tbuckley/cabot-search huggingface dataset:
Abstract 3152: Identification and characterization of inhibitors SHOC2-MRAS-PP1C complex assembly
Authors: Alexei Brooun, Patrick Fagan, Simon Bergqvist, Oleksii Hrabovsky, Fang Fang, Yecenia Peraza, Yin Wu, Dongming Quan, Meiying Cui, Liang Huang, Yujie Chen, Huihui Zhu, Ping Chen, Adriana Irimia, Peter Chua, Mykola Protopopov, Yurii Moroz, Olga Tarkhanova, Jean-Michel Vernier, Robert Shoemaker
Journal: Cancer Research (2025)

Abstract Inhibition of SHOC2 function by either genetic ablation or protein degradation potently sensitizes RAS-driven cells to MEK inhibition and impairs RTK-mediated adaptive reactivation of MAPK signaling induced by a MEK inhibitor (MEKi). The SHOC2-MRAS-PP1C (SMP) complex is responsible for full activation of RAF via dephosphorylation of the phosphoserine in conserved region 2 (CR2-pS). Based on the SMP complex’s critical role in RAF activation and SHOC2 synthetic lethal interaction with MEKi, the SMP complex represents an attractive target for the development of novel therapeutic agents that could prevent adaptive resistance to MEKi. We have conducted a systematic DNA encoding library (DEL) screening campaign against the purified intact SMP complex and all three individual components using the HitGen OpenDEL kit. A series of SHOC2 selective hits were identified and profiled using direct binding and biochemical assays. The lead compounds bind to full-length SHOC2 protein with KDs in the low nM range, inhibit SMP complex formation, and block dephosphorylation of BRAF CR2-pS peptide. Hydrogen/deuterium exchange mass spectroscopy (HDX-MS) analysis of SHOC2 in complex with a lead compound identified a putative binding site, consistent with biochemical studies and supporting the MRAS competitive nature of the lead compounds. To our knowledge, these compounds represent first-in-class examples of direct modulators of the SMP complex, via SHOC2 engagement, that have the potential for optimization as either PPI modulators or selective degraders. Citation Format: Alexei Brooun, Patrick Fagan, Simon Bergqvist, Oleksii Hrabovsky, Fang Fang, Yecenia Peraza, Yin Wu, Dongming Quan, Meiying Cui, Liang Huang, Yujie Chen, Huihui Zhu, Ping Chen, Adriana Irimia, Peter Chua, Mykola Protopopov, Yurii Moroz, Olga Tarkhanova, Jean-Michel Vernier, Robert Shoemaker. Identification and characterization of inhibitors SHOC2-MRAS-PP1C complex assembly [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 3152.
Abstract 6612: Deep and scalable spatial transcriptomics for oncology research
Authors: Joseph W. Foley, Wei K. Teo, Joshua K. Tay
Journal: Cancer Research (2025)

