tbuckley/cabot-search huggingface dataset:
Abstract 5430: Hematopoietic stem cells conditioned media alters the colorectal cancer cells metabolism by disrupting the mitochondrial bioenergetics in vitro
Authors: Sumit Mallick, Sudheer P. Shenoy, Bipasha Bose
Journal: Cancer Research (2025)

Abstract Colorectal cancer (CRC) is a major public health issue, and mitochondrial dysfunction plays a pivotal role in its development. Mitochondria, the "powerhouses of the cell, " are particularly important in cancer cells due to their high energy demands. The dynamic nature of mitochondria, including their ability to fuse and divide, is crucial for their role in signal transduction and metabolism. Enhanced mitochondrial fission, a process that divides mitochondria into smaller fragments, promotes the metabolic reprogramming of CRC cells. These reprogramming fuels cell proliferation, metastasis, and resistance to chemotherapy. However, excessive fission can also trigger apoptosis, leading to cell death. Our work shows that hematopoietic stem cells (HSCs) derived conditioned media (CM) altered metabolic activities by altering the mitochondrial oxidative phosphorylation through an excessive mitochondrial fission by upregulating the Drp-1 and downregulating the fusion protein Opa-1 and Mito-fusion proteins. Moreover, HSCs-CM dysregulated the electron transport chain complexes with high dysregulation of complex-III. Our integrated omics and mitochondria-targeted studies provided the dysregulation of the critical proteins involved in mitochondrial bioenergetics in CM treated CRCs. Our findings reveal the therapeutic nature of HSCs-conditioned media for colorectal cancer therapy. Citation Format: Sumit Mallick, Sudheer P. Shenoy, Bipasha Bose. Hematopoietic stem cells conditioned media alters the colorectal cancer cells metabolism by disrupting the mitochondrial bioenergetics in vitro [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 5430.
Abstract 3869: Targeting anoikis resistance in ovarian cancer via metabolic enzyme inhibition
Authors: Geeta Rao, Pallab Shaw, Shailendra Dwivedi, Priyabrata Mukherjee
Journal: Cancer Research (2025)

Ovarian cancer (OvCa) is the deadliest gynecologic malignancy, with poor prognosis largely due to late-stage diagnosis and metastasis, which limit treatment options and contribute to high mortality. Anoikis resistance, a key mechanism enabling metastatic spheroids to survive in the peritoneal cavity, drives both metastasis and therapy resistance. Therefore, understanding the regulation of anoikis is critical for identifying novel therapeutic targets. Recent studies, including work from our group, have identified overexpression of cystathionine beta-synthase (CBS)—an enzyme that produces hydrogen sulfide (H2S)—as a contributor to OvCa progression. CBS has been shown to promote cancer progression through enhanced lipogenesis and mitochondrial fusion. Based on these findings, we hypothesize that CBS plays a central role in anoikis resistance in OvCa and propose that targeting CBS could inhibit metastasis and improve sensitivity to chemotherapy. To investigate the functional role of CBS in anoikis resistance, we utilized OvCa cell lines (COV318, OVCAR8, OVCAR4, and A2780_CP20) and achieved CBS silencing via siRNA-mediated knockdown. Cells were cultured in both monolayers (2D) and spheroids (3D) to better mimic in vivo tumor conditions. Our findings reveal that: (i) High CBS expression is associated with poor median survival in stage 3 and stage 4 high-grade serous ovarian cancer (HGSOC) patients, (ii)CBS expression directly correlates with elevated expression of stemness and epithelial-to-mesenchymal transition (EMT) markers, (iii) CBS silencing induces anoikis in both COV318 (ascites-derived) and A2780_CP20 (drug-resistant) OvCa cell lines, (iv) CBS silencing disrupts integrin-mediated downstream signaling through focal adhesion kinase (FAK) in both 2D and 3D cultures. These findings establish CBS as a critical regulator of anoikis resistance in ovarian cancer, underscoring its potential as a therapeutic target to suppress metastasis and enhance the efficacy of existing chemotherapy regimens. Citation Format: Geeta Rao, Pallab Shaw, Shailendra Dwivedi, Priyabrata Mukherjee. Targeting anoikis resistance in ovarian cancer via metabolic enzyme inhibition [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 3869.
Abstract 7009: Discovery of UBX-306 as a potent, selective, and orally bioavailable HPK1 degrader
Authors: Ae-Ran Choi, Na-rae Jeong, Sun-Mi Yoo, Han Wool Kim, So Hyuk Kim, Hyun-Hwi Kim, Sun-Kyoung Im, Miyoung Jang, Hohyun Lee, Jungmin Ahn, Je Ho Ryu, Song Hee Lee
Journal: Cancer Research (2025)

