tbuckley/cabot-search huggingface dataset:
Abstract 4838: Epigenetic modulation of polyamine biosynthetic pathways rectifies T cell dysfunction to enhance anti-tumor immunity in lung cancer
Authors: Hsing-Chen Tsai, Yi-Chieh Wu, Yu-Ting Lee, Meng-Wei Chou, Shu-Yung Lin, Sheng-Yao Su, Chia-Lang Hsu, Nai-Wen Chang, Yi-Jhen Huang, Yi-Hsiu Juan, Hsuan-Hsuan Lu, Pei-Shan Wu, Miao-Hsia Lin, Li-Chung Hsu, Yen-Ling Chiu, Shih-Yu Chen, Chong-Jen Yu
Journal: Cancer Research (2025)

T cell exhaustion, a dysfunctional state caused by prolonged antigen exposure, presents a major challenge in cancer immunotherapy. While immune checkpoint inhibitors show therapeutic promise, they fail to rejuvenate T cells in a terminally exhaustion state, potentially due to epigenetic barriers. We hypothesized that targeting epigenetic regulators may provide novel therapeutic strategies to overcome these barriers, thereby rescuing terminally exhausted T cells. In this project, we used malignant pleural effusions from advanced lung cancer patients as a source of primary exhausted T cells. Through high-throughput screening of an epigenetic compound library, we identified several bromodomain inhibitors (BETis) as potent enhancers of T cell polyfunctionality in primary human T cells. Treatment with BETis, like JQ1, reduces inhibitory receptor expression and increases effector cytokine production. Transcriptomic and ATAC-seq profiling revealed that JQ1 modulates key metabolic pathways and induces chromatin accessibility changes in primary effusion-infiltrative T cells. Untargeted metabolomics showed that JQ1 expands the polyamine spermidine pool in T cells. Inhibition of ornithine decarboxylase (ODC1), a key enzyme in polyamine biosynthesis, diminishes JQ1’s reinvigorating effects on these T cells. scRNA-seq analysis revealed that JQ1 reduces terminally exhausted T cells and promotes the expansion of progenitor exhausted T cells, which are more responsive to checkpoint inhibitors, by upregulating ODC1 and its upstream regulator, MYC. Notably, adoptive transfer of JQ1-treated T cells significantly reduced tumor-associated MPE in a syngeneic mouse model. Our study demonstrates that BET inhibitors enhance T cell polyfunctionality and modulate terminally exhausted T cells through metabolic reprogramming, notably by upregulating the polyamine biosynthesis pathway. These findings highlight the potential of epigenetic-based cancer immunotherapy for novel therapeutic strategies. Citation Format: Hsing-Chen Tsai, Yi-Chieh Wu, Yu-Ting Lee, Meng-Wei Chou, Shu-Yung Lin, Sheng-Yao Su, Chia-Lang Hsu, Nai-Wen Chang, Yi-Jhen Huang, Yi-Hsiu Juan, Hsuan-Hsuan Lu, Pei-Shan Wu, Miao-Hsia Lin, Li-Chung Hsu, Yen-Ling Chiu, Shih-Yu Chen, Chong-Jen Yu. Epigenetic modulation of polyamine biosynthetic pathways rectifies T cell dysfunction to enhance anti-tumor immunity in 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 4838.
