0.012 0.0014 0.019 SAHA+Ola 0.00018 0.014 0.0016 0.0068 0.0066 0.029 Pano+TLZ+DAC 4.20E-05 0.00026 0.0015 1.70E-05 1.20E-05 2.70E-06 0.00052 0.00088 0.0064 Pano+Ola+DAC 3.40E-05 0.00049 0.0013 7.10E-07 1.70E-06 2.20E-06 0.00068 0.0028 0.0053 SAHA+TLZ+DAC 0.00016 0.00016 0.0011 1.90E-05 3.70E-06 9.30E-07 0.00018 0.00017 0.011 SAHA+Ola+DAC 4.90E-07 0.00035 0.001 0.00022 0.00026 0.00084 0.00016 0.0016 0.0035 Drug-mediated inhibition of cell proliferation Pano+TLZ+DAC 3.57E-05 3.89E-07 1.30E-07 2.91E-05 3.76E-06 1.80E-08 0.0239 ND 0.0092 Pano+Ola+DAC 7.76E-05 1.43E-07 2.52E-07 6.59E-07 1.03E-08 2.22E-07 0.0013 0.21 0.0034 SAHA+TLZ+DAC 3.04E-06 0.00034 1.17E-05 4.91E-08 4.45E-06 1.74E-07 0.0013 1.75E-01 0.007 SAHA+Ola+DAC 0.00012 0.0032 0.000068 9.64E-09 1.53E-08 9.35E-07 0.0007 0.18 0.0054 Abbreviations: DAC: decitabine; ND: not determined; Ola: olaparib; Pano: panobinostat; SAHA: vorinostat; TLZ: talazoparib P ≤ 0.05 is considered statistically significant. Citation Format: Apostolia M. Tsimberidou, Benigno C. Valdez, Bin Yuan, Yago Nieto, Mehmet Baysal, Abhijit Chakraborty, Borje S. Andersson. Synergistic cytotoxicity of histone deacetylase and poly-ADP ribose polymerase inhibitors and decitabine in pancreatic cancer cells: implications for novel therapy [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 LB158.
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Kulkarni, Aditi, Urbashi Basnet, Abhijeet R. Patil, Rebecca DeJesus, and Sourav Roy. "Abstract 3674: Differential expression of stress-survival pathway genes related to Hispanic colorectal cancer disparities." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3674. http://dx.doi.org/10.1158/1538-7445.am2022-3674.
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Abstract Colorectal cancer (CRC) accounts for 12% and 8% of all estimated new cases of cancer and 11% and 9% of all cancer deaths in Hispanic men and women, respectively. Stress-survival pathways have been implicated in tumorigenesis of CRC and in providing resistance to chemotherapy-induced cell-death by suppressing reactive oxygen species (ROS), repairing DNA damage, and by regulating cell signaling pathways. However, studies related to the role of these pathways in CRC from the Hispanic health disparities perspective, are limited. Essential to improving treatment, prognosis, and detection strategies is the identification and validation of new ethnicity-specific transcriptomic markers within the stress-survival pathways as effective predictors of CRC. In this study, we have explored the role of stress-survival pathway genes in Hispanic and Non-Hispanic White (NHW) CRC tissues. We have used microarray and RNA-seq datasets obtained from the gene expression omnibus (GEO) and the cancer genome atlas (TCGA) to identify 28 genes associated with CRC. These genes were screened for transcript level expression in one normal colon and two CRC cell lines, and in cDNA arrays containing tumor (n=40) from different stages, and control (n=8) samples. The protein level expressions were evaluated by immunohistochemistry (IHC) in CRC tissue microarrays (TMAs) containing different stages of tumor (n = 108) and control (n = 12) tissues. All 28 genes were also analyzed for their transcript level expressions in Hispanic and NHW tissues. Genes related to apoptosis like FOXM1, CDK1, CDK4, Chek1, and MCM10 showed consistent upregulation in CRC cell lines, cDNA arrays and TMAs when compared to normal samples. We could also detect a correlation between the differential expression of these genes and the tumor stages. CDK4, Chek1, FOXM1, and CDC25, were observed to be downregulated in the Hispanic CRC tissues. On the other hand, oxidative stress markers were not seen to be differentially expressed in the two CRC cell lines when compared to the normal cell line. However, some of the known oxidative stress markers like PRDX4, GPX1, and SOD2 were found to be upregulated in Hispanics when compared to NHW tissues. Our results suggest that some of these stress-survival pathway genes could be explored as interesting candidates for ethnicity-specific CRC biomarkers and as novel therapeutic targets in the future. Citation Format: Aditi Kulkarni, Urbashi Basnet, Abhijeet R. Patil, Rebecca DeJesus, Sourav Roy. Differential expression of stress-survival pathway genes related to Hispanic colorectal cancer disparities [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 3674.
