tbuckley/cabot-search huggingface dataset:
Abstract 3922: A p53-deficient, PTK2/cMyc-driven ovarian cancer mouse model for preclinical drug discovery
Authors: Ziping Liu, Wenjing Zhang, Xinxin Zhao, Yongshuai Li, Xiaoya Hou, Satyanarayana Pochampally, Shelby Waddell, Shiji Song, Yaohong Wang, Lawrence M. Pfeffer, Duane D. Miller, Junming Yue, Wei Li
Journal: Cancer Research (2025)

Abstract Background: Ovarian cancer (OC) remains a significant health issue for women due to its late diagnosis and chemoresistance. Currently, there is no relevant mouse OC model for preclinical drug screening and treatment. Methods: We established a mouse OC cell line model, PC53K, by transforming primary ovarian surface epithelial cells through CRISPR/Cas9-mediated TP53 knockout and simultaneous overexpression of human PTK2 and cMyc. We further developed the paclitaxel-resistant PC53K/TxR cell line. PC53K and PC53K/TxR cell lines were validated in vitro and in vivo in an orthotopic mouse model. We also evaluated the efficacy of two novel tubulin inhibitors, the clinical drug VERU-111 and the preclinical compound SB-216, using the PC53K/TxR model in vitro and in vivo. Results: Mice intrabursally injected with PC53K cells exhibited bloody ascites, aggressive primary tumor growth and widespread metastasis, which faithfully recapitulates the phenotypes of human ovarian serous adenocarcinoma. Additionally, the paclitaxel-resistant PC53K/TxR cell line shows significant higher IC50 for paclitaxel than PC53K cell line, indicating it is a valuable tool for studying OC chemoresistance. Compounds VERU-111 and SB-216 significantly inhibited tumor growth and metastasis in orthotopic OC mouse models by overcoming chemoresistance. This study demonstrates the effectiveness of the PC53K and PC53K/TxR models for preclinical drug screening and validates the potential of VERU-111 and SB-216 in overcoming chemoresistance and treating OC. Significance: The development of the PC53K and PC53K/TxR mouse models represents a significant advancement in OC research. By mimicking the genetic profile, aggressive behavior and chemoresistance of human OC, these models provide a robust platform for preclinical drug discovery and development. Citation Format: Ziping Liu, Wenjing Zhang, Xinxin Zhao, Yongshuai Li, Xiaoya Hou, Satyanarayana Pochampally, Shelby Waddell, Shiji Song, Yaohong Wang, Lawrence M. Pfeffer, Duane D. Miller, Junming Yue, Wei Li. A p53-deficient, PTK2/cMyc-driven ovarian cancer mouse model for preclinical drug discovery [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 3922.
Abstract 6301: ARLVPI: A novel machine-learning-informed platform for assessing somatic variant classification and pathogenicity
Authors: Arlen Larry Gyden, Nicole Ambroise, Tarsus Lam, Zehra Ordulu, Petr Starostik, Kimberly Newsom, Mohammed Gbadamosi
Journal: Cancer Research (2025)

Abstract Cancer comprises several heterogeneous multifaceted diseases characterized by dysfunctional cellular differentiation and excessive proliferation. With its prevalence expected to rise, particularly among middle-aged adults, the burden on pathologists to identify and characterize pathogenic variants increases. Current clinical practices rely on molecular profiling, pathologist interpretation, and supplemental information from disease databases to classify these variants. In this context, variants of unknown significance (VUS) pose a significant clinical challenge due to their uncertain biological and clinical effects that make them inhibitive towards diagnoses and treatment decisions. Representing 40% of Next-Generation Sequencing (NGS) signals, VUS indicates a significant unmet clinical need demanding urgent solutions. To meet this unmet clinical challenge, we utilized 20, 756 variants from 415 cancer patient samples to develop the Advanced Risk Locating Variant Pathogenicity Index (ArlVPI). ArlVPI employs a mechanistic model based on information from a random forest classifier and dimensional reduction analyses to identify and flag VUS variants likely to require further investigation from pathologists. In downstream analysis, ArlVPI exhibited a strong correlation with variant pathogenicity and correctly categorized variants as benign or pathogenic with &amp;lt;1% error. With respect to VUS, ArlVPI flagged 16% as requiring potential follow-up, corroborating metrics observed in literature. Furthermore, ArlVPI demonstrated &amp;gt;93% concordance with clinical pathologists in the identification of VUS which were reclassified as pathogenic in an array of solid tumor, hematologic, and myeloproliferative malignancies. Our study illustrates how ArlVPI can be integrated into existing NGS analysis pipelines to support molecular professionals, offering an efficient resource that enhances variant classification and supports targeted cancer treatment strategies. Future work focuses on developing a streamlined application that interfaces with existing clinical diagnostic systems. Citation Format: Arlen Larry Gyden, Nicole Ambroise, Tarsus Lam, Zehra Ordulu, Petr Starostik, Kimberly Newsom, Mohammed Gbadamosi. ARLVPI: A novel machine-learning-informed platform for assessing somatic variant classification and pathogenicity [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 6301.
Abstract 6697: Role of the miR-101-3p/CALCRL/NEAT1 axis in immune modulation and tumorigenesis in non-small cell lung cancer
Authors: Gulnaz Tabassum, Mansoor A. Syed, Kapil Dev
Journal: Cancer Research (2025)

