tbuckley/cabot-search huggingface dataset:
Abstract 1521: High-fat diet-induced tumor promotion was abolished by blocking fatty acid oxidation in PDAC
Authors: Joon Hee Kang, Woojin Ham, Ho Lee, Wonyoung Choi, Jung Won Chun, Sang Myung Woo, Sung Hoon Sim, Soo-Youl Kim
Journal: Cancer Research (2025)

Abstract Purpose: Obesity is well known to promote pancreatic ductal adenocarcinoma (PDAC) tumor development. However, the direct link between obesity and cancer has not been interpreted. We found that ATP production in cancer cells depends on fatty acid oxidation (FAO). Therefore, we propose blocking FAO in cancer may stop obesity from promoting PDAC growth. Experimental Design: To block FAO, SLC25A20 (carnitine-acylcarnitine carrier) was knocked down in human PDAC cells, which was implanted for xenograft in mice and treated with a high-fat diet (HFD, 60% fat) or no-fat diet (NFD, calorie-balanced 0% fat). To compare cancer development, survival rates, and histopathological differences were analyzed with KPC mice (KrasG12D/+; Trp53R172H/+; Pdx1-Cre) and KPC/Slc25a20+/- mice treated with regular diet (RD, 18% fat). Results: The median survival of KPC mice with HFD was decreased by 2.0 weeks compared to KPC mice with RD (regular diet). Xenografts of PDAC cells with HFD promoted tumor growth 2-fold compared to the xenograft with regular diet (RD). Xenograft with SLC25A20 knockdown PDAC cells in NFD reduced a 40-95% of tumor growth, and xenograft with SLC25A20 knockdown PDAC cells in HFD also resulted in a 65-95% reduction in tumor growth compared to controls. Conclusion: Blocking FAO reversed HFD-induced tumor growth promotion in pancreatic cancer. Cancer cells take advantage of HFD for ATP production by FAO. IGF or inflammation by HFD is no longer a direct mechanism to understand how HFD promotes tumor development. Funding source: This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT to SK (NRF-2019M3A9G1104345) and by a grant from the National Cancer Center of Korea to SHS (NCC 24H1210-2). Citation Format: Joon Hee Kang, Woojin Ham, Ho Lee, Wonyoung Choi, Jung Won Chun, Sang Myung Woo, Sung Hoon Sim, Soo-Youl Kim. High-fat diet-induced tumor promotion was abolished by blocking fatty acid oxidation in PDAC [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 1521.
Abstract 3042: Non-covalent thioredoxin reductase inhibitors for TNBC
Authors: Brenna Flowers, Abigail Rullo, Pavel Petukhov, Irida Kastrati
Journal: Cancer Research (2025)

Abstract Triple negative breast cancer (TNBC) has the lowest 5-year mortality and lacks targeted therapeutics. Therefore, there is a need to explore more therapeutic targets and strategies. Previous research has indicated that TXNRD1 may be a relevant target in other cancers and is elevated in TNBC and high levels of TXNRD1 and TXNRD2 correlate to lower recurrence free survival and lower overall survival (TXNRD1) and has emerged as a possible therapeutic target.The thioredoxin system includes thioredoxin reductase (TXNRD) and thioredoxin (Trx). TXNRD takes electrons from NADPH to reduce the disulfide bond in thioredoxin. Reduced thioredoxin then goes on to reduce reactive oxygen species (ROS), other oxidized species, and proteins within the cell. This system is critical in maintaining intracellular redox homeostasis, especially in breast cancer, where tumor cells heavily rely on these detoxifying systems to balance ROS produced by the dysregulated metabolism in cancer.Previous research has shown that targeting the thioredoxin reductase system using FDA approved auranofin has anticancer activity. However, auranofin is a covalent inhibitor of thioredoxin reductases, inhibits isoforms indiscriminately, and has significant side effects.Here, we show that new non-covalent inhibitors developed to target thioredoxin glutathione reductase in Schistosoma mansoni, also inhibit human TXNRD as demonstrated through fluorescent biochemical assays and qPCR of TXNRD related genes. Additionally, these non-covalent TXNRD inhibitors (TXNRD(i)s) show anti-cancer activity in both in vitro and in vivo TNBC models. Treatment with these TXNRD(i)s reduces viability and collagen invasion in TNBC cell lines. Similarly, knocking down TXNRD1 reduces TNBC cell invasion through collagen. Indicating TXNRD1 may be the primary target. In a TNBC xenograft, these TXNRD(i)s inhibit primary tumor growth, alter gene expression levels of multiple epithelial-mesenchymal transition (EMT) associated genes within the tumor and inflammatory markers within the host animal. These data also indicate there is a potential use of these inhibitors in a metastatic model that remains to be explored.Overall, we have shown that these TXNRD(i)s inhibit human TXNRD, have anti-cancer effects in TNBC in vitro and in vivo, inhibit collagen invasion, and alter EMT and inflammatory gene expression levels. Further research on the downstream mechanisms and optimization of these TXNRD(i)s is needed. Citation Format: Brenna Flowers, Abigail Rullo, Pavel Petukhov, Irida Kastrati. Non-covalent thioredoxin reductase inhibitors for TNBC [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 3042.
Abstract 2645: Rnd3 depletion in lung cancer cell lines decreases cell invasion and migration in a ROCK1 independent manner
Authors: Noemi Garcia Garcia, Thanh Ha Vy Nguyen, Dane Richey, Cody Ashby, Analiz Rodriguez, Katie R. Ryan
Journal: Cancer Research (2025)