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Deodhar, A., I. Mcinnes, X. Baraliakos, K. Reich, A. B. Gottlieb, M. Lebwohl, S. Schreiber, et al. "FRI0272 SECUKINUMAB DEMONSTRATES A CONSISTENT SAFETY PROFILE IN PATIENTS WITH PSORIASIS, PSORIATIC ARTHRITIS AND ANKYLOSING SPONDYLITIS OVER LONG TERM: UPDATED POOLED SAFETY ANALYSES." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 722.2–722. http://dx.doi.org/10.1136/annrheumdis-2020-eular.5118.
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Background:Pooled safety data has been reported with secukinumab (SEC) in patients (pts) with Psoriatic arthritis (PsA), Ankylosing Spondylitis (AS) and Psoriasis (PsO).1Objectives:To report longer-term safety data of SEC treatment in PsA, AS, PsO pts up to 5 years.Methods:The integrated clinical trial safety dataset included data pooled from 28 randomised controlled clinical trials of SEC 300 or 150 or 75 mg in PsO (11 Phase 3 and 8 Phase 4 trials), PsA (5 Phase 3 trials), and AS (4 Phase 3 trials), along with post-marketing safety surveillance data with a cut-off date of 25 December 2018. Adverse events (AEs) were reported as exposure-adjusted incident rates (EAIRs) per 100 pt-years. Analyses included all pts who received ≥1 dose of SEC.Results:A total of 12637 pts (8819, 2678 and 1140 pts with PsO, PsA and AS, with an exposure of 15063.1, 5984.6 and 3527.2 pt-years, respectively) were included. The most frequent AE was upper respiratory tract infection and EAIR per 100 pt-years for IBD, malignancies and MACE remained low. The EAIR per 100 pt-years for adverse events (AEs) of special interest are reported in Table 1. The cumulative post-marketing exposure to SEC was estimated to be ~285,811 pt-years across the approved indications. Safety data from post-marketing surveillance are reported in Table 2.Table 1.Selected AEs of interest with SEC across pooled clinical trialsVariablePsOPsAASSECN=8819SECN=2678SECN=1140Exposure (Days), Mean (SD)623.9 (567.7)816.2 (580.7)1130.1 (583.0)Death, n (%)15 (0.2)13 (0.5)10 (0.9)Selected AE’s of interest, EAIR (95% CI)Serious infections11.4 (1.2, 1.6)1.8 (1.5, 2.2)1.2 (0.9, 1.6)Candidainfections22.9 (2.7, 3.2)1.5 (1.2, 1.9)0.7 (0.5, 1.1)IBD3Crohn’s disease3Ulcerative colitis30.01 (0.0, 0.05)0.1 (0.05, 0.2)0.1 (0.08, 0.2)0.03 (0.0, 0.1)0.1 (0.04, 0.2)0.1 (0.04, 0.2)0.03 (0.0, 0.2)0.4 (0.24, 0.7)0.2 (0.1, 0.5)MACE40.4 (0.31, 0.5)0.4 (0.3, 0.6)0.7 (0.4, 1.0)Uveitis30.01 (0.0, 0.05)0.1 (0.04, 0.2)1.2 (0.9, 1.7)Malignancy50.9 (0.7, 1.0)1.0 (0.77, 1.3)0.5 (0.3, 0.8)1Rates for system organ class;2Rates for high level term;3Rates for preferred term (PT; IBD for unspecified IBD);4Rates for Novartis MedDRA Query term;5Rates for standardized MedDRA query term – ‘malignancies and unspecified tumour’; EAIR, exposure adjusted incidence rate per 100 pt-years; N, number of pts in the analysisTable 2.Summary of SEC post-marketing safetyExposure (PTY)PSUR126Dec14 -25Jun15PSUR226 Jun - 25Dec15PSUR326Dec15 -25Jun16PSUR426Jun -25Dec16PSUR526Dec16 -25Dec17PSUR626Dec17 -25Dec18Cumulative18387450168712854993744137325285811 n (Reporting rate PTY)Serious infections89 (4.8)149 (2.0)232 (1.4)475 (1.7)649 (0.7)1841 (1.3)3980 (1.4)Malignancy2 (0.1)15 (0.2)21 (0.1)50 (0.2)225 (0.2)422 (0.3)788 (0.3)Total IBD4 (0.2)12 (0.2)37(0.2)46 (0.2)185 (0.2)340 (0.3)693 (0.2)MACE6 (0.3)15 (0.2)16 (0.1)39 (0.1)151 (0.2)238 (0.2)504 (0.2)PSUR, periodic safety update report; PTY, pt-treatment yearsConclusion:In this long-term analysis across clinical trials and post-marketing surveillance, of pts with PsO, PsA and AS, SEC was well tolerated, with a safety profile consistent with previous reports.1Reference:[1]Deodhar et