Abstract 4840: Investigation of the potential immunomodulatory effect of vitamin D supplementation in vitamin D deficient cancer patients
Authors: Alexandra Kalmar, Zsofia Brigitta Nagy, Liza Dalma Sumegi, Barbara Kinga Bartak, Sandor Spisak, Istvan Takacs, Bela Molnar
Journal: Cancer Research (2025)

Abstract Background: Advantageous effects of vitamin D supplementation have been studied in certain diseases, but the underlying chromatin remodeling processes remains to be explored in detail during the treatment of cancer patients. Aim: We aimed to assess the molecular effects of high-dose vitamin D supplementation in patients diagnosed with various cancer types. Methods: High-dose (30.000 NE) vitamin D per week was supplemented to 8 patients including 5 lung cancer, 2 colorectal cancer, and 1 urothelial cell carcinomas for two months. Following the blood collection before and after the supplementation period, Histopaque density gradient cell separation was applied to retrieve peripheral mononuclear cells (PBMCs). To examine alterations in the chromatin accessibility after the treatment in PBMCs, assay for transposase-accessible chromatin with sequencing (ATAC-Seq) was performed using the 10X Genomics on a NextSeq 550 instrument with a High Output Sequencing kit (Illumina Inc.). DNA integrity was assessed by the alkaline Comet-assay and telomere qPCR. To analyze further potential epigenetic alterations, global DNA methylation level was estimated on the basis of LINE-1 bisulfite-pyrosequencing experiments on cfDNA and PBMC cells. Results: Vitamin D serum levels elevated 2, 5 fold on average after 2 months of supplementation in all patients. Based on ATAC-Seq, the cellular ratio among PMBC cells altered with an elevated number of NK cells following vitamin D supplementation. DNA integrity was significantly better after treatment in mononuclear cells with decreased Comet assay DNA tail average % (p=0.01), but not in granulocytes. Supplemented samples showed significantly altered telomere length in mononuclear cells (p=0.007). However, no significant difference was observed in cfDNA levels between the sample groups. Slight, but not significant LINE-1 methylation alteration was detected in PBMCs and cfDNA after vitamin D supplementation. Conclusion: Vitamin D supplementation caused significant changes in immune cells that might have an influence on the response to the tumors in cancer patients. Citation Format: Alexandra Kalmar, Zsofia Brigitta Nagy, Liza Dalma Sumegi, Barbara Kinga Bartak, Sandor Spisak, Istvan Takacs, Bela Molnar. Investigation of the potential immunomodulatory effect of vitamin D supplementation in vitamin D deficient 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 4840.
Decoding Post-Mortem Infection Dynamics of SARS-CoV-2, IAV and RSV: New Insights for Public Health and Emerging Infectious Diseases Management
Authors: Run Chen, Zeyi Hao, Jian Ye, Xingchun Zhao, Sheng Hu, Jianliang Luo, Junhua Li, Hao Wu, XingGong Liang, Chen Shen, Mingyan Deng, Wanqing Zhang, Zhengyang Zhu, Yudong Qin, Gengwang Hu, Letong Zhang, Fan Cao, Yuzhao Liu, Ruina Liu, Qinru Sun, Hongping Wei, Zhenyuan Wang
Journal: Journal of Infection (2025)
Abstract 4203: Discovery and development of a potent and highly selective ATR inhibitor IMP9064
Authors: Sui Xiong Cai, Ning Ma, Xiaozhu Wang, Yangzhen Jiang, Mingchuan Guo, Ruiyu Zhou, Mu Chen, Ye Edward Tian
Journal: Cancer Research (2025)

Abstract The ataxia telangiectasia and RAD3-related (ATR) kinase is a crucial component of the DNA damage response (DDR) and functions in conjunction with ataxia telangiectasia mutated (ATM). Loss or functional deficiency of ATM may lead to increased reliance on ATR signaling pathways. Preclinical and clinical studies have indicated a potential synthetic lethality between ATR inhibition and ATM deficiency. We have identified a novel, potent, and highly selective ATR inhibitor IMP9064. Herein we present its discovery and IND enabling in vitro and in vivo studies. IMP9064 is highly activity inhibiting ATR, and is highly selective among kinases. IMP9064 also shows potent cytotoxicity to a wide range of cancer cell lines. In addition, IMP9064 has a desirable PK profile in preclinical species. IMP9064 has demonstrated anti-tumor efficacy in human colorectal cancer CDX animal models with good dose-response tumor growth inhibition and tolerability. The results of in vitro and in vivo studies suggest that used alone or in combination with PARP inhibitor, WEE1 inhibitor, PKMYT1 inhibitor or HER2 ADC, IMP9064 has good anti-tumor activity and synergistic effect. IMP9064 has entered a phase 1/2 study to evaluate the safety and efficacy either as monotherapy or in combination with PARP inhibitor Senaparib in patients with advanced solid tumors (ClinicalTrials.gov Identifier: NCT05269316). The recommended phase 2 dose (RP2D) has been determined and IMP9064 is currently in expansion studies for selected tumors. Citation Format: Sui Xiong Cai, Ning Ma, Xiaozhu Wang, Yangzhen Jiang, Mingchuan Guo, Ruiyu Zhou, Mu Chen, Ye Edward Tian. Discovery and development of a potent and highly selective ATR inhibitor IMP9064 [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 4203.