Abstract Background: Hematopoietic progenitor kinase 1 (HPK1), part of the MAP4K family, is a serine/threonine kinase critical for modulating immune cell signaling and function. HPK1 is predominantly expressed in hematopoietic cells, where it acts as a negative regulator of T-cell receptor (TCR) signaling and other immune pathways. Upon activation, HPK1 dampens immune responses by phosphorylating key adapter proteins, such as SLP-76, and promoting their degradation, ultimately inhibiting T-cell activation, proliferation, and cytokine production. Given the critical role of T-cells in anti-tumor immunity, HPK1 has emerged as an attractive target in immuno-oncology for enhancing immune responses. Results: UBX-306;NT2020 demonstrated robust HPK1 protein degradation, achieving single-digit nanomolar DC50 levels in the Jurkat cell line in a dose-dependent manner. The degradation effect of UBX-306-1 is strongly dependent on the ubiquitin-proteasome system (UPS). Both UBX-306-1 and UBX-306-3 significantly enhanced IL-2 secretion in Jurkat cells, demonstrating superior EC50 values compared to the warhead of UBX-306, AZ1, or reference HPK1 degrader. Treatment with UBX-306-1 increased IL-2 production in a concentration-dependent manner, even in the presence of immunosuppressive molecules such as PGE2 and NECA. UBX-306-2 effectively degrades HPK1 protein in Ramos, Raw264.7, THP-1, and KG-1 cell lines. In vivo pharmacodynamic (PD) data demonstrated that UBX-306-1 efficiently degraded the HPK1 protein in the mouse blood. UBX-306-1 induced peak degradation of HPK1 at 6 hours after oral administration, with the degradation activity sustained for up to 24 hours. The antitumor efficacy of UBX-306-1 was evaluated in the CT-26 (Colorectal cancer) syngeneic tumor mouse model. Daily oral administration of UBX-306-1 at doses of 10 mg/kg and 30 mg/kg resulted in robust tumor growth inhibition. Conclusion: We demonstrate that potent HPK1 degraders, effectively activate immune cells and inhibit tumor growth in mouse syngeneic tumor models as single agents. These degraders enhance IL-2 and IFNγ production while overcoming immunosuppressive factors. Further, in vivo studies will deepen our understanding of HPK1 degradation as a promising immunomodulatory strategy for enhancing anti-tumor immunity. Citation Format: Ae-Ran Choi, Na-rae Jeong, Sun-Mi Yoo, Han Wool Kim, So Hyuk Kim, Hyun-Hwi Kim, Sun-Kyoung Im, Miyoung Jang, Hohyun Lee, Jungmin Ahn, Je Ho Ryu, Song Hee Lee. Discovery of UBX-306 as a potent, selective, and orally bioavailable HPK1 degrader [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 7009.
Abstract 6621: Multi-modal profiling reveals the role of somatic structural variations in renal cell carcinoma
Authors: Yuwei Zhang, Kapur Dhami, Yize Li, Cody Weimholt, Wagma Caravan, John Herndon, Reyka Jayasinghe, Song Cao, Melissa Reimers, Russell Pachynski, Feng Chen, Li Ding
Journal: Cancer Research (2025)

