tbuckley/cabot-search huggingface dataset:
Abstract 1119: SoMatt: A foundation model for the tumor genome
Authors: David Andreas Arredondo, Ala Jararweh, Luis Tafoya, Avinash Sahu
Journal: Cancer Research (2025)

Abstract Somatic mutations in cancer cells can lead to diverse phenotypic consequences due to variations in mutation types and locations within the same gene. Interactions between mutations across different genes further contribute to tumor heterogeneity, affecting pathology, phenotype, and clinical outcomes. Current computational methods often treat all mutations within a gene as functionally equivalent and overlook combinatorial effects between genes. Additionally, the diversity of sequencing platforms and gene panels poses significant challenges for integrative genomic analysis across datasets. Here, we introduce Somatic Attention (SoMatt), a foundation model for tumor genomes that leverages self-attention mechanisms to model interactions among mutations within a tumor. Trained on 167, 335 tumors from 149, 831 unique cancer patients from AACR Project GENIE, SoMatt generates comprehensive tumor embeddings suitable for various downstream tasks. The model addresses three critical challenges in tumor genome analysis: (a) distinguishing the effects of different mutations within the same gene, (b) capturing complex interactions among multiple mutations within a tumor, and (c) integrating data from diverse targeted mutation panels without requiring uniformity. We demonstrate that SoMatt accurately predicts patient survival outcomes, achieving a concordance index (C-index) of 0.76 across 90 cancer types, and classifies cancer types with an accuracy of 59%, outperforming baseline models in both tasks. Notably, SoMatt also enables patient stratification beyond traditional subtyping methods by identifying previously unrecognized, molecularly defined patient subgroups with significantly different outcomes, suggesting a novel approach to cancer subtype classification based on tumor molecular profiles. SoMatt produce a robust and scalable framework for comprehensive modeling of tumor genomes, addressing key challenges in cancer genomics and advancing the potential for precision oncology. Citation Format: David Andreas Arredondo, Ala Jararweh, Luis Tafoya, Avinash Sahu. SoMatt: A foundation model for the tumor genome [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 1119.
Abstract 682: PCDHGB10: a unique, sensitive, and specific serum cfDNA methylation biomarker for stomach adenocarcinoma diagnosis
Authors: Donghong Zhang, Chaoyan Niu, Daoyu Yan, Ruo-Pan Huang
Journal: Cancer Research (2025)

Abstract Serum cell-free DNA (cfDNA) methylation has demonstrated its potential in detecting and screening for multiple cancers, offering a critical window for identifying patients eligible for effective treatment. Our objective was to evaluate the efficacy of high methylation-sensitive restriction enzyme combined quantitative PCR (MSRE-qPCR) in identifying a serum cfDNA methylation biomarker for a spectrum of cancer types. We initially developed a 6-gene panel comprising 11 pan-cancer cell-differentially methylated regions across 15 prevalent cancer types, utilizing data from the TCGA methylome database (n = 6981). This panel was then validated using MSRE-qPCR on serum cfDNA samples from 825 participants, encompassing 632 cancer patients across 11 cancer types and 193 healthy controls, collected from multiple cancer centers in China. We assessed the specificity and sensitivity of the panel for diagnosing individual cancers at multiple sites, including the colorectum, esophagus, stomach, liver, lung, ovary, lymphoma, cervix, endometrium, nasopharynx, and pancreas. Among the 11 cancer types, stomach adenocarcinoma (STAD) demonstrated the highest sensitivity and specificity for DNA methylation-based diagnosis in real-world scenarios. PCDHGB10 methylation particularly stood out for STAD diagnosis, achieving a sensitivity of 93.16% and specificity of 88.24% in the training cohort, and 84.09% sensitivity and 96.67% specificity in the validation cohort. For early-stage (I and II) patients, PCDHGB10 sensitivity was 78.48%, rising to 86.89% in late-stage patients. In contrast, PCDHGB10 methylation showed suboptimal diagnostic performance (less than 65% sensitivity) in the other 10 cancer types. This extensive public database and clinical validation study underscores the role of PCDHGB10 methylation as a highly sensitive, specific, and distinctive serum cfDNA methylation biomarker for STAD diagnosis, with particular promise for early-stage detection. Citation Format: Donghong Zhang, Chaoyan Niu, Daoyu Yan, Ruo-Pan Huang. PCDHGB10: a unique, sensitive, and specific serum cfDNA methylation biomarker for stomach adenocarcinoma diagnosis [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 682.