al. Arthritis Research & Therapy (2019) 21:111.Disclosure of Interests:Atul Deodhar Grant/research support from: AbbVie, Eli Lilly, GSK, Novartis, Pfizer, UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Iain McInnes Grant/research support from: Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, and UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, Novartis, Pfizer, and UCB, Xenofon Baraliakos Grant/research support from: Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Consultant of: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Kristian Reich Grant/research support from: Affibody; Almirall; Amgen; Biogen; Boehringer Ingelheim; Celgene; Centocor; Covagen; Eli Lilly; Forward Pharma; Fresenius Medical Care; GlaxoSmithKline; Janssen; Kyowa Kirin; LEO Pharma; Medac; Merck; Novartis; Miltenyi Biotec; Ocean Pharma; Pfizer; Regeneron; Samsung Bioepis; Sanofi Genzyme; Takeda; UCB; Valeant and Xenoport., Consultant of: Affibody; Almirall; Amgen; Biogen; Boehringer Ingelheim; Celgene; Centocor; Covagen; Eli Lilly; Forward Pharma; Fresenius Medical Care; GlaxoSmithKline; Janssen; Kyowa Kirin; LEO Pharma; Medac; Merck; Novartis; Miltenyi Biotec; Ocean Pharma; Pfizer; Regeneron; Samsung Bioepis; Sanofi Genzyme; Takeda; UCB; Valeant and Xenoport., Speakers bureau: Affibody; Almirall; Amgen; Biogen; Boehringer Ingelheim; Celgene; Centocor; Covagen; Eli Lilly; Forward Pharma; Fresenius Medical Care; GlaxoSmithKline; Janssen; Kyowa Kirin; LEO Pharma; Medac; Merck; Novartis; Miltenyi Biotec; Ocean Pharma; Pfizer; Regeneron; Samsung Bioepis; Sanofi Genzyme; Takeda; UCB; Valeant and Xenoport., Alice B Gottlieb Grant/research support from:: Research grants, consultation fees, or speaker honoraria for lectures from: Pfizer, AbbVie, BMS, Lilly, MSD, Novartis, Roche, Sanofi, Sandoz, Nordic, Celltrion and UCB., Consultant of:: Research grants, consultation fees, or speaker honoraria for lectures from: Pfizer, AbbVie, BMS, Lilly, MSD, Novartis, Roche, Sanofi, Sandoz, Nordic, Celltrion and UCB., Speakers bureau:: Research grants, consultation fees, or speaker honoraria for lectures from: Pfizer, AbbVie, BMS, Lilly, MSD, Novartis, Roche, Sanofi, Sandoz, Nordic, Celltrion and UCB., Mark Lebwohl Grant/research support from: AbbVie, Amgen, Arcutis, AstraZeneca, Boehringer Ingelheim, Celgene, Clinuvel, Eli Lilly, Incyte, Janssen Research & Development, LLC, Kadmon Corp., LLC, Leo Pharmaceutucals, Medimmune, Novartis, Ortho Dermatologics, Pfizer, Sciderm, UCB, Inc., and ViDac, Consultant of: Allergan, Almirall, Arcutis, Inc., Avotres Therapeutics, BirchBioMed Inc., Boehringer-Ingelheim, Bristol-Myers Squibb, Cara Therapeutics, Castle Biosciences, Corrona, Dermavant Sciences, Evelo, Foundation for Research and Education in Dermatology, Inozyme Pharma, LEO Pharma, Meiji Seika Pharma, Menlo, Mitsubishi, Neuroderm, Pfizer, Promius/Dr. Reddy’s Laboratories, Theravance, and Verrica, Stefan Schreiber Consultant of: AbbVie, Arena, BMS, Biogen, Celltrion, Celgene, IMAB, Gilead, MSD, Mylan, Pfizer, Fresenius, Janssen, Takeda, Theravance, provention Bio, Protagonist and Falk, Weibin Bao Shareholder of: Novartis, Employee of: Novartis, Kwaku Marfo Shareholder of: Novartis, Employee of: Novartis, Hanno Richards Shareholder of: Novartis, Employee of: Novartis, Luminita Pricop Shareholder of: Novartis, Employee of: Novartis, Abhijit Shete Shareholder of: Novartis, Employee of: Novartis, Jorge Safi Shareholder of: Novartis, Employee of: Novartis, Philip J Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – grant/research support, Consultant of: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – consultant, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Eli Lilly, Genentech, Janssen, Pfizer, UCB – speakers bureau
