tbuckley/cabot-search huggingface dataset:
Abstract 2741: Novel murine models of epigenetic dysregulation in SWI/SNF-mutated cholangiocarcinoma
Authors: Jayla Millender, Jennifer Tomlinson, Ryan Watkins, Danielle Carlson, Jack Sample, Nathan Werneburg, Rory Smoot, Keith Robertson, Gregory Gores, Caitlin Conboy
Journal: Cancer Research (2025)

Abstract SWI/SNF chromatin remodeling complexes are frequently mutated across human cancers, including cholangiocarcinoma (CCA). Dysregulation of this complex due to loss of function mutations in AT-rich interaction domain-1A (ARID1A) and polybromo-1 (PBRM1) occur in up to 18% and 10% of cases respectively. SWI/SNF subunit mutations frequently co-occur alongside PI3K/AKT pathway activation. Preexisting literature suggests altered gene expression and protein synthesis contribute to CCA oncogenesis, but our understanding of these mechanisms remains immature. Genetically accurate preclinical models are needed to define the roles of ARID1A and PBRM1 in CCA and identify therapeutic targets. We developed novel murine models of CCA with either ARID1A, PBRM1 or dual ARID1A/PBRM1 (APAC) knockout in the context of AKT activation, utilizing a surgical biliary transfection method for somatic gene editing with CRISPR/Cas9. Within 8 months, mice formed numerous liver tumors, predominantly CCA and mixed CCA/HCC. Knockout of ARID1A and PBRM1 was confirmed through genomic PCR, qRT-PCR, and immunoblot assays. Histologically, murine APAC tumors displayed phenotypic similarities to human CCA, including dense cancer-associated fibroblast infiltration and variable CD45+ immune cell infiltration. A novel, syngeneic CCA cell line was isolated from a dual ARID1A/PBRM1 knockout tumor (APAC-2). RNA-sequencing of primary tumors and the APAC-2 cell line versus a non-invasive cholangiocyte cell line with AKT activation only (AC), was performed to identify differentially expressed genes (DEGs) of interest in ARID1A and PBRM1-deficient CCA. Periostin (Postn) was among the top upregulated genes in the APAC-2 cell line. POSTN is a secreted glycoprotein that is upregulated in human CCA and may be therapeutically targetable. Knockdown of periostin inhibited the in vitro growth of APAC-2 cells and a human CCA cell line with ARID1A mutation and periostin overexpression (HuH-28). These studies serve to characterize and validate a genetically relevant murine model of epigenetic dysregulation in ARID1A and PBRM1-deficient CCA. This model can be used for identification and validation of potential drug targets. Ongoing work focuses on studying multiple dysregulated pathways and testing dependence on genes of interest, including periostin, as potential treatment strategies for CCA. Citation Format: Jayla Millender, Jennifer Tomlinson, Ryan Watkins, Danielle Carlson, Jack Sample, Nathan Werneburg, Rory Smoot, Keith Robertson, Gregory Gores, Caitlin Conboy. Novel murine models of epigenetic dysregulation in SWI/SNF-mutated cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2741.
Abstract 2774: Pan-cancer chromatin state profiling suggests enhancer-heterogeneity and precision medicine approach
Authors: Mayinuer Maitituoheti, Emre Arslan, Ayush T. Raman, Christopher Terranova, Kunal Rai
Journal: Cancer Research (2025)

Abstract Epigenetic aberrations are a hallmark of cancer; however, systematic chromatin state maps of cancer cells are unavailable. We generated and analyzed 803 histone mark profiles in 142 cancer cell lines and 114 human tumors belonging to 9 solid tumor types. Irrespective of their cell-of-origin, cancer cells segregate from normal tissues based on their enhancer patterns, suggesting enhancer deregulation is a fundamental epigenetic feature in cancer. Enhancer based clustering defined 5 distinct subgroups of cancer cells (EpiC1-5) with unique developmental trajectories, molecular features and dependencies. Importantly, we define a set of core TFs that are critical for EpiC-specific enhancer patterns and survival. Notably, EpiC4 represented a predominantly epigenetic, pan-cancer subtype that displays poor survival, activation and dependence on a FN1-CAV1-SRC-PI3K-AKT signaling network. Together, these data uncover enhancer heterogeneity in pan-cancer systems with identification of a novel enhancer-based subtype and identify potential new therapeutic targets associated with unique epigenetic features. Citation Format: Mayinuer Maitituoheti, Emre Arslan, Ayush T. Raman, Christopher Terranova, Kunal Rai. Pan-cancer chromatin state profiling suggests enhancer-heterogeneity and precision medicine approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2774.
Abstract 2103: Pharmacogenomic biomarkers of oncology drugs approved by the US FDA classified on the basis of BEST (Biomarkers, EndpointS, and other Tools) resource: systematic review
Authors: Tariq H. Alqurayshah
Journal: Cancer Research (2025)