Abstract Renal cell carcinoma (RCC) is a heterogeneous malignancy with complex genetic underpinnings. While short-read sequencing has provided valuable insights into RCC genomics, the detection of large and complex structural variants (SVs) remains limited. In this study, we analyzed 17 pairs of RCC samples and identified 555 somatic SVs in RCC tumor samples using both long-read and short-read sequencing. All somatic SVs except repeat expansions are singleton variants, indicating high inter-tumor heterogeneity. Repeat expansions are recurrent, with the GAAGGG expansion in intron 7 of ARHGAP19 occurring with the highest prevalence of 64.29%. Next, to explore the potential impact of SVs on gene expression and chromatin accessibility, we generated snMultiome and bulk transcriptome data. We found that &amp;gt;25% SV-related genes exhibited significant changes in either gene expression or chromatin accessibility. The expression comparisons among mutant samples, non-mutant RCCs, and normal-adjacent kidneys identified putative protumor SVs (e.g. MET exon 14-15 duplication induced expression elevation in pRCC) and protective SVs (e.g. VCAN deletion induced expression loss in ccRCC). By integrating spatial transcriptome data, we investigated the spatial expression variations of SV-related genes and linked them to the clonal status of SVs. The most representative example is the differential MET expression observed in tumor cells within vascular cores and those lining the papillae membranes, suggesting the subclonal nature of MET duplication in pRCC. Finally, we constructed an RCC-specific pangenome to enhance SV calling and genotyping. Taken together, our results provide a comprehensive landscape of somatic SVs in RCC, shedding light on their effects on epigenomic and transcriptomic alterations. This study enhances our understanding of the role of SVs in RCC development and offers new insights into their potential clinical significance. Citation Format: Yuwei Zhang, Kapur Dhami, Yize Li, Cody Weimholt, Wagma Caravan, John Herndon, Reyka Jayasinghe, Song Cao, Melissa Reimers, Russell Pachynski, Feng Chen, Li Ding. Multi-modal profiling reveals the role of somatic structural variations in renal cell carcinoma [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 6621.
Abstract 7393: Occupational benzene exposure and solid cancers: A systematic review and meta-analysis
Authors: Paolo Boffetta, Monireh Sadat Seyyedsalehi
Journal: Cancer Research (2025)

Abstract Benzene, an aromatic hydrocarbon, is an established cause of leukemia. The association between benzene exposure and solid cancers is currently being investigated. We conducted a systematic review and meta-analysis to assess the association between occupational benzene exposure and the incidence and mortality of breast, female genital, kidney, bladder, prostate, testis, esophageal, gastric, colorectal, liver, gallbladder, pancreas, lung, head and neck, brain, and skin cancers. We included cohort and case-control studies referenced in the 2018 IARC Monograph on benzene and also reviewed studies published up to April 2024 in PubMed, SCOPUS, and EMBASE. We evaluated the quality of the studies using a modified version of the Newcastle-Ottawa Scale. We used forest plots of relative risk (RR) to present and analyze the data and employed a random-effects model to address heterogeneity between studies. Stratified analyses were performed to explore potential effect modification. Our meta-analysis included 80 independent studies, and the findings are summarized in Table 1. The results of our study indicated an association between overall occupational benzene exposure and breast, kidney, colorectal, head and neck, and brain cancer and a dose-effect association between benzene exposure and lung, hepatobiliary, bladder cancer. In addition, non-significant RR&amp;gt;1.25 were derived for ovarian and gallbladder cancer. Additional well-designed studies, incorporating detailed exposure assessment and control for potential confounders, are required to clarify these relationships. It is essential to implement occupational safety measures, such as proper ventilation, personal protective equipment, and workplace monitoring, to minimize exposure and safeguard workers in industries where benzene is present. Citation Format: Paolo Boffetta, Monireh Sadat Seyyedsalehi. Occupational benzene exposure and solid cancers: A systematic review and meta-analysis [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 7393.
Abstract 5583: Small molecule mediated restoration of PAX3 inhibits malignant features in neuroblastoma cells
Authors: Abinayaselvi Murugan, Sowndharyalatha Balasubramanian, Narenkumar Muralidharan, Ann Mary Alappat Sanjive, Prabhuraj Andiperumal Raj, Mathivanan Jothi
Journal: Cancer Research (2025)