Abstract Lung cancer (LC), particularly Non-Small Cell Lung Cancer (NSCLC), remains a global health challenge with a five-year survival rate of 17.8%, largely due to delayed diagnosis and limited understanding of tumor progression. MicroRNAs (miRNAs), key regulators of gene expression, play critical roles in immune modulation, metabolism, and tumorigenesis, but their role in immunometabolic reprogramming in LC is underexplored. This study investigated novel molecular targets in LC using integrated bioinformatics and in vitro approaches, focusing on the regulatory interplay between miRNAs, mRNAs, and long non-coding RNAs (lncRNAs). RNA-Seq datasets of lung adenocarcinoma (LUAD) were analyzed to identify differentially expressed genes (DEGs) and miRNAs (DEMs). Immune-related genes (IRGs) were curated and intersected with DEGs to identify differentially expressed immune-related genes (DEIRGs). A protein-protein interaction (PPI) network was constructed, and enrichment analyses were performed to identify hub DEIRGs. A ceRNA regulatory network involving miRNA (miR-101-3p), mRNA (CALCRL), and lncRNA (NEAT1) was constructed and analyzed using survival (KM Plotter) and tumor immune infiltration (TIMER) analyses. Experimental validation included expression analysis of miR-101-3p, CALCRL, and NEAT1 using Real-Time PCR and functional studies involving overexpression of NEAT1 and miR-101-3p via transfection. Real-time PCR, Western Blotting &amp; Dual-luciferase assays confirmed CALCRL as a direct target of miR-101-3p. Functional assays—including cell proliferation (MTT assay), ROS production, mitochondrial membrane potential, ATP content, and apoptosis analysis (FACS)—were performed to assess the biological impact of this regulatory network. This study revealed a novel ceRNA axis involving miR-101-3p, CALCRL, and NEAT1. miR-101-3p was significantly downregulated, correlating with increased expression of CALCRL and NEAT1. Functional studies revealed that NEAT1 overexpression suppressed miR-101-3p while enhancing CALCRL expression, promoting tumor progression. Restoration of miR-101-3p suppressed tumor cell proliferation, induced ROS accumulation, impaired mitochondrial function, reduced ATP levels, and triggered apoptosis, underscoring its tumor-suppressive potential. In conclusion, this study provides a detailed framework for the miR-101-3p/CALCRL/NEAT1 axis, offering novel insights into immunometabolic reprogramming in LC. These findings highlight miR-101-3p as a promising therapeutic target, paving the way for miRNA-based therapies in NSCLC Citation Format: Gulnaz Tabassum, Mansoor A. Syed, Kapil Dev. Role of the miR-101-3p/CALCRL/NEAT1 axis in immune modulation and tumorigenesis in non-small cell lung 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 6697.
Abstract 6715: Cross-species investigation of gene copy number and cancer resistance
Authors: Morla Phan, Thompson Worden, Sarah Adamowicz, Stéphane Lair, Mauricio Seguel, Claire Jardine, Geoffrey Wood, Dirk Steinke
Journal: Cancer Research (2025)