Abstract The purpose of this study is to investigate how altered expression levels of the small Rho GTPase, Rnd3, affects lung cancer cells. Lung cancer is among the most common and deadliest forms of cancer in the US. Most lung cancers metastasize, with lung to brain metastasis being the number one killer of lung cancer patients. Studying mechanisms that drive metastatic potential is key to unlocking new strategies for the treatment of this deadly form of cancer. Our focus for this study is Rnd3, an atypical GTPases, which has roles in regulating proliferation and cell migration in other cancer types. Our analysis of The Cancer Genome Atlas data predicts that lung adenocarcinoma patients with low levels of Rnd3 have significant higher survival rate. We investigated the role of Rnd3 by depleting its expression in the lung adenocarcinoma cell line (A549), and also patient-derived lung to brain metastasis (PDLBM) cell lines (601 and 620) as a proxy for advance disease. We observed no significant difference in cell viability or cell cycle progression between Rnd3-depeled and control groups. We did observe a significant effect on cell invasion and migration, Rnd3 depletion significantly decreases cell invasion and migration across all three tested cell lines. Previous studies on Rnd3 in melanoma cells found that Rnd3 signals via the RhoA-ROCK1 pathway, which impacts cell adhesion and the actin cytoskeleton, ultimately regulating cell invasion. However, when we either chemically inhibited ROCK1 or knocked down ROCK1 expression in our lung adenocarcinoma and PDLBM cells, it did not rescue the invasive phenotype. Our findings indicate that Rnd3 regulates cell invasion and migration, two hallmarks of metastasis, in lung cancer via a distinct pathway, independently from ROCK1. Identifying this novel mechanism will provide crucial insights for developing treatment for lung cancer metastasis. Citation Format: Noemi Garcia Garcia, Thanh Ha Vy Nguyen, Dane Richey, Cody Ashby, Analiz Rodriguez, Katie R. Ryan. Rnd3 depletion in lung cancer cell lines decreases cell invasion and migration in a ROCK1 independent manner [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 2645.
Abstract 2482: Inferring cancer type-specific patterns of metastatic spread using Metient
Authors: Divya Koyyalagunta, Karuna Ganesh, Quaid Morris
Journal: Cancer Research (2025)