Abstract 493: Cingulin plays a role in PDAC organoid polarity and subtype
Authors: Mariaelena Nabors, Sandra Zarmer, Yi Xu, Jen Jen Yeh
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with a dismal five-year survival rate of 12.5%. Our lab previously identified two transcriptomic PDAC tumor subtypes, termed basal-like and classical. Basal-like tumors are more aggressive while classical tumors have a better prognosis and are more sensitive to chemotherapy. However, many of the biological differences and drivers of the two subtypes remain unknown. We defined the proteomic landscape of PDAC tumors and found that classical tumors are enriched for cell polarity processes compared to basal-like tumors, and that one of the significantly enriched polarity proteins in classical PDAC tumors was cingulin (CGN). Classical organoids recapitulate the well-differentiated architecture of classical PDAC with well-organized hollow lumens. We found that CGN is required for the well-differentiated architecture of classical PDAC organoids and overexpression of CGN is sufficient to drive basal-like organoids to a more well-differentiated state. Additionally, overexpression of CGN in basal-like cell lines decreased invasion. Our results indicate CGN plays a role in PDAC organoid polarity, subtype, and aggression and further study could increase our understanding of the biological differences between PDAC subtypes. Citation Format: {Authors}. {Abstract title} [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 493.
Abstract 203: TCF12 regulates PD-L1 expression through TGF-beta signaling and modulates the immune microenvironment in micropapillary lung cancer
Authors: Yifei Liu, Ting Wang, Tingting Bian, Jia Feng, Qiushi Lin, Xiaoqun Dong
Journal: Cancer Research (2025)

Abstract Background: The prognosis of lung adenocarcinoma (LUAD) is strongly influenced by its histologic growth patterns, with the micropapillary component (MPC) being a poor prognostic indicator. However, the molecular mechanisms driving the poor prognosis of the MP subtype remain unclear, particularly regarding spatial transcriptomic (ST) insights. Methods: Spatial transcriptomics (10X Genomics) was performed on 4 LUAD cases to map gene expression. Targeted next-generation sequencing (NGS) on 72 LUAD samples evaluated genetic alterations. The roles of TCF12 and its regulation via the TGF-β pathway were explored through in vitro and in vivo studies, including CCK-8 assays for cell proliferation, Transwell migration and invasion assays, and sphere formation assays to assess tumorigenic potential. Western blotting and PCR were used to analyze protein and gene expression levels, respectively. Immunohistochemistry of 160 LUAD samples validated TCF12 and PD-L1 expression correlations. Furthermore, mouse xenograft tumor models were employed to verify the effects of TCF12 on tumor growth and its interaction with the TGF-β pathway and PD-L1 expression in vivo. Results: The first spatial transcriptomic map of LUAD revealed significant spatial heterogeneity, with the MP pattern strongly linked to TGF-β signaling and immune responses. TCF12 was highly expressed in MP regions, activating TGF-β signaling and upregulating PD-L1 expression. Functional assays demonstrated that TCF12 overexpression promoted proliferation, invasion, and angiogenesis in LUAD, which were suppressed by TGF-βRI kinase inhibition. In animal models, dual inhibition of TGF-β and PD-L1 significantly reduced tumor growth in TCF12-overexpressing tumors compared to single-drug and control groups. Immunohistochemistry showed that increased TCF12 expression correlated with poor survival, lymph node metastasis, and MP pattern presence. Conclusions: TCF12 drives PD-L1 expression via TGF-β signaling, fostering an immunosuppressive microenvironment in LUAD. Dual inhibition of TGF-β and PD-L1 restores immune function, offering a promising strategy for MP-LUAD precision therapy. Keywords: TCF12, Spatial transcriptomics, TGF-β signaling, PD-L1, Lung adenocarcinoma, Micropapillary component Citation Format: Yifei Liu, Ting Wang, Tingting Bian, Jia Feng, Qiushi Lin, Xiaoqun Dong. TCF12 regulates PD-L1 expression through TGF-beta signaling and modulates the immune microenvironment in micropapillary 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 203.