Abstract Neuroblastoma is the most common extracranial childhood tumor diagnosed in the first year of life. A complete molecular understanding of neuroblastoma is necessary to identify novel therapeutic targets for their management, particularly for high-risk groups. Many transcription factors play an essential role during development, and their expression is restricted to specific cells/tissues after development is completed. PAX3 belongs to the paired box family of transcription factors involved in various cellular processes like cellular proliferation, migration, lineage specificity, and differentiation. Reexpression of PAX3 is reported in various childhood tumors, including neuroblastoma; however, its role in tumor development is contradicting. Here, we investigated the contribution of PAX3 in neuroblastoma in a panel of neuroblastoma cell lines and identified a PAX3-targeted small molecule activator that can alter tumorigenic phenotypes. Specifically, we have analyzed the PAX3 mRNA, protein, subcellular localization, and its isoform expression in various neuroblastoma cell lines and correlated the results with their tumorigenic potential. Our results showed that most of the PAX3 expressed in these cells are PAX3a/b isoforms that lack PAX3’s transactivation domain. Further, we have observed the depletion of PAX3a/b isoforms could not alter the malignant properties of neuroblastoma cells. Interestingly, the ectopic PAX3 expression in the absence of PAX3a/b isoform in these cells inhibited malignant phenotypes including growth, colony formation and migration potentials. Furthermore, we have identified potential small molecule PAX3 activators from our previous small molecule screening. PAX3 activators effectively inhibited in vitro malignant properties of neuroblastoma cell lines. Our results revealed that tumor inhibitory properties of transcriptionally active PAX3 and its reactivation using small molecules have great potential in inhibiting neuroblastoma development. Citation Format: Abinayaselvi Murugan, Sowndharyalatha Balasubramanian, Narenkumar Muralidharan, Ann Mary Alappat Sanjive, Prabhuraj Andiperumal Raj, Mathivanan Jothi. Small molecule mediated restoration of PAX3 inhibits malignant features in neuroblastoma cells [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 5583.
Abstract 4283: PLK4 inhibition: A therapeutic strategy to treat patients with TRIM37 amplified tumors
Authors: Kristen Wong, Debashish U. Menon, Weichao Zhang, Boris Wilson, Jared Spletstoser
Journal: Cancer Research (2025)

Abstract TRIM37 is a breast cancer oncogene and crucial regulator of pericentriolar matrix (PCM) components. Tumors with amplified TRIM37, an E3-ubiquitin ligase, undergo mitotic catastrophe when Polo-like kinase 4 (PLK4) is inhibited. PLK4 is essential for centriole duplication, a key process in cell division. While several PLK4 kinase inhibitors have been identified, their selectivity and in vivo pharmacokinetic properties are suboptimal. In this study, cellular proliferation and pharmacodynamic assays were developed to optimize the activity and selectivity of PLK4 inhibitors. PLK4 inhibition more effectively inhibited cell proliferation in TRIM37-amplified breast and neuroblastoma cell lines. Conversely, TRIM37 knockout breast cancer cells showed reduced sensitivity to PLK4 inhibition. Mechanistically, PLK4 stability is controlled by its auto-phosphorylation, which triggers rapid degradation via the proteasomal pathway. Tool compounds confirmed that inhibition of PLK4 leads to its stabilization, establishing PLK4 stabilization as a pharmacodynamic biomarker for PLK4 inhibition. These assays will enable evaluation of PLK4 inhibitor activity and selectivity in TRIM37 amplified cells. Citation Format: Kristen Wong, Debashish U. Menon, Weichao Zhang, Boris Wilson, Jared Spletstoser. PLK4 inhibition: A therapeutic strategy to treat patients with TRIM37 amplified tumors [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 4283.
Abstract 4321: Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma
Authors: Charles S. Umbaugh, Marie Groth, Cihan Erkut, Kwang-Seok Lee, Joana Marinho, Florian Iser, Jonas N. Kapp, Petra Schroeter, Simay Dolaner, Asli Kayserili, Julia Hartmann, Philipp Walch, Thomas F. Barth, Kevin Mellert, Birgit Dreier, Jonas V. Schäfer, Andreas Plückthun, Stefan Fröhling, Claudia Scholl
Journal: Cancer Research (2025)