Abstract Objective: To characterize pharmacogenomic biomarkers of oncology indications approved by the US FDA classified on the basis of BEST (Biomarkers, EndpointS, and other Tools). Resource Design: Systematic review. Data sources: FDA oncology/hematologic malignancies approvals and databases, BEST (Biomarkers, EndpointS, and other Tools) Resource, and CDER / CBER’s DDT Qualification Project Search database: Stage 1: Letter of Intent (LOI), Stage 2: Qualification Plan (QP), and Stage 3: Full Qualification Package (FQP). Study Inclusion: All Biomarkers include germline or somatic gene variants (polymorphisms, mutations), functional deficiencies with a genetic etiology, gene expression differences, chromosomal abnormalities; and selected protein biomarkers in all approved labeling sections published by the FDA. Results: BEST Resource defines seven biomarker categories: susceptibility/risk, diagnostic, monitoring, prognostic, predictive, pharmacodynamic/response, and safety. The biomarkers are more linked to three cancers: breast, lung and colorectal cancers. Citation Format: Tariq H. Alqurayshah, SFDA Oncology and Hematology Group. Pharmacogenomic biomarkers of oncology drugs approved by the US FDA classified on the basis of BEST (Biomarkers, EndpointS, and other Tools) resource: systematic review [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2103.
Abstract 2752: Analysis of epigenetic regulation by mutant p53 gain-of-function in anaplastic thyroid cancer
Authors: Wataru Kawase, Yukihiko Hiroshima, Takashi Oshima, Katsuhiko Masudo, Yohei Miyagi
Journal: Cancer Research (2025)

Thyroid cancer is one of the most common endocrine malignancies. It is primarily classified into four types : papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer and anaplastic thyroid cancer (ATC). Among them, ATC is particularly rare, has a very poor prognosis and is insensitive to conventional treatments. Consequently, the development of effective therapeutic strategies for ATC is urgently needed. Mutations in TP53 have been reported to play a role in the anaplastic transformation of thyroid cancer. TP53 is the most frequently mutated gene across all human cancers. Although common TP53 missense mutations cause loss of its tumor-suppressive function, ‘gain-of-function’ (GOF) mutations of TP53 have recently been reported to promote several types of cancer. Mutant p53 (mut-p53) GOF can manipulate epigenetic regulators and alter the chromatin landscape. However, the impact of mut-p53 GOF on epigenetic regulation in ATC remains unclear. In this study, we aim to elucidate the mechanisms of epigenetic regulation underlying tumor progression driven by mut-p53 GOF in ATC. Hotspot gene mutation analysis revealed the presence of known mut-p53 GOF mutations in three out of seven ATC cell lines. Distribution analysis of ATAC-seq peaks in enhancer regions revealed that certain promising transcription factor binding motifs were enriched in ATC cell lines with mut-p53 GOF. Moreover, we demonstrated that these candidate transcription factors are involved in cell proliferation and migration of ATC cell lines with mut-p53 GOF. These results suggest that the exploration of gene expression regulatory mechanisms by mut-p53 GOF may provide a clue for a novel therapeutic strategy for ATC. Citation Format: Wataru Kawase, Yukihiko Hiroshima, Takashi Oshima, Katsuhiko Masudo, Yohei Miyagi. Analysis of epigenetic regulation by mutant p53 gain-of-function in anaplastic thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2752.
Abstract 1742: Discovery and preclinical profiling of a novel PKMYT1 inhibitor, EVT-0003023, with high efficacy in late-stage, post-treatment non-small cell lung cancer models
Authors: Daniel Miller, Alfie Brennan, Jan Lanz, Oliver Vipond, Noah Harrison, James Aaronson, Anna Hercot
Journal: Cancer Research (2025)