Abstract 484: Mechanisms of synergy between TGF-beta inhibitor and IL12 expression from the systemically deliverable clinical oncolytic immunotherapy VET3-TGI
Authors: Steve Thorne
Journal: Cancer Research (2025)

Abstract Oncolytic vaccinia virus therapies actively recruit T-cells towards the tumor microenvironment. These can be combined with IL-12 expression to help enhance the immune response by stimulating Th1 cells. However, IL-12 mediated induction of IFN-gamma was also found to increase TGF-beta signaling within the tumor microenvironment.TGF-beta mediated resistance is one of the major mechanisms of immune suppression utilized across multiple solid tumor types. Blockade of TGF-beta (TGFBi) will therefore likely improve response to immunotherapy. Combining TGF-beta inhibition with IL-12 expression can maximize therapeutic benefits through simultaneously reducing immunosuppression and enhancing anti-tumor immune response. Current studies describe a vaccinia-based immunotherapy, VET3-TGI, combining enhanced systemic virus delivery to tumors and locally expressed IL-12 and TGFBi within the tumor microenvironment, for efficient control of multiple tumor models. In vivo mouse studies demonstrated potent therapeutic activity, including many CRs, even at doses several logs below equivalent clinical doses after systemic (intravenous) delivery. In addition, toxicity studies demonstrated the safety of VET3-TGI in mouse models. This data led to the selection of VET3-TGI as a lead clinical candidate and clinical testing has begun. Citation Format: Steve Thorne. Mechanisms of synergy between TGF-beta inhibitor and IL12 expression from the systemically deliverable clinical oncolytic immunotherapy VET3-TGI [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 484.
Abstract 202: CRISP3 and PSP94 as soluble mediators shaping P2RX7 mediated signalling probably via CITED2 in tumor microenvironment
Authors: Vaidehi Miya, Bhakti Rajesh Pathak
Journal: Cancer Research (2025)

Abstract The dynamic interplay between the tumor and the infiltrating immune cells within the tumor microenvironment (TME) critically shapes cancer progression, particularly through mechanisms of immune evasion and tumor cell survival. Cysteine Rich Secretory Protein 3 (CRISP3) is elevated in prostate cancer and linked to poor prognosis. Originally identified in neutrophilic granules and body secretions, CRISP3 levels are frequently dysregulated in inflammation. Whether overexpressed CRISP3 modulates tumor immune microenvironment remains largely unexplored. Our study unravelled a potential mechanism whereby CRISP3 controlled the expression of P2RX7 (Purinergic Receptor X7), a key player in the inflammasome pathway, in tumor cells as well as in macrophages. Using antibody array, we identified CITED2 (cAMP-responsive element-binding protein (CBP)/p300-interacting transactivator with glutamic acid (E) and aspartic acid (D)-rich tail) levels to be upregulated in cells exposed to CRISP3. CITED2 is a transcriptional coregulator and a potent molecular switch that promotes macrophage polarisation. In silico analysis of human P2RX7 promoter demonstrated presence of p300/CBP binding sites suggesting possible sequestration of p300/CBP in presence of CITED2, thus downregulating P2RX7. Publicly available single cell RNA-seq data also highlighted the involvement of CITED2 in regulating the expression of P2RX7. Ectopically added CRISP3 significantly altered ATP-induced cytotoxicity and IL-1β maturation due to downregulation of P2RX7. Interestingly, when CRISP3 was complexed with its binding partner, PSP94 (Prostate Secretory Protein of 94 amino acids), its regulatory action on P2RX7 was inhibited. The presence of PSP94 also affected CRISP3 endocytosis which was via flotillin-2 dependent pathway. Together, our data provides evidence for an important role for CRISP3 and PSP94 in regulating P2RX7 levels. Upregulated CRISP3, in prostate tumorigenesis, suppresses P2RX7 expression, impacting IL-1β maturation and potentially driving macrophage polarization to M2 like by upregulating CITED2. This supports poor prognostic outcomes in prostate cancer patients showing upregulated CRISP3. Inhibition of CRISP3 can be an interesting therapeutic strategy in alleviating immunosuppressive tumor milieu. Citation Format: Vaidehi Miya, Bhakti Rajesh Pathak. CRISP3 and PSP94 as soluble mediators shaping P2RX7 mediated signalling probably via CITED2 in tumor microenvironment. [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 202.