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Paxson, Allan I., Loren H. Chang, Kendra D. Marr, Jaime M. Gard, Colin S. Nelson, Abhijeet Kapoor, William L. Harryman, et al. "Abstract 4301: Increasing the therapeutic vulnerability of heterogenous cell phenotypes within prostate cancer." Cancer Research 84, no. 6_Supplement (March 22, 2024): 4301. http://dx.doi.org/10.1158/1538-7445.am2024-4301.
Full textAbstract:
Abstract Phenotype heterogeneity is a hallmark of prostate adenocarcinoma and is a major source of recurrent disease. We tested pre-clinical therapies to eradicate phenotypically distinct cell populations derived from the parental DU145WT prostate cancer cell line. The derived cell lines are called DU145AA, DU145J7, and DU145G6. The DU145AA variant is a non-aggressive cell population while the DU145J7 and DU145G6 are aggressive phenotypes that invade through muscle and metastasize to bone. Flow cytometry analysis documented the phenotypic plasticity of the DU145 cell variants since DU145 aggressive lines expressed 1.3-fold increases in matrix metalloprotease 14 surface expression and a 2-fold increase in tri-methyl Histone H3 at lysine 27 as compared to the DU145WT parent line. The DU145AA non-aggressive line expressed an epithelial cell-cell lineage phenotype with up to 2-fold increases in E-cadherin, claudin 4, claudin 7, and a unique cytokeratin 6A expression and a 2-fold loss of Zinc finger E-box-binding homeobox 1, EVL, and Kindlin 2. A collaboration with the National Center for Advancing Translational Science (NCATS) resulted in the identification of pharmacological agents active in eradicating DU145J7 and DU145G6 cells as compared to the DU145WT population. The agents were selected from a quantitative high-throughput screen of 10,677 combined investigative and approved anti-cancer agents using the Cell Titer-Glo Luminescent Cell Viability assay. We independently validated 31 compounds from the assay that have 2-fold, or greater, differences in concentration to inhibit 50% cell growth (IC50) between the wild-type and aggressive variants of DU145 cells. The top 10 hits were tested for the efficacy of different combinations to eradicate defined admixtures of aggressive and non-aggressive phenotypes, including the DU145AA cells, to model tumor heterogeneity. Tested compounds with differential sensitivity between aggressive and non-aggressive cells were those inhibiting histone deacetylase (vorinostat, fimepinostat, and pracinostat), proteasomes (bortezomib, delanzomib, ixazomib), topoisomerases (gimatecan and daunorubicin), and other compounds identified independently by us targeting nicotinamide phosphoribosyl transferase (FK866) and DNA (bleomycin). Using admixtures of tumor cell phenotypes, we determined optimal combinations of compounds that would selectively eradicate the sub-populations. The results suggest that determination of phenotypes within tumor populations may eliminate the heterogenous tumor and prevent recurrent disease. Funding was provided by the University of Arizona Cancer Center (NCI-P30 CA23074 and NCI-R01 CA159406) and by the Partnership in Native American Cancer Prevention at the University of Arizona (U54CA143924) and Northern Arizona University (U54CA143925). Collaborators at NCATS were supported by the intramural research program. Citation Format: Allan I. Paxson, Loren H. Chang, Kendra D. Marr, Jaime M. Gard, Colin S. Nelson, Abhijeet Kapoor, William L. Harryman, Juan J. Marugan, Mark J. Henderson, Tino W. Sanchez, Anne E. Cress. Increasing the therapeutic vulnerability of heterogenous cell phenotypes within 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 4301.