The emerging field of spatial transcriptomics is revolutionizing histopathology by simultaneously quantifying numerous RNA transcripts in situ across a tissue section. However, current technologies provide a broad survey of the spatial environment at the expense of low-complexity genomic data. We present the Picoception RNA platform, which produces deep genomic data from spatially targeted regions of a tissue section. This platform combines laser-capture microdissection (LCM) with comprehensive mRNA-sequencing, which reads all polyadenylated transcripts including pathogens and model organisms. From a single &amp;lt;10 µm section of formalin-fixed paraffin-embedded (FFPE) tissue, Picoception RNA can profile an unlimited number of target regions smaller than 0.1 mm2, typically reading 200,000-1,000,000 unique molecules each with a dynamic range of more than 100:1. By isolating small areas of a tissue section, Picoception RNA allows deep molecular profiling of pure, distinct cellular regions such as tumor epithelial vs. normal or immune microenvironment. Combined with the depth of the gene-expression data, the cost-effectiveness of this technique enables statistically powerful analyses from large clinical cohorts. Furthermore, Picoception RNA’s compatibility with archived FFPE samples unlocks genomic signals from patients with known clinical outcomes, allowing the process of biomarker and pathway discovery to begin immediately without prospectively recruiting new subjects. We have applied this technique successfully in a wide range of applications, including oncology clinical trials for targeted therapy and immunotherapy, rare cancers, and cancers with limited biopsy material (including punch biopsies and core-needle biopsies), as well as rodent models. We have had consistent success profiling FFPE samples more than 20 years old. Picoception RNA complements previous spatial transcriptomics techniques, filling the need for deep genomic analysis at microscopic resolution using large-scale cohorts of FFPE samples. Citation Format: Joseph W. Foley, Wei K. Teo, Joshua K. Tay. Deep and scalable spatial transcriptomics for oncology research [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 6612.
Abstract 3632: Analysis of supportive care medication use in metastatic colorectal cancer across racial and ethnic groups using SEER-Medicare
Authors: Olga Trejos Kweyete, Yi Guo, Sherise Rogers, Lisa Scarton, David Deremer, Diana Wilkie, John Allen
Journal: Cancer Research (2025)

Abstract Background: This study investigates disparities in the use of adjunctive supportive care medications (SCM) among metastatic colorectal cancer (CRC) patients across different racial and ethnic groups. SCMs are central to symptom management and improving health-related quality of life in cancer treatment. Our goal was to identify potential disparities in medication use for neurological symptoms that may impact quality of life and symptom management in end-of-life care for metastatic colorectal cancer patients. Methods: Data were acquired from Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database covering 2005-2017. We included patients diagnosed with metastatic CRC who died between 2005-2017 with more than one year of Medicare enrollment. Logistic regression models evaluated the relationship between SCM use and race while adjusting for various covariates, including sex, race, age, marital status, education, income, residence, and Charlson Comorbidity Index. Non-Hispanic White (NHW) CRC patients served as the reference group for all comparisons. Results are reported as the adjusted Odds Ratio and 95% Confidence Interval. Results: After applying the inclusion/exclusion criteria, 28, 212 patients were included in the final analysis (NHW:72.81%, Black 12.67%, Hispanic 9.51%, Asian/Pacific Islander 4.65%). Racial and ethnic disparities in the use of multiple SCM drug classes were identified. The results are summarized in Table 1 Conclusion: Black CRC patients had significantly lower use of multiple SCM drug classes than NHW patients. Hispanic and Asian CRC patients' results were more heterogeneous, demonstrating both increased and decreased use for various SCM drug classes than NHW patients. These findings suggest varying patterns in medication use across racial and ethnic groups and require further investigation to understand further the causes and potential consequences of these differences in use Citation Format: Olga Trejos Kweyete, Yi Guo, Sherise Rogers, Lisa Scarton, David Deremer, Diana Wilkie, John Allen. Analysis of supportive care medication use in metastatic colorectal cancer across racial and ethnic groups using SEER-Medicare [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 3632.
Abstract 5146: E-cadherin expression as a prognostic biomarker in colorectal cancer
Authors: Anika Bhandare, Anjana Saxena, Mintoo Patel
Journal: Cancer Research (2025)