Abstract 44: PDX-derived cellular models for pharmacological screening and functional studies
Authors: Léa Sinayen, Enora Le Ven, Emilie Indersie, Ester Morgado, Laurent Pouyet, François Romagné, Olivier Déas
Journal: Cancer Research (2025)

Abstract Despite substantial advancements in understanding the biology and genetics of cancer, the development of effective therapies is hindered by the lack of adequate experimental models that replicate the genetic diversity of this disease. Patient-derived xenografts (PDXs) have become the gold standard in preclinical oncology for the evaluation of new anticancer drug candidates. The faithful reproduction of patients' cancer features, and the ability to generate models that recapitulate the genetic heterogeneity of the patient population, confer PDXs with a critical added value in the preclinical field. Over the past 15 years, we have generated and characterized a collection of over 200 PDXs from various solid tumors that accurately reproduce the histological and molecular heterogeneity of original tumors. This panel has enabled the preclinical validation of several anticancer drugs that are now used in the clinic. Although an indispensable tool for conducting preclinical studies, the use of in vivo PDX systems for large-scale screening during early drug discovery is restricted by ethical, economic, and throughput limitations that limit the number of drug candidates tested. To address this challenge, we have developed a panel of PDX-derived cells (PDXDCs) that we propose as a time- and cost-effective, medium-throughput screening tool to profile the anticancer activity of early test compounds. To date, over 50 PDXDCs from various indications such as breast, prostate, lung, and several others have been generated and tested for their in vitro response to standard of care, targeted anticancer agents, and immunotherapies, used as monotherapy or in combination to study potential synergistic effects. PDXDCs were obtained from dissociated PDX tumors cultured under various media and matrix conditions. They were characterized by comparison with the parental PDX through short tandem repeat (STR) profiling prior to establishing a master bank. PDXDC RNA and exome sequencing data faithfully match the parental PDX features, and by modulating experimental parameters, such as 2D or 3D growth conditions, drug exposure duration, and endpoint readouts, we could phenocopy in vitro the corresponding PDXs' sensitivities to drug candidates. These results support our PDXDCs panel as a valuable in vitro tool for drug screening to help selecting drug candidates for further in vivo validation, as well as the most appropriate in vivo PDX models to use. Citation Format: Léa Sinayen, Enora Le Ven, Emilie Indersie, Ester Morgado, Laurent Pouyet, François Romagné, Olivier Déas. PDX-derived cellular models for pharmacological screening and functional studies. [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 44.
Abstract 554: Nanoparticle enabled miR-205 restoration in docetaxel resistant prostate cancer
Authors: Neeraj Chauhan, Eswara NHK Ghali, Rahul Tiwari, Iris Enriquez, Rajasekhar Baru, Subhash C. Chauhan, Murali M. Yallapu
Journal: Cancer Research (2025)

Background: Prostate cancer (PrCa) is the second most diagnosed malignancy and a leading cause of cancer-related death in men worldwide. Docetaxel (Dtxl)-based chemotherapy remains a cornerstone of treatment for PrCa. However, most patients develop resistance to Dtxl treatment, leaving limited therapeutic options. Although cabazitaxel offers a secondary line of therapy, it is associated with many severe adverse effects. Restoring miR-205, a tumor-suppressor microRNA frequently downregulated in PrCa, has emerged as a promising strategy to reverse Dtxl resistance and achieve tumor regression. Methods: A novel nanoformulation (MNP-miR-205) was developed using iron oxide magnetic nanoparticles (MNPs) layered with polyethylene imine (PEI) polymer to deliver miR-205. The optimized nanoformulation of MNP-miR-205 was characterized by size, surface charge, biochemical properties using DLS, gel retardation, and biochemical analyses. Chemo-sensitizing and anti-cancerous effects of MNP-miR-205 were evaluated in Dtxl-resistant PrCa cell