tbuckley/cabot-search huggingface dataset:
Abstract 6918: TEAD inhibition as a therapeutic strategy for diffuse-type gastric cancer
Authors: Lawrence W. Wu, Sung Joo Jang, Jimyung Park, Cameron Shapiro, Tracy T. Tang, Ryan H. Moy
Journal: Cancer Research (2025)

Abstract Introduction: Diffuse-type gastric cancer (DGC) accounts for one third of gastric cancers and is associated with poor differentiation, discohesive growth, chemoresistance, and worse survival compared to intestinal-type tumors. DGC is typically genomically stable, and there are no approved DGC-targeted therapies. Recent studies utilizing multi-omic profiling of patient samples and DGC mouse models have identified a tumor-promoting role for Yes-associated protein 1 and transcriptional coactivator with PDZ-binding motif (YAP/TAZ), which interact with TEAD transcription factors to regulate gene expression. Therefore, we evaluated the activity and mechanism of TEAD inhibitors in DGC preclinical models. Methods: Gastric cancer patient-derived organoids (PDOs) and cell lines were treated with TEAD inhibitors (VT103, VT107) and/or 5-fluorouracil (5-FU) for in vitro assays evaluating cell proliferation or invasion. The in vivo activity of VT103 and/or 5-FU was tested with a subcutaneous xenograft model using a genetically engineered mouse model of gastric cancer driven by oncogenic KrasG12D and loss of Trp53/Cdh1. Results: TEAD inhibition with VT103 and VT107 reduced proliferation, colony formation, and invasion in DGC cell lines and PDOs. We observed no effect of TEAD inhibitors on the viability of a normal gastric tissue cell line. Combining the TEAD1-selective inhibitor VT103 with 5-FU chemotherapy resulted in further reduction of DGC PDO viability relative to monotherapy. In flank tumors, inhibition of the YAP/TAZ-TEAD pathway using VT-103 in combination with 5-FU significantly reduced tumor growth. We hypothesized that TEAD inhibition blocks an epithelial-to-mesenchymal transition (EMT) program and promotes apoptosis. Consistent with this hypothesis, TEAD1 inhibition with VT-103 reduced expression of the EMT marker Slug and increased expression of the apoptosis marker cleaved caspase 3 in tumor xenografts. Conclusions: The YAP/TAZ-TEAD pathway is an important driver of gastric cancer growth and metastasis, particularly in DGC where it may promote EMT. TEAD inhibition reduces gastric cancer growth and invasion in vitro and in vivo in preclinical models and demonstrates synergistic activity with 5-FU chemotherapy. These results suggest a potential role for further investigation of clinical efficacy of TEAD inhibitors in patients with DGC. Citation Format: Lawrence W. Wu, Sung Joo Jang, Jimyung Park, Cameron Shapiro, Tracy T. Tang, Ryan H. Moy. TEAD inhibition as a therapeutic strategy for diffuse-type gastric 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 6918.
Abstract 7267: Development and validation of a novel humanized B-hTRBC1/hTRBC2 mouse model for T cell activation
Authors: Hannah Horton, Zhixia Li, Shufeng Wang, Zhenlan Niu, Lei Zhao, Yanling Wang, Xiaofei Zhou
Journal: Cancer Research (2025)