Abstract 4206: Investigation into the mechanisms and therapeutic potential of R-loop-induced DNA damage in ER+ breast cancer
Authors: Alyssa Roberts, Nicole Traphagen, Anneka Johnson, Eugene Demidenko, Patricia Muskus, Xiaofeng Wang, Todd W. Miller
Journal: Cancer Research (2025)

A potential therapeutic vulnerability of endocrine-resistant estrogen receptor alpha (ER)-positive breast cancer is R-loop-mediated DNA damage induced by 17b-estradiol (E2). This study aims to elucidate the mechanism of DNA damage and test combination therapies to exacerbate the anti-cancer effects of E2. ER+ breast cancer cells overexpressing exogenous ER, which induces sensitivity to the growth-inhibitory effects of E2, were exposed to E2 and inhibitors of DNA damage repair proteins including poly-ADP ribose polymerases (PARP) and CHK1/2. Experimental endpoints included immunoblotting, flow cytometry, immunofluorescence, DNA fiber analysis, and growth assays using cell lines and patient-derived xenografts (PDXs). Cells overexpressing ER showed R-loop-dependent DNA damage in replicating cells. Combination therapy of E2 and the PARPi olaparib increased DNA damage in replicating cells without negatively impacting the elevated replication rates induced by E2. E2 significantly increased single-stranded DNA in ER-overexpressing cells; ssDNA is known to be susceptible to damage. These effects of E2 were exacerbated by PARPi. E2 increased the proportion of cells replicating DNA, but E2 paradoxically interfered with replication fork progression as shown by DNA fiber analysis. These findings suggest that replication interference contributes to DNA damage and eventual cell death but does not impair the ability for the cell to replicate. An alternative therapeutic approach is combination therapy with E2 and Chk1/2 inhibitor. This combination successfully inhibits growth of both parental and ER overexpressing cells indicating that E2 and Chk1/2 inhibition may have clinical potential. E2 induced DNA damage mediated by R-loops can be amplified using combination therapies targeting DNA damage repair or cell cycle inhibition. While it is clear that replication conflicts plays an important role in DNA damage, the mechanism in which the DNA damage is occurring has yet to be elucidated. Citation Format: Alyssa Roberts, Nicole Traphagen, Anneka Johnson, Eugene Demidenko, Patricia Muskus, Xiaofeng Wang, Todd W. Miller. Investigation into the mechanisms and therapeutic potential of R-loop-induced DNA damage in ER+ breast 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 4206.
Abstract 1293: PMed-TRIAL database: an efficient and intelligent data integration platform shaping the future of drug development
Authors: Xinlei Chen, Youbing Guo, Loc Van, Josh Caggiula, Danyi Wen
Journal: Cancer Research (2025)

Abstract With the rapid advancements in artificial intelligence (AI) and big data technologies, the fields of precision medicine and drug development have entered a transformative data-driven era. Leveraging years of accumulation and expertise, LIDE launched the PMed-TRIAL Database in 2023. Through continuous iteration and expansion, PMed-TRIAL has evolved into a comprehensive data integration and query platform, encompassing PDX (Patient-Derived Xenograft), CDX (Cell Line-Derived Xenograft), Syngeneic models, and Conditional Reprogramming Cell Lines. The platform enables efficient data retrieval and intelligent integration, providing indispensable support for clinical and drug research in this new era. The database currently hosts nearly 1, 800 PDX models, making it one of the largest PDX repositories worldwide. These models integrate and standardize a wide range of key datasets, including clinical information, treatment history, growth curves, SOC (standard of care), and H&amp;E (hematoxylin and eosin staining) results, among others, which greatly facilitates the filtering and selection of suitable models for drug research. Furthermore, the associated whole-exome sequencing (WES) and RNA sequencing datasets provide critical evidence for drug mechanisms research. In addition to standard PDX models, the database also includes induced drug-resistance models, providing an essential resource for studying drug resistance mechanisms and screening drugs to overcome resistance. In addition to PDX models, the PMed-TRIAL Database incorporates information on Patient/PDX-derived conditional reprograming cell lines, PDXO (PDX Derived Organoids), Syngeneic models, and CDX models. This expanded scope addresses the multi-faceted demands of drug development, accelerating research timelines and enhancing the efficiency of the drug discovery process. Most importantly, the PMed-TRIAL Database standardizes and efficiently integrates diverse model datasets. The accumulation of large-scale, high-quality data not only streamlines current research efforts but also lays the groundwork for advancing AI applications in drug development in the future. By bridging innovative technologies with comprehensive data resources, PMed-TRIAL empowers researchers to unlock new possibilities in precision medicine and therapeutic innovation. Citation Format: Xinlei Chen, Youbing Guo, Loc Van, Josh Caggiula, Danyi Wen. PMed-TRIAL database: an efficient and intelligent data integration platform shaping the future of drug 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 1293.