Abstract Reconstructing the metastatic spread of a cancer from molecular sequencing of primary and metastatic tumors is a challenging problem with broad applications in clinical cancer research. In particular, this problem often yields multiple solutions, which current methods resolve with ad hoc criteria that assume the most likely patterns of metastatic spread - thus sidestepping a core question of metastasis research. Here we introduce Metient, a statistical method which proposes multiple possible hypotheses of metastatic spread in a cohort of patients and rescores these hypotheses using independent data on genetic distance of metastasizing clones and organotropism. Metient is more accurate and is up to 50x faster than the current state-of-the-art, making it the first method capable of scaling to lineage tracing datasets with thousands of cells while providing a multi-hypothesis approach to metastatic spread. In a reanalysis of metastasis in 169 patients based on 490 tumors, Metient automatically identifies cancer type-specific trends of metastatic dissemination in melanoma, high-risk neuroblastoma, and non-small cell lung cancer. Its reconstructions often align with semi-manual expert analyses but frequently reveal more plausible migration histories, including those with metastasis-to-metastasis seeding. Furthermore, Metient’s heightened sensitivity suggests that polyclonal seeding is far more common than previously reported. Together, these findings challenge existing assumptions about metastatic spread, enhance our understanding of cancer type-specific metastasis, and offer insights that could inform future clinical treatment strategies of metastasis. Citation Format: Divya Koyyalagunta, Karuna Ganesh, Quaid Morris. Inferring cancer type-specific patterns of metastatic spread using Metient [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 2482.
Abstract 3068: The clonal nature of FGFR3-TACC3 in glioma: Mechanism discovery and preclinical study
Authors: Yiming Li, Tao Li, Xiude Ren, Jianshen Liang, Jikang Fan, Xisen Wang, Shengping Yu, Wei Zhang, Xuejun Yang
Journal: Cancer Research (2025)

Abstract During the course of treatment, tumor cells can undergo a Darwinian process of clonal evolution, where resistant cell clones emerge, proliferate and replace more vulnerable ones, ultimately leading to increased treatment resistance. Numerous oncogenic fusion genes have recently been identified in gliomas, promoting malignant transformation and serving as potential therapeutic targets. Among these, the FGFR3-TACC3 (F3-T3) fusion gene was initially detected in glioblastoma multiforme (GBM), with its fusion protein comprising primarily FGFR3 structural domains and a smaller portion of TACC3. F3-T3 fusions are consistently expressed in both untreated and recurrent tumors, confirming the clonal persistence of these fusion events. Our previous study implicated F3-T3 in chemotherapy resistance in GBM, though the underlying mechanism remained unclear. In this study, we further investigate the clonal nature and functional role of F3-T3 in GBM cells. Through bioinformatics data mining, we discovered that F3-T3 functionally enriches DNA repair pathways, as shown by Gene Set Enrichment Analysis (GSEA). Experimental results demonstrated that GBM cells harboring F3-T3 maintain their proliferation, invasion and migration capabilities under temozolomide (TMZ) treatment. Subsequent RNA sequencing revealed activation of the PI3K-AKT signaling pathway in F3-T3 GBM cells under TMZ conditions. Further analysis identified PKM2 as a downstream substrate of the F3-T3 protein, linking it to the DNA damage response. Experimental evidence highlights the critical role of the F3-T3/PI3K-AKT/PKM2 axis in mediating chemoresistance in F3-T3 GBM. Importantly, our preclinical models demonstrated synergistic efficacy when combining TMZ with either FGFR or PI3K inhibitors in F3-T3 GBM. In summary, our findings underscore the significance of the F3-T3/PI3K-AKT/PKM2 axis in driving chemotherapy resistance in F3-T3 GBM and present a potential therapeutic strategy for gliomas with F3-T3 fusions, providing empirical support for future fusion gene-targeted investigations. Citation Format: Yiming Li, Tao Li, Xiude Ren, Jianshen Liang, Jikang Fan, Xisen Wang, Shengping Yu, Wei Zhang, Xuejun Yang. The clonal nature of FGFR3-TACC3 in glioma: Mechanism discovery and preclinical study [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 3068.
Abstract 1476: Enhancing radiation sensitivity in CHD5 dysregulated NSCLC by targeting NHEJ repair pathway
Authors: Seohyun Kim, Sandip K. Rath, Gina Cutlip, David S. Yu
Journal: Cancer Research (2025)