Low cancer incidence rates are observed in large mammals such as elephants and whales, despite their mass and long lifespan hypothetically contributing to a higher lifetime probability of acquiring oncogenic mutations. Few studies have investigated cancer-related genes in these animals. One reported that bowhead whales possess two functional copies of PCNA. Multiple studies have investigated the presence of multiple retrogene copies of TP53 in elephants. Extra copies of genes involved in DNA damage detection and repair could contribute to cancer resistance. Droplet digital PCR (ddPCR) was used to quantify gene copy number for TP53, PCNA, HER2, DLG1, and DLG2 in genomic DNA extracted from frozen skin samples of beluga, narwhal and bowhead whales (n=20 each). Results showed that all 3 whale species had more than one copy of PCNA. Agarose gel PCR showed the simultaneous presence of wild-type PCNA (possessing introns) and variable numbers of pseudogene sequences (lacking introns) within individuals for belugas, narwhals, and bowheads. ddPCR found that elephants did not have increased PCNA copy number, but agarose gel PCR showed the presence of PCNA pseudogenes. Similar patterns were also observed in rhinos, horses, cows and other ungulate species. To investigate copy number loss in cancer, ddPCR was performed on formalin-fixed, paraffin embedded normal and matched tumor tissue of 7 individual belugas from the St. Lawrence estuary, an area that was historically contaminated with industrial carcinogens. Copy number loss was not observed for any investigated tumor suppressor gene in tumor tissue compared to normal tissue. Our results show that bowhead whales are not unique in having multiple copies of PCNA. The presence of incomplete copies with unknown function may influence copy number quantification. Further study is required to understand the significance of the variable PCNA pseudogene copies. Understanding natural copy number variation in tumor suppressor genes may provide insight into risk factors and prevention methods across species. Citation Format: Morla Phan, Thompson Worden, Sarah Adamowicz, Stéphane Lair, Mauricio Seguel, Claire Jardine, Geoffrey Wood, Dirk Steinke. Cross-species investigation of gene copy number and cancer resistance [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 6715.
Abstract 6713: RB1 and TP53 restrict lineage plasticity in prostate cancer by regulating chromatin accessibility
Authors: Mauricio Rodrigo Flores, David W. Goodrich, Justine Jacobi
Journal: Cancer Research (2025)

Abstract Lineage plasticity has been widely recognized in various cancers as a driver of therapeutic resistance, but the molecular basis of this plasticity remains incompletely defined. Evidence from the literature reveals that the inactivation of RB1 and TP53 in prostate cancer (PC) results in the emergence of alternative lineage states that are resistant to androgen receptor (AR)-targeted treatment. How RB1 and TP53 loss cause this lineage plasticity is not clear. This study proposes that RB1 and TP53 help maintain heterochromatin in order to restrict chromatin accessibility and maintain the fidelity of lineage specific gene expression. To test this hypothesis, changes in chromatin accessibility (ATAC-seq) and lineage gene expression (RNA-seq) are monitored in single prostate organoid cells over time following deletion of PTEN (SKO) or PTEN/RB1/TP53 (TKO). Analysis of resulting data indicates that TKO organoids have increased transcriptional diversity and elevated expression pathways like JAK-STAT that have been functionally linked to lineage plasticity and resistance to AR-targeted therapies. These gene expression changes are preceded by increased chromatin accessibility at relevant gene promoters. Enrichment of neuroendocrine PC gene signatures is found in both SKO and TKO organoids likely driven by histone methyltransferase EZH2 as well as DNA methyltransferase DNMT1. TKO organoids also exhibit increased ability to adapt to changing growth conditions, likely facilitated by their increased transcriptional plasticity. Future directions for this study will assess the influence of EZH2 and DNMT1 on chromatin accessibility, gene expression, lineage plasticity, and therapeutic resistance following tumor suppressor deletion. Overall, results are consistent with the hypothesis that RB1 and TP53 loss in PC cells creates a more accessible chromatin state permissive for transcription. Findings may also reveal approaches to suppress therapeutic resistance in PC by therapeutic targeting of lineage plasticity. Citation Format: Mauricio Rodrigo Flores, David W. Goodrich, Justine Jacobi. RB1 and TP53 restrict lineage plasticity in prostate cancer by regulating chromatin accessibility [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 6713.
Abstract 7353: Evaluating the LinC CHW program's effect on emergency department visits and health outcomes in cancer patients
Authors: Tishiya Carey, Alexis Roach, Elizabeth Hansen
Journal: Cancer Research (2025)

Abstract This study examines the impact of the Liaisons in Care (LinC) Community Health Worker (CHW) program on emergency department (ED) utilization and survival outcomes among cancer patients at the University of Chicago Medicine. Designed to reduce ED visits by enhancing patient engagement, the LinC program provides targeted support through follow-ups, resource provision, and coordinated care. Our cohort included 72 cancer patients enrolled in LinC from January 2022 to December 2023, each with at least one recorded home visit or extensive engagement through other encounters. Key engagement metrics indicated that 83% of all encounters were CHW-initiated, with 77% conducted virtually. ED utilization decreased, with the average number of visits per patient dropping from 1.68 visits before program enrollment to 0.81 visits post-enrollment. Patients experienced an average interval of 102 days between ED visits and a 30-day readmission rate of 35.3%. The median survival time for the cohort was 557 days, with a one-year survival probability of 66.7%. Kaplan-Meier analysis revealed a significant difference in survival outcomes based on diagnosis timing: patients diagnosed within six months of enrollment had a lower median survival time (284 days) compared to those diagnosed before six months of enrollment (835.5 days; p = 0.005).These findings highlight the potential of CHW programs to improve healthcare outcomes for high-risk cancer populations by enabling timely interventions and providing access to resources. The results support the expansion of similar CHW-led initiatives to reduce health disparities and enhance the quality of life for cancer patients. Future analyses will incorporate social determinants of health (SDOH) to further refine engagement strategies and optimize CHW allocation across service lines. Citation Format: Tishiya Carey, Alexis Roach, Elizabeth Hansen. Evaluating the LinC CHW program's effect on emergency department visits and health outcomes in cancer patients [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 7353.
Abstract 6701: CircRNA-derived neoantigen identification in cancer vaccine development
Authors: Yi-Cian Zheng, Chun-Kan Chen
Journal: Cancer Research (2025)