lines and corresponding xenograft mouse models. Biodistribution of the formulation was evaluated by incorporation of indocyanine green (ICG) dye to track tumor accumulation. Results: The MNP-miR-205 nanoformulation demonstrated optimal particle size and zeta potential, ensuring efficient cancer cell delivery. Hemocompatibility studies confirmed its safety profile. The formulation achieved an excellent cellular uptake via endocytosis, by passing endosomal and lysosomal degradation pathways. In Dtxl resistant PrCa cells, MNP-miR-205 enhanced chemosensitivity to Dtxl, as evident by increased apoptosis, Caspase 3/7 activity, and reduced mitochondrial membrane potential. In vivo studies confirmed that MNP-miR-205 exhibited superior tumor accumulation, significantly reducing tumor volume and weight, and prolonging overall mice survival in xenograft mouse models. Conclusion: This innovative MNP-miR-205 nanoformulation offers a groundbreaking theranostic approach to address Dtxl resistance in prostate cancer. By enhancing chemo-sensitization and providing a safer imaging platform, it holds significant potential to improve prostate cancer management. Citation Format: Neeraj Chauhan, Eswara NHK Ghali, Rahul Tiwari, Iris Enriquez, Rajasekhar Baru, Subhash C. Chauhan, Murali M. Yallapu. Nanoparticle enabled miR-205 restoration in docetaxel resistant 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 554.
Abstract 455: Targeting CARM1- expressing ovarian cancers with HSP-70 inhibitors
Authors: Sangeeta Kumari, Shraddha Gupta, Aisha Jamil, Sergey Karakashev
Journal: Cancer Research (2025)

Abstract Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer-related deaths in the United States, characterized by its genetic heterogeneity and the urgent need to develop novel therapeutic strategies in a personalized manner. Coactivator-associated arginine methyltransferase 1 (CARM1) is an enzyme responsible for post-translational modifications of protein substrates on arginine residues. CARM1 is often overexpressed and functions as an oncogene in several cancer types. Notably, high-grade serous ovarian carcinoma (HGSOC) exhibits the highest rates of CARM1 amplification, with approximately 20% of cases showing overexpression, which correlates with poor survival outcomes in EOC patients. This study aimed to identify potential therapeutic targets for EOC cells with CARM1 amplification. We conducted an unbiased evaluation of a custom set of 27 small-molecule inhibitors to identify agents selectively effective against CARM1-expressing EOC cells, leading to the identification of the HSP-70 inhibitor AP-4-139B as the most potent candidate. HSP-70 is a crucial part of the protein folding machinery, and its levels are upregulated in multiple types of cancer and serve as a substrate for CARM1 enzymatic activity; however, the implications of HSP-70 modification by CARM1 remain unclear. The CRISPR-Cas9-based knockout technology was employed to analyze the effect of CARM1 knockout on cell proliferation in EOC cells, which demonstrated that CARM1 knockout significantly slowed cell growth in EOC cells. Synthetic lethality of CARM1-expressing cells upon HSP-70 inhibition by AP-4-139B was validated in both the ovarian cancer cell model system and the xenograft model. Mechanistically, AP-4-139B treatment induced apoptotic cell death in CARM1-high EOC cells through activation of the apoptotic pathway as analyzed by cell proliferation assay, apoptotic assay, and immunoblotting of apoptotic markers. Our findings indicate that CARM1-high cells are selectively sensitive to HSP-70 inhibitors as a single agent. HSP-70 inhibition alone will be sufficient to induce apoptosis and inhibit tumor growth in a CARM1-dependent manner ex vivo and in vivo. Thus, these findings will have far-reaching implications for developing personalized therapeutic strategies based on CARM1 amplification. The therapeutic and mechanistic rationale for targeted therapy on patients with CARM1 high EOC who are most likely to benefit from HSP-70 inhibitor treatment. Citation Format: Sangeeta Kumari, Shraddha Gupta, Aisha Jamil, Sergey Karakashev. Targeting CARM1- expressing ovarian cancers with HSP-70 inhibitors [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 455.