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Basnet, Urbashi, Aditi Kulkarni, Frances A. Rangel, Abhijeet R. Patil, and Sourav Roy. "Abstract 5232: Differential expression of stress-survival pathway genes related to Hispanic colorectal cancer disparities." Cancer Research 83, no. 7_Supplement (April 4, 2023): 5232. http://dx.doi.org/10.1158/1538-7445.am2023-5232.
Full textAbstract:
Abstract Colorectal cancer (CRC) is one of the most life-threatening gastrointestinal cancers, with around 1.9 million new cases and 935,000 deaths in the year 2020 worldwide. It accounts for 12% and 8% of all estimated new cases of cancer and 11% and 9% of all cancer deaths in Hispanic men and women, respectively. Long-term cumulative exposure to environmental factors such as reactive oxygen species (ROS) has been implicated to cause molecular damage and DNA modifications that are critical for CRC pathogenesis through stress-survival pathway genes. However, limited number of studies related to the role of these pathways have not been conducted for the Hispanic population. The identification and validation of new ethnicity-specific transcriptomic markers within the stress-survival pathways is important for improving treatment, prognosis, and detection strategies. In this study, we have explored the role of stress-survival pathway genes in Hispanic and Non-Hispanic White (NHW) CRC tissues. In one of the previously published studies from our lab we used microarray and RNA-seq datasets obtained from the gene expression omnibus (GEO), the cancer genome atlas (TCGA), and the oncomine databases to identify 28 genes associated with CRC. These genes were screened for transcript level expressions in six CRC cell lines and a normal colon cell line, and in cDNA arrays containing the tumor (n=40) from different CRC stages, and control (n=8) samples by qRT-PCR. The protein level expressions were evaluated by immunohistochemistry (IHC) in CRC tissue microarrays (TMAs) containing different stages of tumor (n = 108) and control (n = 12) tissues. All 28 genes were also analyzed for their transcript-level expressions in Hispanic (n=10) and NHW (n=10) tumors and corresponding non-tumor adjacent (NATs; n=3) tissues. The stress-survival pathway genes associated with cell cycle regulation such as CHEK1, MCM10, PDCD2L, CCNB1, CDK1 and CDK4, and an oxidative stress marker PRDX4 were upregulated at both transcript and protein levels when compared to its normal counterparts. Additionally, the genes CHEK1, MCM10, BCL2L1, CSE1L, ESPL1, GLA, GPX2, RRM2B, SH3GLB1, TNFRSF12A, TRAF5 and TRIB3 were observed to be upregulated whereas GPX1, NOXA, NQO1, SLC7A11, BCL2L12, CCNB1, CDK1, CDK4, FOXM1, PDCD2L and SOD2 were found to be downregulated in Hispanic tumor tissues when compared to NHWs. Only CDK1, CHEK1, FOXM1 and NQO1 were seen to be differentially expressed in the Hispanic and NHW NATs; however, their expression patterns were different from that observed in the respective tumor tissues. Overall, our current findings evaluate the expression of stress-survival pathway genes across different CRC cell lines, stages, and Hispanic and NHW tissues. The genes identified to be differentially expressed in Hispanic tissues may be used as potential biomarkers or as therapeutic targets specific to the Hispanic population in future. Citation Format: Urbashi Basnet, Aditi Kulkarni, Frances A. Rangel, Abhijeet R. Patil, Sourav Roy. Differential expression of stress-survival pathway genes related to Hispanic colorectal cancer disparities. [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 5232.