Abstract Protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1) is a negative regulator of CDK1 activity and has been identified as a putative synthetic lethal target in cancers which up-regulate cyclin E (CCNE1) or harbor mutations in genes such as FBXW7. We used our internal Frobenius platform to identify highly potent and differentiated inhibitors of PKMYT1 with exceptional selectivity over key off targets, including the Raf family and WEE1. Machine learning-driven optimization delivered a preclinical candidate compound, EVT-0003023, with best-in-class selectivity and a significantly improved pharmacokinetic profile in relevant animal models, and in vivo efficacy in CCNE1-high and FBXW7-mutated xenograft models. Compounds from this series were used to validate a differentiated biomarker for sensitivity to PKMYT1 inhibition in cellular and PDX-derived models, expanding the patient population treatable with PKMYT1 inhibitors into non-small cell lung cancer. Using clinical data, we demonstrated that this biomarker is significantly up-regulated in patients who have progressed on existing standard-of-care treatment, and demonstrated exceptional monotherapy activity for EVT-0003023 in PDX models reflecting this patient population, as well as tumor regression when combined with low doses of chemotherapy. Citation Format: Daniel Miller, Alfie Brennan, Jan Lanz, Oliver Vipond, Noah Harrison, James Aaronson, Anna Hercot. Discovery and preclinical profiling of a novel PKMYT1 inhibitor, EVT-0003023, with high efficacy in late-stage, post-treatment non-small cell lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1742.
Abstract 1751: Beta catenin c-mods are orally bioavailable small-molecules targeting Wnt-driven tumors
Authors: Isaac Klein, Kip West, Doug Baumann, Adam Talbot, Thomas Durand-Reville, Karl Hsu, Ann Boija
Journal: Cancer Research (2025)

Abstract Constitutive activation of the Wnt/beta catenin pathway drives malignancy in a wide range of cancers. The oncogenic transcription factor beta catenin has been notoriously difficult to target due to its disordered nature and lack of defined drug-binding pockets. Using Dewpoint’s proprietary AI/ML-powered discovery platform, we have identified and optimized small molecule condensate modulators (c-mods) that act via a novel mechanism of action, sequestering beta catenin into inactive condensate depots. Sequestering beta catenin into nuclear condensates selectively inhibits beta catenin-driven transcription and induces robust cancer cell death. The development candidate DPTX3186 is an orally bioavailable small molecule that demonstrates strong anti-tumor activity across multiple tumor types driven by various defects along the Wnt/beta catenin pathway and modulates Wnt pathway activity in vivo. Profound pharmacological efficacy, including regressions and complete responses, has been observed in murine models of gastric cancer. Collectively, these findings highlight the potential of condensate biology to target previously undruggable, high-value oncology targets, paving the way for novel treatments for patients with significant unmet medical needs. Citation Format: Isaac Klein, Kip West, Doug Baumann, Adam Talbot, Thomas Durand-Reville, Karl Hsu, Ann Boija. Beta catenin c-mods are orally bioavailable small-molecules targeting Wnt-driven tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1751.
Abstract 1447: Histone demethylase JMJD1A regulates glutamine metabolism in prostate cancer
Authors: Sudeep Khadka, Majid Pornour, Hee-Young Jeon, Arif Hussain, Jianfei Qi
Journal: Cancer Research (2025)

Abstract Epigenetic regulation plays a crucial role in the development and progression of prostate cancer. JMJD1A (also called KDM3A) promotes prostate cancer progression by upregulating gene expression through the removal of repressive H3K9 methylation marks. Here, we found a role for JMJD1A in the regulation of glutamine biosynthesis in prostate cancer cells. JMJD1A knockdown (KD) significantly reduced cellular glutamine levels and inhibited prostate cancer cell growth under glutamine-deprivation conditions. RNA-seq studies showed that JMJD1A KD reduced the levels of GLUL, a key enzyme in de novo glutamine synthesis. mRNA levels of JMJD1A and GLUL were positively correlated in human prostate cancer datasets. Re-expression of GLUL in JMJD1A-KD cells significantly restored cellular glutamine levels and partially rescued the growth defect of prostate cancer cells in glutamine-free growth media. Further, ChIP-seq studies showed that JMJD1A interacted with the methyltransferase EZH2 on the GLUL gene promoter, and JMJD1A/EZH2 cooperatively upregulated H3K27ac levels to promote GLUL expression. Our study revealed cooperation between JMJD1A and EZH2 in regulating gene expression and glutamine metabolism and supports the co-targeting of JMJD1A and EZH2 for potential prostate cancer therapy. Citation Format: Sudeep Khadka, Majid Pornour, Hee-Young Jeon, Arif Hussain, Jianfei Qi. Histone demethylase JMJD1A regulates glutamine metabolism in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1447.
Abstract 3307: Utilizing endocytosis as a predictive biomarker for ADCs
Authors: Anette Weyergang, Astrid Medhus, Kay Oliver Schink, Kristian Berg, Olav Engebraaten
Journal: Cancer Research (2025)