Abstract The gene encoding the TCR constant β chain (TRBC) has two isoforms: TRBC1 and TRBC2. Each TCR (and therefore each T cell) irreversibly selects a TCR β-chain constant region encoded by either TRBC1 or TRBC2 for expression in a mutually exclusive manner. Normal T cells consist of both TRBC1 and TRBC2; however, malignant T cells contain only one of the two isoforms. In the treatment of TRBC1+ or TRBC2+ T cell malignancies, selectively targeting TRBC1 or TRBC2, respectively, can effectively eliminate the malignant clone without significantly compromising the integrity of the T cell compartment, thereby preventing severe immunosuppression. This study introduces a novel B-hTRBC1/hTRBC2 mouse model for the investigation of T cell activation and includes an extensive analysis of its phenotypic and immunological characteristics. Gene and protein expression of human TRBC1/TRBC2 in these mice were confirmed using RT-PCR and flow cytometry, respectively. The study also found comparable development, differentiation, and distribution of immune cells in the spleen, blood, and lymph nodes between B-hTRBC1/hTRBC2 mice and wild-type C57BL/6 mice. Notably, normal T cell proliferation and cytokine production were observed in vitro in response to anti-mCD3E and anti-hTRBC1 antibody treatments, demonstrating the functionality of humanized T cells in these mice. In summary, our data indicate that B-hTRBC1/hTRBC2 mice provide a powerful preclinical model for in vivo/ex vivo evaluation of T cell activation. Citation Format: Hannah Horton, Zhixia Li, Shufeng Wang, Zhenlan Niu, Lei Zhao, Yanling Wang, Xiaofei Zhou. Development and validation of a novel humanized B-hTRBC1/hTRBC2 mouse model for T cell activation [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 7267.
Abstract 7269: The humanized CRBN mice model facilitates PROTACs studies based on CRBN ligands
Authors: Mari Kuraguchi, Ying Zhao, Chonghui Liu, Xiao Liu, Jiansu Zhang
Journal: Cancer Research (2025)

Abstract CRBN ligands, which have become increasingly popular as E3 ligase ligands, are important in designing PROTACs (Proteolysis Targeting Chimeras) and molecular glue degraders, aiding in targeted protein degradation. CRBN, part of the CRL4 E3 ubiquitin ligase complex, binds to specific proteins and promotes their degradation, a process essential for cell regulation and apoptosis. In multiple myeloma (MM) treatment, drugs targeting CRBN, like thalidomide and lenalidomide, show effectiveness by altering substrate specificity of CRBN, targeting tumor-associated proteins for degradation. CRBN-based PROTACs are emerging as promising cancer treatments by directing CRBN to target proteins for degradation. Biocytogen has developed the B-hCRBN mouse model, engineered to express human CRBN instead of the mouse version by inserting the full-length human CRBN CDS into the mouse Crbn exons 2-3. Expression of human CRBN mRNA and proteins were exclusively detected in homozygous humanized mice and these mice also demonstrated increased IL2 production in CD4+ T cells in response to lenalidomide treatment, confirming successful generation of the model. In summary, B-hCRBN mice are effective tool for preclinical in vivo efficacy and safety evaluation of CRBN-targeted drugs, including CRBN-based small molecules, molecular glues, and PROTAC drugs. Citation Format: Mari Kuraguchi, Ying Zhao, Chonghui Liu, Xiao Liu, Jiansu Zhang. The humanized CRBN mice model facilitates PROTACs studies based on CRBN ligands [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 7269.
Abstract 6919: Targeting CLIC3 as a novel strategy to inhibit metastasis in breast cancer
Authors: Paul Mellor, Stephanie Kendall, Shari Smith, Jonas Olsen, Henok Sahile, Brent Page, Anurag Saxena, Deborah Anderson
Journal: Cancer Research (2025)

Abstract Women with metastatic breast cancer have a 5-year survival rate of only 28%. This study aims to investigate the role of CLIC3 (chloride intracellular channel 3) in breast cancer metastasis and explore its potential as a therapeutic target. CLIC3, secreted by cancer cells and cancer-associated fibroblasts, promotes tumor invasion and angiogenesis through its oxidoreductase activity that inhibits TGM2 (transglutaminase-2). High CLIC3 levels correlate with poor prognosis across all breast cancer subtypes. CLIC3 was knocked down in metastatic breast cancer cells, which were evaluated for cell migration and invasion using Boyden chambers, non-adherent growth in soft agar, and tumor formation and metastasis in mice. Small molecule inhibitors of CLIC3 activity were identified using an in silico screen of &amp;gt;10 million commercially available small molecules and 94 compounds were tested as possible CLIC3 inhibitors (CLIC3i) using recombinant CLIC3. We synthesized over 70 analogs of the top inhibitor for structure-activity relationship analysis, with the most promising inhibitors also assessed for CLIC3 binding using thermal shift assays and migration in scratch assays. CLIC3 knockdown significantly reduced cell migration, invasion, and growth in soft agar, effects rescued by shRNA-insensitive CLIC3. In vivo, CLIC3 knockdown decreased tumor growth and completely blocked lung metastasis, underscoring its role in the colonization and growth of macroscopic metastases. Four promising compounds with mid-μM IC50 values for CLIC3 activity inhibition were identified (E5, D1, A5, D5). Among them, HA-22-31 emerged as a lead compound (IC50 = 1.7 μM), demonstrating direct binding to CLIC3 and significant inhibition of migration. In conclusion, CLIC3 enhances metastasis in breast cancer through its enzymatic activity. These findings suggest that further development of small molecule CLIC3 inhibitors may represent a promising new strategy for targeting metastatic breast cancer. Citation Format: Paul Mellor, Stephanie Kendall, Shari Smith, Jonas Olsen, Henok Sahile, Brent Page, Anurag Saxena, Deborah Anderson. Targeting CLIC3 as a novel strategy to inhibit metastasis in 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 6919.
Abstract 7457: Personalized treatment for hepatocellular carcinoma (HCC) patients
Authors: Jinhee Kim, Miseol Son, Da Som Kim, Yunjeong Oh, Naeun Jeon, Inhee Roh, Jayeon Kim, Vinay Tergaonkar, Do-Hyun Nam, Pierce Kah-Hoes Chow, Yong Jae Shin
Journal: Cancer Research (2025)