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Li, Daneng, Anthony F. Shields, Hirva Mamdani, Patrick Travis, Gavin Wright, Wallace Akerley, Alex Spira, et al. "Abstract CT182: Oncolytic virus CF33-hNIS for the treatment of advanced cancer." Cancer Research 84, no. 7_Supplement (April 5, 2024): CT182. http://dx.doi.org/10.1158/1538-7445.am2024-ct182.
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Abstract Background: CF33-hNIS is a novel vaccinia virus engineered with the human sodium-iodide symporter (hNIS) gene. CF33-hNIS selectively replicates in tumor cells and promotes anti-tumor immunity. Here, we report results on a first-in-human phase 1 dose escalation study of CF33-hNIS, administered intratumorally (IT) or intravenously (IV) in adult patients with metastatic or advanced solid tumors (MAST). Methods: The MAST study is evaluating the safety of CF33-hNIS administered IT or IV, alone or in combination with pembrolizumab in patients with advanced or metastatic solid tumors with ≥ 2 prior lines of therapy (NCT05346484). CF33-hNIS is administered in 21-day cycles on C1D1 and C1D8, then D1 of each cycle thereafter. Pembrolizumab begins C2D1 for the combination groups and is administered Q3W. The study consists of two parts. Part 1 follows a 3+3 dose escalation scheme independent of each route of CF33-hNIS administration (IT and IV) and for each therapy regimen (monotherapy and combination therapy) with up to 7 dose levels of CF33-hNIS ranging from 8.6x105 to 3.0x109 PFU. Part 2 is a cohort expansion in select indications at the optimal dose. The co-primary endpoints are safety and identification of the recommended phase 2 dose. Secondary endpoints include objective response rate according to RECIST v1.1 and iRECIST, and assessment of viral replication in tumor lesions via Single-Photon Emission Computerized Tomography (SPECT). Results: As of Dec 2023, 36 patients have been treated in Part 1 of the study with a median age of 59 (range 23-81). Twenty-two (61%) patients were heavily pretreated with ≥3 prior lines of systemic therapy, and 14 (39%) received prior treatment with checkpoint blockade. Treatment-related adverse events consisted predominantly of ‘flu-like’ symptoms, such as grade 1/2: fatigue (31%), pyrexia (22%), and chills (14%). No dose-limiting toxicities have occurred. The highest dose treated to date is 1.1x108 PFU by IT and IV delivery; dose escalation continues. In the IT cohorts (14 patients), 7 of 15 (47%) injected lesions had a reduction in tumor burden, three lesions were completely eradicated. Three patients (21%) had an objective response: one complete response by iRECIST in a patient with cholangiocarcinoma; and two partial responses in patients with melanoma by RECIST. In IV cohorts (17 patients), 53% of patients achieved stable disease as their best response. Patients who received prior checkpoint blockade therapy derived clinical benefit with and without pembrolizumab. Viral replication, assessed by SPECT was higher in patients that saw a reduction in tumor burden. Immunological changes in peripheral blood and tumor biopsies will be presented. Conclusions: CF33-hNIS alone or in combination with pembrolizumab is a safe treatment option for advanced cancer patients. Encouraging efficacy has warranted advancement to part 2 of this study with a cohort expansion of patients with cholangiocarcinoma and other tumor types. Citation Format: Daneng Li, Anthony F. Shields, Hirva Mamdani, Patrick Travis, Gavin Wright, Wallace Akerley, Alex Spira, Gregory Daniels, Jaime Merchan, Abhijeet Kumar, Emerson Lim, Colt Egelston, Oscar Flores, Stanley Hamilton, Janet Austria, Amanda Seiz, Sharon Yavrom, Seymour Fein, John Byon, Paul Woodard, Grey A. Wilkinson, Jennifer Leddon. Oncolytic virus CF33-hNIS for the treatment of advanced cancer [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 CT182.