Abstract Immunotherapy has been a popular topic in combating cancer for its great performance in specificity, versatility and durability recently. Cancer vaccines targeting neoantigens have shown clinical efficacy against cancer, eliciting long-lasting immune response and offering a more selective therapeutic approach with less side effects. However, rare mutation rates and low expression levels of neoantigen make it challenging to identify suitable neoantigens. Traditionally, researchers focus on the canonical mRNA transcriptome and proteome to find potential targets. Recent studies suggest that exploring the non-canonical transcriptome and proteome, particularly circular RNAs (circRNAs), can expand the search. CircRNAs, endogenously formed by the unique back-splicing events during pre-RNA processing, can serve as templates for protein synthesis. Some of these non-canonical peptides are specifically expressed in cancer cells, making circRNAs a valid source for neoantigen discovery. We have developed high-throughput circRNA reporter screening methods and mass spectrometry-based peptidomic workflow to pinpoint translating circRNAs and their derived peptides. Using these techniques, we have identified circRNA-derived neoantigens in breast cancer (BC) cell lines that can be used as possible targets for cancer vaccines. These circRNA-derived neoantigens are immunogenic and can trigger dendritic cell (DC) maturation and T cell activation in vitro. Next, we will test these findings by transferring to in vivo mouse system. We will assess cancer vaccine efficacy by targeting the neoantigens using syngeneic mouse tumor models. Our long-term goal is to apply the circRNA neoantigen identification technology to BC patient samples to facilitate cancer vaccine development and improve cancer immunotherapy. Our work will demonstrate the potential of circRNA-derived non canonical neoantigens in cancer vaccines, serving as a crucial first step to prove their effectiveness in therapy. By expanding our search beyond the traditional transcriptome and proteome, we will explore new targets and transform the neoantigen-based treatment. This innovative effort shifts the current understanding of neoantigen sources and opens up new possibilities for targeted cancer therapy strategies. Citation Format: Yi-Cian Zheng, Chun-Kan Chen. CircRNA-derived neoantigen identification in cancer vaccine development [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 6701.
Abstract 6712: Epigenetic reactivation of a tumor suppressor program in leukemia
Authors: Eric Wang, Cuijuan Han, Alexander Calderon, Iannis Aifantis, Aristotelis Tsirigos, Abimbo Lawal, Sakthi H. Rajendran, Sadik Karma, Hussein A. Abbas, Mhd Y. Yassouf, Zhiping Zhang, Pedro Miura
Journal: Cancer Research (2025)

Tumor suppressor genes (TSGs) impart a cellular fitness in human cancers, including acute myeloid leukaemia (AML). In contrast to genetic alterations, silencing of TSGs without direct mutations lacks genomic scars, thereby complicating the clinical management of AML. Here we conducted genome-scale phenotypic CRISPR/Cas9 screens to uncover genes that suppress leukaemia differentiation. We identified ZBTB7A, a transcriptional repressor that is downregulated in leukaemia stem cells (LSCs) and associated with poor survival outcomes in AML patients. Our results show that the mRNA decay factor ZFP36L2 binds to the 3’-untranslated region (UTR) of ZBTB7A to induce its mRNA degradation. Mechanistically, the loss of ZBTB7A promotes a dysregulated inflammatory state that drives leukaemia progression. To explore the translational potential, we coupled in situ Flow-FISH readout with CRISPR-based screening which identified KDM4 as a therapeutic vulnerability to restore the tumor suppressive function of ZBTB7A. Pharmacologic inhibition of KDM4 elevated ZBTB7A levels, induced terminal leukaemia differentiation, and broad anti-leukemic efficacy across AML subtypes. Inhibition of KDM4 in vivo prolonged survival of leukemic mice while sparing normal haematopoiesis. Together, our findings reveal regulatory circuits underlying the tumor suppressive role of ZBTB7A and highlights an epigenetic therapy to restore its function in myeloid malignancies. Citation Format: Eric Wang, Cuijuan Han, Alexander Calderon, Iannis Aifantis, Aristotelis Tsirigos, Abimbo Lawal, Sakthi H. Rajendran, Sadik Karma, Hussein A. Abbas, Mhd Y. Yassouf, Zhiping Zhang, Pedro Miura. Epigenetic reactivation of a tumor suppressor program in leukemia [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 6712.