Abstract Predicting drug response is crucial for personalized medicine, especially in cancer research and drug resistance studies. Accurate prediction of drug response, such as the half-maximal inhibitory concentration (IC50) in cell culture models, is vital for establishing personalized treatment models. In particular, patient-derived cell culture models have garnered increasing attention due to their precise prediction of therapeutic responses in targeted drug therapies. However, the prediction of drug response in hepatocellular carcinoma (HCC) patient-derived cells (PDCs) has not been fully explored. In this study, we aimed to predict personalized drug responses to anticancer drugs in HCC. We characterized hepatic stem-like cancer cells using various human HCC cell lines (Hep3B, SkHep1, PLCPRF5, MHCC-LM3, HepG2, Huh-7). Different types of cell culture media were tested to identify HCC-specific conditions. Anticancer agents such as sorafenib and regorafenib were found to increase drug resistance in 3D cell culture models of HCC. A high-throughput screening of 300 media conditions, each with varying growth factor compositions, was conducted, and cell viability was assessed in 17 HCC patient-derived PDC models. Drug resistance profiles varied among HCC patients, with some demonstrating sensitivity to sorafenib and lapatinib, while others showed resistance to tivantinib. Next-generation sequencing (NGS) revealed unique mutations across different HCC patients. In particular, one individualized HCC patient showed the best drug response to lenvatinib and sunitinib. Furthermore, our prediction model revealed that lapatinib exhibited higher drug resistance, mirroring patterns observed in tumor cells associated with regulatory T cells, tissue-resident memory T cells (TRM), and tumor-associated macrophages (TAMs). These findings suggest that our approach offers a promising framework for predicting drug responses in HCC, supporting its application in personalized medicine. Citation Format: Jinhee Kim, Miseol Son, Da Som Kim, Yunjeong Oh, Naeun Jeon, Inhee Roh, Jayeon Kim, Vinay Tergaonkar, Do-Hyun Nam, Pierce Kah-Hoes Chow, Yong Jae Shin. Personalized treatment for hepatocellular carcinoma (HCC) 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 7457.
Abstract 6922: MDM2 inhibitor alrizomadlin induces ferroptosis through p53 dependent and independent pathways in TP53 wildtype NSCLC
Authors: Shan Shi, Qiu Yun Luo, Wen Tao Pan, Miaozhen Qiu, Da Jun Yang
Journal: Cancer Research (2025)