Abstract 2656: Sec23b governs the migration of MDA-MB-231 breast cancer cells by regulating collagen I processing and secretion
Authors: E. Emily Joo, Audrey Astori, Jonathan St-Germain, Brian Raught, Michael F. Olson
Journal: Cancer Research (2025)

Abstract Cancer metastasis is a complex, multi-step process that begins with the dissociation of primary cancer cells from their original site. These cells then migrate to distant areas, where they establish colonies and undergo uncontrolled proliferation at secondary locations. Thus, dysregulation of cell migration is one of the hallmarks of solid tumour metastasis. Given that the actin cytoskeleton plays crucial roles in normal cell migration, we developed a robust method that combines an amino acid sequence that binds to actin (LifeAct) with biotin-mediated proximal labelling (BioID) to identify actin-binding proteins. Specifically, to identify actin-associated protein complexes during the early stages of cells migrating into scratched areas, we conjugated LifeAct with the newest derivation of BioID (miniTurbo-LifeAct-BioID) and controlled its expression with doxycycline in MDA-MB-231 cells. After inducing cell migration by scratch wounding, we allowed cells to migrate into the scratched areas for 1.5 hours then pulse-labelled with biotin for 30 minutes. As controls, using the same system, we labelled actin-associated proteins in resting cells and in cells that had been treated with cytochalasin D (CD) to depolymerize actin filaments. Compared to the untreated cells, the CD-treated cells increased labelling of the G-actin binding proteins (e.g., profilin and JMY) while decreased labelling of the F-actin binding proteins (e.g., Coronin2A and ABLIM1/ABLIM2/ ABLIM3), validating the ability of miniTurbo-LifeAct-BioID to detect dynamic changes in cytoskeleton-associated protein complexes. By comparing miniTurbo-LifeAct-BioID labelled proteins in migrating versus stationary cells, eighteen proteins were significantly more biotin labelled and eight proteins were less biotin labelled. Unexpectedly, Sec23b, a component of the COPII secretion complex, was labelled to a greater extent in cells migrating into scratched areas. Depletion of Sec23b increased secretion of procollagen I but decreased deposition of collagen I filaments. Interestingly, the reduced migration of cells depleted of Sec23b was rescued by collagen I but not by fibronectin or gelatin. Based on our findings, metastatic breast cancer MDA-MB-231 cells appear to control the secretion and processing of collagen I to govern their extracellular matrix organization for efficient cell migration. Citation Format: E. Emily Joo, Audrey Astori, Jonathan St-Germain, Brian Raught, Michael F. Olson. Sec23b governs the migration of MDA-MB-231 breast cancer cells by regulating collagen I processing and secretion [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 2656.