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Goetz, Matthew, Masakazu Toi, Jens Huober, Joo Hyuk Sohn, Olivier Trédan, Inhae Park, Mario Campone, et al. "Abstract GS01-12: MONARCH 3: Final overall survival results of abemaciclib plus a nonsteroidal aromatase inhibitor as first-line therapy for HR+, HER2- advanced breast cancer." Cancer Research 84, no. 9_Supplement (May 2, 2024): GS01–12—GS01–12. http://dx.doi.org/10.1158/1538-7445.sabcs23-gs01-12.
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Abstract Background: Abemaciclib is approved both for high-risk early breast cancer as well as advanced breast cancer (ABC) in the first- and second-line setting. In MONARCH 2, the addition of abemaciclib to fulvestrant significantly improved both progression-free survival (PFS) and overall survival (OS) in patients with HR+, HER2- ABC with disease progression on prior endocrine therapy (ET). In MONARCH 3, the addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) significantly improved PFS (HR, 0.540; 95% CI, 0.418-0.698; p=0.000002) as initial therapy in HR+, HER2- ABC. At the last interim OS analysis (~252 events, at 5.8 years follow-up [FU]), a numerically favorable median OS difference (12.6 months) was observed (HR, 0.754; 95% CI, 0.584-0.974; p=0.0301, non-significant [NS]). Here, we present the final OS analysis of MONARCH 3 (NCT02246621). Methods: MONARCH 3 is a randomized, double-blind, Phase 3 study of abemaciclib + NSAI (anastrozole or letrozole) vs placebo + NSAI in postmenopausal women with HR+, HER2- ABC without prior systemic therapy in the advanced setting. OS was a gated secondary endpoint and chemotherapy-free survival (CFS) an exploratory endpoint. Final OS analysis was planned after approximately 315 OS events had occurred in the intent-to-treat (ITT) population with a split alpha between the ITT population and the subgroup with visceral disease (sVD) according to a prespecified graphical testing scheme. Kaplan-Meier method and stratified Cox proportional hazards models were used for time-to-event analyses. All reported p-values are two-sided. Results A total of 493 women were randomized 2:1 to receive abemaciclib + NSAI (n=328) or placebo + NSAI (n=165). After a median FU of 8.1 years, 7% of patients were still receiving treatment in the abemaciclib arm vs 3% in the placebo arm. In the ITT population, 314 OS events were observed (198 deaths among 328 patients [60%] in the abemaciclib arm and 116 among 165 [70%] in the placebo arm; HR, 0.804; 95% CI, 0.637-1.015; p=0.0664, NS). Median OS was 66.8 months in the abemaciclib arm and 53.7 months in the placebo arm, a numerical difference of 13.1 months in the ITT population. In the sVD, 178 events were observed (113 deaths among 173 patients [65%] in the abemaciclib arm and 65 among 90 [72%] in the placebo arm; HR, 0.758; 95% CI, 0.558-1.030; p=0.0757, NS). Median OS was 63.7 months in the abemaciclib arm and 48.8 months in the placebo arm, a numerical difference of 14.9 months in the sVD. Consistent OS differences were observed across prespecified subgroups. PFS benefit was sustained (median 29.0 vs 14.8 months; HR, 0.535; 95% CI, 0.429-0.668; nominal p<0.0001) with substantial difference in 6-year PFS rates (23.3% vs 4.3% for abemaciclib vs placebo). CFS was also improved with abemaciclib vs placebo (median 46.7 vs 30.6 months; HR, 0.693; 95% CI, 0.557-0.863; nominal p=0.0010). No new safety signals were observed with longer term use. Conclusion In patients with HR+, HER2- ABC, abemaciclib in combination with a NSAI resulted in numerically longer OS compared to NSAI alone; however, statistical significance was not reached after a median FU of 8.1 years. The clinically meaningful improvement in median OS (>13 