Abstract Alrizomadlin (APG-115) is a second-generation MDM2 inhibitor that blocks the MDM2-p53 interaction, thereby stabilizing p53 protein and restoring its transcriptional regulatory functions in cell cycle control and apoptosis. Recent study indicated that APG-115 also exerted an anticancer effect in various cancers, but the specific function and underlying mechanism in TP53-wildtype NSCLC has not been elucidated. My project aims to determine whether APG-115 exerts anti-tumor effects by mediating ferroptosis through P53 dependent and non dependent pathways. We repeatedly validated the induction effect of APG-115 on ferroptosis using multiple recognized iron death detection methods, searched for ubiquitinases in public databases, and constructed a mouse tumor model to further verify the in vitro experimental results. In this study, we found that APG-115 exerted potent antitumor efficacy in TP53-wildtype NSCLC both in vitro and in vivo. Further experiments demonstrated that APG-115 induced ferroptosis, thereby facilitating the tumor cell death. Ferroptosis -related pathways genes, such as PTGS2, were significantly enriched after APG-115 treatment. APG-115 promotes PTGS2-mediated ferroptosis through a well-characterized mechanism. Specifically, APG-115 upregulates the expression of the deubiquitinase USP22, a key regulator in protein homeostasis. USP22, once upregulated, acts on PTGS2 by removing its ubiquitin tags through the ubiquitin-proteasome system. This deubiquitination prevents PTGS2 from being targeted for proteasomal degradation, thereby stabilizing the PTGS2 protein. The sustained expression of PTGS2 enhances ferroptosis, ultimately contributing to the cytotoxic effects of APG-115 in tumor cells. Collectively, our study reveals that APG-115 induces ferroptosis in TP53-wildtype NSCLC by stabilizing the expression of PTGS2 protein, providing a new direction for further clinical investigation of APG-115 as a monotherapy or combination therapy.Keywords:Alrizomadlin; Ferroptosis; PTGS2; USP22; Ubiquitin-proteasome system Citation Format: Shan Shi, Qiu Yun Luo, Wen Tao Pan, Miaozhen Qiu, Da Jun Yang. MDM2 inhibitor alrizomadlin induces ferroptosis through p53 dependent and independent pathways in TP53 wildtype NSCLC [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 6922.
Deprivation and general practitioners’ working lives: Repeated cross-sectional study
Authors: Michael Anderson, Jonathan Gibson, Benjamin Walker, Joseph Hutchinson, Katherine Checkland, Matt Sutton
Journal: Journal of the Royal Society of Medicine (2025)

Objectives To examine how area deprivation affects the working lives of general practitioners (GPs). Design We analysed responses to four repeated cross-sectional surveys between 2015 and 2021. We used linear regression to relate the population deprivation ranking of the GP’s practice to job pressures, job satisfaction, intentions to quit direct patient care and hours worked. We used interval regression to relate reported income from GP work to this same deprivation ranking. We adjusted for GP characteristics, including employment status, gender, age and years qualified. Setting Primary medical care in England. Participants GPs. Main outcome measures Fourteen reported job pressures, 10 domains of job satisfaction, intentions to quit direct patient care, reported income from GP work and hours worked per week. Results Deprivation ranking was significantly associated with higher pressures related to perceived problem patients (difference between lowest and highest deprivation = 0.258 on five-point scale, 95% CI: 0.165, 0.350), insufficient resources within the practice (0.229, 95% CI: 0.107, 0.351), and finding a locum (0.260, 95% CI: 0.130, 0.390). Deprivation ranking was also associated with significantly lower reported annual income (−£5,525, 95% CI: −£8,773, −£2,276). There were no statistically significant associations between deprivation ranking and the other outcome measures. Conclusions Perceived problem patients, insufficient resources and finding temporary cover are key drivers of GP job pressures in practices serving more deprived populations. GPs in more deprived areas also report lower incomes. These factors should be the target of increased investment and policy interventions to improve recruitment and retention of GPs in these areas.
Abstract 3691: Integrated multiomics unlocks holistic phenotypic insights allowing for deep molecular exploration
Authors: Andrea J. O'Hara, Tom Cohen, Ethan Stancliffe, Adam Richardson, David Corney, Laure Turner, Haythem Latif, Ginger Zhou
Journal: Cancer Research (2025)