Abstract 4095: Advancing cancer prognosis: FFPE-CUTAC for comprehensive and affordable transcription profiling in oncology
Authors: Ye Zheng, Kami Ahmad, Steven Henikoff
Journal: Cancer Research (2025)

Abstract RNA-seq has been the method of choice for profiling patient samples. However, it predominantly detects genes expressed at moderate-to-high levels and is limited by the fragility of RNA, especially in Formalin-Fixed Paraffin-Embedded (FFPE) sections. We introduce Cleavage Under Targeted Accessible Chromatin (CUTAC) with an antibody to RNA Polymerase II (RNAPII) as a sensitive, cost-effective alternative for directly profiling transcription in FFPEs. Our findings reveal that FFPE-CUTAC libraries are significantly more comprehensive than RNA-seq libraries from both frozen and FFPE clinical sections, capturing low-level transcription of most active genes often missed by RNA-seq. Integrating RNAPII FFPE-CUTAC data from meningioma tumor samples with RNA-seq data from 1,298 patients, we demonstrate that RNAPII occupancy correlates strongly with transcriptional output. Embedding RNAPII FFPE-CUTAC datasets within a meningioma RNA-seq UMAP enhances the prediction of poor clinical outcomes, offering a powerful and economical replacement for RNA-seq in general cancer diagnosis. Moreover, we observed widespread hypertranscription in human cancers, which correlates with poor prognosis. Using FFPE-CUTAC, we demonstrated genome-wide hypertranscription in transgene-driven mouse gliomas and various human tumors at active regulatory elements. Notably, hypertranscription challenges most normalization strategies that assume equal fragment volumes across samples. Tumor burden varies greatly across patients and tumor types, with significantly more cells in tumors compared to their corresponding normal samples. Within tumor cells, hypertranscription results in substantially higher FFPE-CUTAC fragment count. Assuming equal reads between tumor and normal samples can obscure hypertranscription signals. To address this, we developed a background-driven normalization strategy for FFPE-CUTAC data, accounting for the variations of cell numbers and fragment volumes to ensure accurate comparison across tumor and normal samples. We validated this strategy using both single-cell simulated data and specially designed experiments with known cell proportions and signal fold changes. Our experimental and computational results affirm that FFPE-CUTAC provides a sensitive and affordable approach for detecting hypertranscription and classifying tumors using small tissue sections, advancing genome-wide strategies for personalized medicine. Citation Format: Ye Zheng, Kami Ahmad, Steven Henikoff. Advancing cancer prognosis: FFPE-CUTAC for comprehensive and affordable transcription profiling in oncology [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 4095.
Abstract 1351: Ephrin receptor A4 regulation of the tumor microenvironment in triple-negative breast cancer
Authors: Hoi Wan (Karen) Lee, Wenchao Liu, Madeline Henn, Marsha Rosner
Journal: Cancer Research (2025)

Metastasis is the leading cause of mortality for cancer patients and is particularly difficult to manage in Triple-Negative Breast Cancer (TNBC), a subtype of breast cancer with limited targeted therapies and biomarkers. Ephrin Receptor A4 (EPHA4) is a receptor tyrosine kinase activated by cell-cell contact that regulates various developmental pathways, and a cell surface receptor that has the potential to be targeted pharmacologically. In the context of TNBC, EPHA4 has been found to have mixed effects on regulating factors that may influence metastasis: while EPHA4 expression promotes in-vitro cell invasion, EPHA4 activation also enhances T cell-mediated antitumor immunity. Considering EPHA4’s function of mediating cell-cell interaction, it may play an important role in modulating the tumor microenvironment via cancer-immune cell interactions. However, EPHA4’s functions within the tumor microenvironment and how this relates to its regulation of metastasis remain poorly understood. To characterize EPHA4 as a potential target for TNBC metastasis, we conducted single-cell RNA-sequencing of a syngeneic, orthotopic TNBC mouse model to investigate how EPHA4 regulates the tumor microenvironment. Control or EPHA4 knockout 4T1 cells were injected into BALB/C mice and primary tumors were isolated and sequenced. There is no literature consensus on methods of marker-based annotation of tumor cells in the 4T1 syngeneic model, and we instead applied an aneuploidy analysis algorithm to increase the accuracy of tumor cell annotations. EPHA4 was found to increase the proportion of T cells, NK cells and B cells in the tumor microenvironment. EPHA4 also promoted tumor-intrinsic genetic pathways regulating T cell activation and antigen processing and presentation via MHC class II. Overall, EPHA4 modulates the immune landscape in TNBC, serving as a potential mechanism by which it regulates metastasis. Citation Format: Hoi Wan (Karen) Lee, Wenchao Liu, Madeline Henn, Marsha Rosner. Ephrin receptor A4 regulation of the tumor microenvironment in triple-negative breast 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 1351.