Abstract Lung cancer, particularly non-small cell lung cancer (NSCLC), is a leading cause of cancer deaths, with 5-year survival rates decreasing from 65% for localized cases to 9% for distant metastases. Radiation therapy's effectiveness is often limited due to the upregulation of DNA repair pathways like non-homologous end joining (NHEJ), which helps cancer cells survive DNA damage from radiation. Chromatin remodeling plays a crucial role in regulating DNA repair pathways, including NHEJ. We have identified CHD5, a tumor suppressor involved in chromatin remodeling, as a regulator of DNA double-strand break repair pathway choice. DNA reporter assays show that CHD5 promotes homologous recombination (HR), and its depletion enhances NHEJ activity. Analysis of The Cancer Genome Atlas (TCGA) reveals that CHD5 is downregulated in lung adenocarcinoma (LUAD) patients. This suggests that NSCLC cells may rely more on NHEJ due to reduced CHD5 function. Therefore, targeting CHD5-dysregulated NSCLC cells with NHEJ inhibitors could increase their sensitivity to radiation therapy. Our data indicate that overexpressing CHD5 in H460 NSCLC cells reduces levels of phosphorylated and total DNA-dependent protein kinase catalytic subunits (DNA-PKcs), essential components of the NHEJ pathway. This suggests that CHD5 negatively regulates NHEJ. Cell viability assays confirm that CHD5 depletion via siRNA in H460 NSCLC cells sensitizes them to ionizing radiation (IR) when combined with the DNA-PK inhibitor Nu7441, leading to increased cell death. In summary, CHD5 regulates NHEJ in NSCLC, and its depletion makes cancer cells more dependent on NHEJ for DNA repair. Targeting NHEJ in CHD5-deficient NSCLC cells offers a promising therapeutic strategy for enhancing the efficacy of radiation therapy in NSCLC. Citation Format: Seohyun Kim, Sandip K. Rath, Gina Cutlip, David S. Yu. Enhancing radiation sensitivity in CHD5 dysregulated NSCLC by targeting NHEJ repair pathway [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 1476.
Abstract 509: Synergistic inhibition of TNBC via enhancer of zeste homologue 2 (EZH2) inhibition and D1 receptor agonism
Authors: Rajni Kant Shukla, Kate Ormiston, Gautam Sarathy, Shivani Dhekne, Sanjay Gupta, Daniel Stover, Christian Rolfo, Eswar Shankar
Journal: Cancer Research (2025)

Abstract EZH2, a histone methyltransferase linked to poor outcomes in cancer, is overexpressed in triple-negative breast cancer (TNBC), disproportionately affecting African-American and Hispanic women. EZH2 regulates the tumor immune microenvironment (TIME) by inhibiting MHC-I antigen presentation, upregulating PD-L1, leading to reduced antitumor immune responses. Current EZH2 inhibitors target its catalytic activity; however, the development of resistance mechanisms in cancer cells frequently undermines their effectiveness. The neurotransmitter dopamine, through activation of its D1 receptor, promotes apoptosis and autophagy while suppressing cancer cell invasion. Dopamine D1 receptor signaling mitigates the immunosuppressive effects of myeloid-derived suppressor cells (MDSCs) on T cell proliferation and IFN-γ production. Using in silico approaches such as cryptic pocket identification, docking, and molecular dynamics (MD) simulations, initially we assessed the binding affinity of the DRD1 agonist to EZH2. Our in-silico analyses uncovered stable binding profiles, indicating novel interactions at previously uncharacterized sites within the CXC domain and the EED-binding region for both GSK126 and A77636. Next, we performed in vivo experiments combining GSK126 and A77636 to evaluate their effect on tumor growth and the TIME using an NSG mouse model. MDA-MB-231 cells were injected into the breast fat pads of 4-6-week-old female NSG mice. Once tumors were palpated, the mice were randomized into four groups: vehicle treatment, GSK126 (2 mg/kg), A77636 (50 mg/kg), and the combination of both, with treatments administered intraperitoneally for four weeks. Tumor growth was monitored throughout the treatment period, and at the termination, blood, tumor, and spleen were collected and processed into single-cell suspensions for high-dimensional flow cytometry analysis. GSK126 and A77636 treatment in combination significantly reduced tumor volume and decreased EZH2 expression in monocytes and neutrophils within the blood and tumor microenvironment and lowering the levels of pro-inflammatory cytokine IL-1β. In summary, this approach unveils new possibilities for treating TNBC by concurrently targeting EZH2 and DRD1 through a combinatorial strategy. (This work is supported by DOD: W81XWH2010065, for Eswar Shankar). Citation Format: Rajni Kant Shukla, Kate Ormiston, Gautam Sarathy, Shivani Dhekne, Sanjay Gupta, Daniel Stover, Christian Rolfo, Eswar Shankar. Synergistic inhibition of TNBC via enhancer of zeste homologue 2 (EZH2) inhibition and D1 receptor agonism [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 509.
Abstract 1124: Mining the Kras-p53 mutational interface for synthetic lethality (SL) in pancreatic adenocarcinoma (PA)
Authors: Nishanth Thalambedu, Nadia Safar, Ahmad Mazin M. Safar
Journal: Cancer Research (2025)