months) combined with the sustained significant improvement in median PFS (>14 months) and substantial extension in median CFS (>16 months) continue to support the use of abemaciclib in combination with NSAI as first-line therapy in ABC. Citation Format: Matthew Goetz, Masakazu Toi, Jens Huober, Joo Hyuk Sohn, Olivier Trédan, Inhae Park, Mario Campone, Shin-Cheh Chen, Luis Manual Manso, Shani Paluch-Shimon, Orit C. Freedman, Valerie Andre, Abhijoy Saha, Gertjan van Hal, Ashwin Shahir, Hiroji Iwata, Stephen RD Johnston, Joyce O'Shaughnessy, Xavier Pivot, Sara Tolaney, Sara Hurvitz, Antonio Llombart. MONARCH 3: Final overall survival results of abemaciclib plus a nonsteroidal aromatase inhibitor as first-line therapy for HR+, HER2- advanced breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS01-12.
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Galina, Jesse. "Critical Events Before Spinal Cord Injury in a Porcine Compression Model." Journal of the Pediatric Orthopaedic Society of North America 2, no. 1 (May 1, 2020). http://dx.doi.org/10.55275/jposna-2020-72.
Full textAbstract:
Recipient: Jesse Galina, BS
Critical Events Before Spinal Cord Injury in a Porcine Compression Model
Jesse Galina, BS1; Vishal Sarwahi, MD1; Aaron Atlas, BS1; Sayyida Hasan, BS1; Beverly Thornhill, MD2; Alan Legatt, MD, PhD3; Abhijit Pawar, MD2; Marina Moguilevich, MD2; Terry Amaral, MD1, (1) Cohen Children's Medical Center, New Hyde Park, NY, (2) Montefiore Medical Center, Bronx, NY, (3) Montefiore Medical Center, New Hyde Park, NY
Purpose: Spinal cord injuries are one of the most devastating in spine surgery. Some cases of intraoperative neuromonitoring changes can occur as a secondary characteristic of spinal cord compression and decrease in blood flow. Laser Doppler flowmetry has been well validated for measuring blood flow. The objective of this study is to identify measurable, critical events that occur before and during an evolving spinal cord injury.
Methods: After prone positioning and induction, multi-level laminectomies are performed in the midthoracic region. LDF electrodes were placed on the exposed dura in multiple areas to measure real-time spinal cord blood flow. Spinal cord injury was induced by incremental balloon inflation after being placed in the epidural space. After MEP loss (injury), several interventions were carried out: raising the systolic BP, expanding the intravascular volume with colloids, and IV lidocaine. After interventions, wake up test is performed and CT scan was done to measure the thoracic spinal canal volume. Two groups based on timing of intervention. Group A: medical interventions were administered before balloon deflation; Group B: balloon deflated first.
Results: 17 pigs were studied, 14 of which survived and completed the experiment. Recordable SCBF changes (-13% - 13%) from baseline were seen 3 – 32 minutes before MEP loss in all pigs. For this reason, we considered 3 minutes to be the critical time before spinal cord injury. However, the 20% threshold interval was often reached before the 3 minute mark. Three minutes before MEP loss, change in SCBF was -24.9% and balloon pressure was 9 psi. Balloon volume was 0.63 cc. The spinal canal compromise 3 minutes before MEP signals loss was 69.3%, while SCBF three minutes before MEP loss was 71. This was a 24.85% change from baseline SCBF. In Group A, no pigs were moving their hind limbs. In Group B, 9/10 were found to be moving their hind legs.
Conclusion: Compression SCI is the end of a cascade involving increasing pressure, decreasing volume and hypoperfusion. Rapid relief of compression leads to MEP return and function. SCBF monitoring can detect ischemia pre-injury, giving surgeons an opportunity for early intervention.