Abstract Antibody drug conjugates (ADCs) consist of an antibody conjugated to a chemotherapeutic drug. These therapeutic compounds are designed to exert improved targeted toxicity as compared to conventional chemotherapy. However, variable therapeutic outcome has been experienced and predictive markers for response are warranted. ADCs are dependent on endocytosis to exert their effect, and we have hypothesized that proteins regulating the endocytic machinery can be utilized as predictive biomarkers. We have shown, for the first time, that the expression level of Rab5A, a protein regulating endocytosis correlates to the efficacy of Trastuzumab Emtansine, a HER2 targeted ADC. Furthermore, we have documented Rab5A as a predictive biomarker for Trastuzumab emtansine in three independent clinical cohorts. We are currently investigating the interplay between different ADCs and the endo/lysosomal machinery, and aim to develop this concept to a diagnostic tool for patients to be treated with ADCs. We use Trastuzumab emtansine, Trastuzumab deruxtecan and Sacituzumab Govitecan as model ADCs and evaluate the impact of different Rab GTPases on their mechanism of actions in cell lines from breast- and lung-cancer. Citation Format: Anette Weyergang, Astrid Medhus, Kay Oliver Schink, Kristian Berg, Olav Engebraaten. Utilizing endocytosis as a predictive biomarker for ADCs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3307.
Abstract 3128: Nonclinical efficacy and safety evaluation of IL-12 mRNA delivered by a novel lipid nanoparticle
Authors: Qing He, Chunyan Dong, Dejiang Tan, Huimin Sun, Yiyang Zheng, Zhuang Li, Linyu Zhang, Sihan Liu, Yu Zhang, Jijun Yuan, Peng Gao, Liang Du, Huayuan Yan, Bo Ying
Journal: Cancer Research (2025)

Abstract Interleukin-12 (IL-12) is considered to be a promising cytokine for enhancing anti-tumor immune response. However, systemic recombinant IL-12 had significant toxicity and limited efficacy in early clinical trials. Recently, many strategies to express IL-12 in the tumor tissue are being pursued preclinically and in clinical trials. Here, we report on ABO2011 (LNP-IL12 mRNA), developed by Abogen Bioscience, an innovative mRNA therapeutic cancer vaccine with novel lipid nanoparticles encoding IL-12.The LNP-IL12 mRNA significantly activates a robust T-cell-mediated adaptive immune response and exhibits strong anti-tumor potential. In the anti-tumor efficacy evaluation of B16F10, MC38 and EMT6 tumor-bearing mice, LNP-IL12 mRNA successfully eradicated tumors with a single administration. In the preliminary evaluation of safety, LNP-IL12 mRNA treatment did not significantly change body weight, HE staining of major organs did not significantly change, and serum cytokine levels were extremely low, indicating a good safety. Flow cytometry detected that LNP-IL12 mRNA induced large infiltration of total lymphocytes in B16F10, MC38 and EMT6 tumor-bearing mice, especially the proportion of cytotoxic CD8+ T cells and NK cells increased significantly, while the proportion of immunosuppressive Treg cells decreased. In addition, the levels of pro-inflammatory factors such as IL-1β, IL-6, IFN-γ and TNF-α in tumors induced by LNP-IL12 mRNA were significantly increased by CBA method, but IL-10 was not detected. It was shown that LNP-IL12 mRNA mediated immunotherapy can safely and effectively induce a strong immune response. In conclusion, we conducted relevant evaluation studies with LNP-mIL12 mRNA as an example, trying to establish non-clinical efficacy evaluation criteria for mRNA therapeutics. Citation Format: Qing He, Chunyan Dong, Dejiang Tan, Huimin Sun, Yiyang Zheng, Zhuang Li, Linyu Zhang, Sihan Liu, Yu Zhang, Jijun Yuan, Peng Gao, Liang Du, Huayuan Yan, Bo Ying. Nonclinical efficacy and safety evaluation of IL-12 mRNA delivered by a novel lipid nanoparticle. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3128.
Abstract 1531: The role of HDAC1 in pancreatic cancer metabolism
Authors: Don-Gerard Cavakiah Blanchard Conde, Evan J. Zhou, Maximillian Farma, Chiamaka J. Ezeh, Laiba Shiekh, Matthew Cheung, Zeribe C. Nwosu, Nwosu Lab, Cornell University
Journal: Cancer Research (2025)