Abstract Kras activating mutations are frequent in cancer but are insufficient alone for full malignant transformation. Mutations in the tumor suppressor (TSG) p53 cooperate with mutant Kras and permit full display of oncogenic Ras, both in clinical cases and in experimental models of Kras tumorigenesis. Interestingly, p53 mutations almost never fully abrogate its function, suggesting to us a possible essential role for the (either directly or indirectly) retained transcriptional targets within the p53 network. The phenomenon of oncogene addiction may be the result of this rigid but sufficient TSG output providing adaptations to constant oncogene signaling. It is also plausible that each mutation might provide different adaptations and therefore be differentially selected for in various cases. Drugging the dependency on this adaptation machinery provides an opportunity for SL sparing normal cells. This approach is especially valuable given the limited therapeutic impact of available Kras inhibitors (in scope or in potency). We have shown that specific mutations in p53 with their unique transcriptional lesions cooperate with various Kras mutants in tissue-specific manner. In this work we provide a broader and comparative assessment in PA. We hypothesize that frequency of the top 8 p53 mutational hotspots in PA is non-random with recurring comparable frequencies across independent public datasets (project GENIE, MSK and TCGA). Our work included 4 Kras PA mutants. Results: Table reports on the frequency of respective mutational pairs. Conclusion: The available cases in TCGA were limited in number. In the 2 more comprehensive datasets, the frequency of certain pairs between Kras and p53 is remarkably close suggesting a mechanistic justification. For SL considerations, therefore, one needs to examine the transcriptional spectra within defined pairs of Kras-p53 to nominate the appropriate genes for multiplexed gene editing experiments and inform drug discovery. Citation Format: Nishanth Thalambedu, Nadia Safar, Ahmad Mazin M. Safar. Mining the Kras-p53 mutational interface for synthetic lethality (SL) in pancreatic adenocarcinoma (PA) [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 1124.
Abstract 3641: Predicting treatment outcomes using cross-modality correlations in multimodal oncology data
Authors: Aakash Gireesh Tripathi, Asim Waqas, Yasin Yilmaz, Matthew B. Schabath, Ghulam Rasool
Journal: Cancer Research (2025)

Abstract Accurate prediction of treatment outcomes in oncology requires modeling the intricate relationships across diverse data modalities. This study investigates cross-modality correlations by leveraging imaging and clinical data curated through the Multimodal Integration of Oncology Data System (MINDS) and HoneyBee frameworks to uncover actionable patterns for personalized treatment strategies. Using data from over 10, 000 cancer patients, we developed a machine learning pipeline that employs advanced embedding techniques to capture associations between radiological imaging phenotypes and histopathological features, aiming to predict survival outcomes and treatment efficacy. The HoneyBee framework played a key role in preprocessing and feature extraction, using foundation models for imaging and text data. Radiological imaging, such as computed tomography (CT) and magnetic resonance imaging (MRI), was transformed into high-dimensional embeddings with vision transformers and convolutional neural networks. Clinical data, including electronic health records and pathology reports, was structured into embeddings using biomedical language models. These embeddings ensured standardization and cross-modal alignment while capturing modality-specific features. HoneyBee also applied data augmentation and preprocessing, such as stain normalization and tokenization, to maintain data quality. MINDS provided a scalable, metadata-driven architecture for integrating datasets like patient demographics and treatment histories, supporting seamless ingestion, harmonization, and storage. Together, these frameworks created a unified, multimodal dataset optimized for predictive modeling and resilient to missing data. In training, embeddings were combined through late-stage fusion techniques to generate unified patient-level representations in latent space. These representations were used to train machine learning models, including gradient-boosted trees and neural networks, for survival analysis and treatment response prediction. Testing was conducted using stratified cross-validation to ensure generalizability across cancer subtypes and demographic groups. Results demonstrated significant predictive correlations, such as imaging-derived phenotypes linked to histopathological indicators of treatment response. The machine learning pipeline achieved a 12% improvement in concordance indices over unimodal approaches, underscoring the enhanced accuracy of cross-modality learning. Citation Format: Aakash Gireesh Tripathi, Asim Waqas, Yasin Yilmaz, Matthew B. Schabath, Ghulam Rasool. Predicting treatment outcomes using cross-modality correlations in multimodal oncology data [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 3641.