Abstract Aberrant expression of the embryonal transcription factor TBXT (also known as brachyury) drives chordoma, a rare spinal neoplasm with no effective drug therapies. The gene network regulated by TBXT is poorly understood, and strategies to disrupt its abnormal activity for therapeutic purposes are lacking. We developed TBXT-targeted designed ankyrin repeat proteins (T-DARPins) that selectively bind TBXT and inhibit its binding to DNA. In chordoma cells, T-DARPins reduced cell cycle progression, spheroid formation, and tumor growth in mice. Combining T-DARPin-mediated TBXT inhibition with transcriptomic and proteomic analyses, we determined the TBXT regulome in UM-Chor1 chordoma cells, which comprises in particular networks involved in cell cycle regulation, DNA replication and repair, embryonal cell identity, metabolic processes, and interferon response. The analysis of selected TBXT regulome components provided new insights into chordoma biology, such as the strong upregulation of IGFBP3 upon TBXT inhibition to fine-tune part of TBXT’s downstream effectors. Finally, we assigned each TBXT regulome member a druggability status to create a resource for future translational studies and found high interferon response signaling in chordoma cell lines and patient tumors, which was promoted by TBXT and associated with strong sensitivity to clinically approved JAK2 inhibitors. These findings demonstrate the potential of DARPins to interrogate the function of nuclear proteins to understand the regulatory networks of cancers driven by aberrant transcription factor activity, including novel entry points for targeted therapies that warrant testing in patients. Citation Format: Charles S. Umbaugh, Marie Groth, Cihan Erkut, Kwang-Seok Lee, Joana Marinho, Florian Iser, Jonas N. Kapp, Petra Schroeter, Simay Dolaner, Asli Kayserili, Julia Hartmann, Philipp Walch, Thomas F. Barth, Kevin Mellert, Birgit Dreier, Jonas V. Schäfer, Andreas Plückthun, Stefan Fröhling, Claudia Scholl. Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma [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 4321.
Abstract 7404: Screening patterns among high-risk individuals for pancreatic cancer at a tertiary academic center
Authors: Alice Ahyoung Lee, Naoko Fushimi, Audrey Sutton, Andrea Leung, Sharon Pneh, Walter Park
Journal: Cancer Research (2025)

Abstract Background: Multiple guidelines have developed in the last decade on recommendations for pancreatic cancer screening among high-risk individuals (HRIs). The International Cancer of the Pancreas Screening (CAPS) Consortium, American Gastroenterology Association (AGA), and American Society for Gastrointestinal Endoscopy (ASGE) are three widely known societies that have each published screening guidelines. At our tertiary care hospital, we perform annual pancreatic cancer screening for individuals meeting high-risk screening criteria by any of the 3 above guidelines. We aimed to describe real-world screening patterns within our cohort. Methods: Patients followed by Stanford’s Benign Pancreas Clinic were identified as HRIs if they met screening criteria per the 2019 CAPS, 2020 AGA, and/or 2022 ASGE guidelines and either underwent at least 1 screening modality or were counseled on pancreatic cancer screening. Screening was deemed completed for a calendar year if the HRI underwent either an abdominal MRI with contrast or an EUS of the pancreas. Patterns of annual pancreatic cancer screening were reviewed retrospectively. Results: A total of 341 HRIs were identified from March 2009 to July 2024. 97 (28.4%) met high-risk criteria due to family history only, while 244 (71.6%) met high-risk criteria due to a high-risk hereditary mutation. The mean follow-up time from first screening encounter was 4.6 years. 51.4% of patients completed at least 50% of their recommended annual screenings. There were no significant differences in gender, race/ethnicity, age at first encounter, or risk factor among those in the lowest quartile of successfully screened patients compared to the entire cohort. Conclusions: It is difficult to achieve high compliance rates for annual pancreatic cancer screening of high-risk individuals as recommended by the CAPS, AGA, and ASGE. Analysis of our lowest performing quartile suggest no disparity by gender, race/ethnicity, age at first encounter, or risk factor. Citation Format: Alice Ahyoung Lee, Naoko Fushimi, Audrey Sutton, Andrea Leung, Sharon Pneh, Walter Park. Screening patterns among high-risk individuals for pancreatic cancer at a tertiary academic center [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 7404.