Abstract The omics era has greatly expanded the repertoire of approaches available for researchers and clinicians to unravel the complexity underpinning human health: Next Generation Sequencing (NGS) approaches can characterize genomes, epigenomes, transcriptomes, and proteomes. The analyses are critical to assess in individuals both pre- and post-treatment during therapeutic development and early-stage clinical trials. Peripheral blood mononuclear cells (PBMCs) offer a non-invasive approach that, when combined with omics tools, can provide a near holistic view of immune processes across patient cohorts. For fresh blood draws, this starts with automated sample handling and processing to ensure high viability and yield of PBMCs, along with simultaneous plasma separation and collection, which is then aliquoted for downstream analysis. These PBMC and plasma aliquots were then processed such that whole exome sequencing, whole genome methylation sequencing, single cell and bulk RNA sequencing, Olink Explore HT and Seer proteomic analysis, and metabolomic analysis can all be collected from patient blood draw. Integrated analysis across multiple data modalities allows for holistic views of pathways and processes that are highly impacted, with increased statistical significance than any one modality alone. Inclusion of dual proteomics assays provided a greater breadth of downstream functional results, revealing complementarity between assays. While genomics, transcriptomics, and proteomics provide information about genetic and functional potential, inclusion of metabolomics grants deeper phenotypic insights within and across individuals within a patient cohort. Ultimately, this approach reduces the need for repeated patient collections and lowers bio-storage requirements, making it a more patient-friendly and cost-effective solution, while rapidly producing a diverse set of multiomics results and allows for deep exploration of the molecular underpinnings of cancerous tissue. Citation Format: Andrea J. O'Hara, Tom Cohen, Ethan Stancliffe, Adam Richardson, David Corney, Laure Turner, Haythem Latif, Ginger Zhou. Integrated multiomics unlocks holistic phenotypic insights allowing for deep molecular exploration [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 3691.
Abstract 3677: Early detection of pancreatic cancer using methylated circulating cell-free DNA of <i>ZFP30</i> and <i>ZNF781</i>genes
Authors: Ruo-Kai Lin, Yao Yu Hsieh, Hsieh-Tsung Shen
Journal: Cancer Research (2025)

Abstract Background: Pancreatic cancer (PC) is often diagnosed at advanced stages, leading to limited treatment options and poor survival rates. Current biomarkers, such as CA19-9, have high false-positive rates, with only 4 out of 1, 000 abnormal cases confirmed as cancer. Aberrant DNA methylation, a stable and early epigenetic event in tumorigenesis, has emerged as a promising biomarker for early detection and disease monitoring. Objective: This study presents a novel blood test analyzing methylated cell-free DNA (mcfDNA) of ZFP30 and ZNF781genes for the early detection of pancreatic cancer. Functional assays were also performed to explore the tumor-suppressive roles of ZFP30 and ZNF781 in pancreatic cancer cell lines. Methods: ZFP30 and ZNF781 were identified through analyses of plasma samples from Taiwanese pancreatic cancer patients combined with data from The Cancer Genome Atlas (TCGA). A novel test was developed to assess methylation levels in cfDNA extracted from plasma. Clinical validation was conducted on PC patients and healthy controls, while functional studies assessed the effects of exogenous ZFP30 and ZNF781 expression on cancer cell proliferation and migration. Results: The methylation levels of ZFP30 and ZNF781 were significantly elevated in 87% of pancreatic cancer (PC) tumor tissues compared to adjacent normal tissues in PC patients. Furthermore, these methylation markers were detected in circulating cell-free DNA (cfDNA) in 99% of plasma samples from PC patients, demonstrating an area under the curve (AUC) of 0.96, with a sensitivity of 99% and a specificity of 93.9%. Methylation signals were nearly undetectable in plasma from healthy subjects, and the test accurately identified PC patients across all stages. Comparative analysis demonstrated superior performance over traditional biomarkers such as CA19-9 and CEA. Functional studies showed that exogenous expression of ZFP30 and ZNF781significantly inhibited pancreatic cancer cell proliferation and migration, supporting their roles as tumor suppressor-like genes. Conclusion: The methylated cfDNA of ZFP30 and ZNF781 offers a highly sensitive and specific biomarker for the early detection of pancreatic cancer. Integrating this blood test into clinical practice could greatly enhance diagnostic accuracy. Additionally, the tumor suppressor-like functions of ZFP30 and ZNF781 highlight their potential as therapeutic targets, providing further avenues for pancreatic cancer management and treatment. Citation Format: Ruo-Kai Lin, Yao Yu Hsieh, Hsieh-Tsung Shen. Early detection of pancreatic cancer using methylated circulating cell-free DNA of ZFP30 and ZNF781genes [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 3677.