Abstract Pancreatic cancer is a malignant disease often driven by mutations in the KRAS gene. It is associated with significant metabolic reprogramming driving tumor growth, drug resistance, and adaptation in its dense, nutrient-limited tumor microenvironments. To date, the mediators of PDAC metabolism are not fully understood. Analyzing gene expression changes in PDAC tumors compared to normal tissues identified histone deacetylase 1 (HDAC1) as a consistently upregulated gene. We found that HDAC1-high tumors display strong metabolic alterations, including the upregulation of genes in glycolysis and other metabolic processes, and that treatment with Class I selective HDAC inhibitors (HDACi) selectively blunted growth. Initial experiments altering HDAC1 expression transiently in multiple pancreatic cancer cell lines demonstrate alternate metabolic responses. Consistent with existing literature, we observe that HDACi effectively suppressed pancreatic cancer cell growth, primarily class I selective inhibitors. Furthermore, we recently developed HDAC1 knockout cell lines that demonstrate shifts in metabolic profiles of pancreatic cancer and slowed growth rates in HDACi sensitive cell lines through immunoblotting, metabolomics and Seahorse assay. We expect that our findings will show the significance and prospects of targeting HDAC1 in pancreatic cancer therapy and its potential to overcome resistance with current therapeutic. Citation Format: Don-Gerard Cavakiah Blanchard Conde, Evan J. Zhou, Maximillian Farma, Chiamaka J. Ezeh, Laiba Shiekh, Matthew Cheung, Zeribe C. Nwosu, Nwosu Lab, Cornell University. The role of HDAC1 in pancreatic cancer metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1531.
Abstract 1418: Mapping the FOXA1 interactome in ER+ breast cancer cells using proximity labeling reveals a novel interaction with NR2C2
Authors: Carla Sofia Rodriguez-Tirado, Rosemary Plagens, Shen Li, Christine Mills, Laure Herring, Hector Franco
Journal: Cancer Research (2025)

Abstract Approximately 70% of breast cancers are driven by the estrogen receptor alpha (ER), and despite the advent of endocrine therapy to block ER signaling pathways, a significant proportion of women develop resistance to these drugs. The pioneer factor FOXA1 has been shown to facilitate nearly all DNA-binding events of ER in response to estrogen in ER-positive breast cancer (ER+BC). Notably, up-regulation of FOXA1 is a hallmark of endocrine-resistant tumors. Furthermore, FOXA1 has been shown to alter the transcriptome in endocrine therapy resistance. FOXA1 interacting partners, such as ER, androgen receptor (AR), MLL3, YAP1 and GATA-3 mediate transcription activation of genes important for cancer progression. There have been previous studies showing interactors of FOXA1, but none have addressed a comprehensive list of interactors of FOXA1, especially in breast cancer. To address this challenge, we generated MCF-7 cell lines stably expressing the biotin ligase miniTurbo fused to the N- or C-terminus of FOXA1 to classify interactors of FOXA1 in ER+BC. Using proximity labeling (PL) coupled with LC-MS/MS, we aimed to comprehensively catalog interactors of FOXA1. We were able to identify expected proteins such as ER, AR, MLL3, YAP1, and GATA-3. Moreover, we have discovered 157 previously unpublished interactors of FOXA1. Importantly, poorer prognosis for relapse-free survival among ER+BC patients is associated with several of these novel interactors, including NR2C2, an orphan nuclear receptor previously shown to regulate various nuclear receptor signaling but whose roles in breast cancer remain unclear. NR2C2 ChIP-seq in MCF-7 cells under FOXA1-depleted conditions revealed NR2C2 binding loci dependent on FOXA1 levels and binding. By integrating proteomic and genomic approaches, we highlight new mechanisms of FOXA1-mediated transcriptional regulation, with promising potential for endocrine therapy resistance. Citation Format: Carla Sofia Rodriguez-Tirado, Rosemary Plagens, Shen Li, Christine Mills, Laure Herring, Hector Franco. Mapping the FOXA1 interactome in ER+ breast cancer cells using proximity labeling reveals a novel interaction with NR2C2. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1418.