Colorectal cancer (CRC) represents the third most common cancer in the United States, with increasing incidence among younger populations despite remaining predominantly prevalent in individuals over 65 years of age. E-cadherin, a critical cell-cell adhesion molecule, plays a significant role in the development and progression of colorectal cancer by regulating intricate cellular mechanisms including polarity, differentiation, proliferation, and migration through complex cytoskeletal network associations. Loss of E-cadherin expression fundamentally disrupts intercellular adhesion, triggering enhanced cellular motility and facilitating the epithelial-to-mesenchymal transition (EMT)—a critical transformative process that enables metastatic potential. This molecular mechanism represents a crucial turning point in cancer progression, where cellular architectural integrity becomes compromised. This study investigated E-cadherin expression across different stages of colorectal cancer using immunohistochemical analysis of de-identified formalin-fixed paraffin-embedded biopsy tissue samples categorized as precancerous, cancerous, and normal noncancerous groups. Complementing the primary immunohistochemical analysis, a rigorous systematic meta-analysis was conducted through an extensive PubMed literature search to validate and contextualize the findings. Immunohistochemical staining revealed a robust E-cadherin expression in the mucosal epithelial cells of the normal tissues, whereas cancerous tissue samples exhibited reduced E-cadherin levels that correlated directly with advanced cancer staging. Low E-cadherin levels correlate significantly with adverse clinicopathological features and potentially more aggressive disease progression. The comprehensive meta-analysis substantiated these immunohistochemical observations, reinforcing the potential diagnostic and prognostic significance of E-cadherin as a sophisticated molecular biomarker. This study underscores the potential of E-cadherin as a supplementary biomarker in routine histopathological examinations. By providing more nuanced molecular insights into cancer stage and progression, E-cadherin analysis could facilitate further personalized, targeted clinical treatment strategies for colorectal cancer patients. Citation Format: Anika Bhandare, Anjana Saxena, Mintoo Patel. E-cadherin expression as a prognostic biomarker in colorectal 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 5146.
Abstract 6616: LMNA-FOSB fusions are a recurrent event in meningiomas
Authors: Mateo Gomez Hjerthen, Josiah Wong, Juan Wang, Harrshavasan Congivaram, Priscilla K. Brastianos, Akash J. Patel, Craig M. Horbinski, James P. Chandler, E. Zeynep Erson Omay, Jennifer Moliterno, Murat Günel, Stephen T. Magill, David R. Raleigh, Feng Yue, Mark W. Youngblood
Journal: Cancer Research (2025)

Meningiomas are common tumors of the central nervous system associated with a small number of mutually exclusive genetic events. We identify a cohort of seven meningiomas that harbor fusions between the genes LMNA and FOSB, with no other known meningioma mutations. Previous reports of LMNA-FOSB fusions in epithelioid hemangiomas suggest a broader oncogenic potential for this event across tumor types. Lamin A/C is a structural protein involved in chromatin organization expressed ubiquitously in nearly all differentiated cells, while FOSB is an AP-1 family transcription factor implicated in cell proliferation and differentiation. Targeted, whole-genome, and RNA-sequencing approaches revealed a near identical LMNA-FOSB fusion comprising exons 1-2 of LMNA (chr1) and exons 2-4 of FOSB (chr19). The fusion event therefore includes key phosphorylation sites in Lamin A/C such as Ser22 that interact with active enhancers, while preserving the DNA binding domain of FOSB. Expression of these genes was not significantly altered among fusion samples, suggesting neomorphic protein function as an underlying oncogenic mechanism. Transfection of the LMNA-FOSB constructs into CH157 and IOMM-LEE meningioma cell lines resulted in changes to chromatin architecture and gene expression, which were validated using Hi-C and ChIP-seq profiling of frozen tumor tissues harboring this event. Our findings suggest that LMNA-FOSB fusions represent a novel and recurrent meningioma genetic event, providing new insights into the molecular pathogenesis of these tumors and role of FOSB across cancer. Citation Format: Mateo Gomez Hjerthen, Josiah Wong, Juan Wang, Harrshavasan Congivaram, Priscilla K. Brastianos, Akash J. Patel, Craig M. Horbinski, James P. Chandler, E. Zeynep Erson Omay, Jennifer Moliterno, Murat Günel, Stephen T. Magill, David R. Raleigh, Feng Yue, Mark W. Youngblood. LMNA-FOSB fusions are a recurrent event in meningiomas [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 6616.
Abstract 4818: CSPG4-targeting CAR-macrophages inhibit melanoma growth
Authors: Daniel Greiner, Minna Roh-Johnson
Journal: Cancer Research (2025)

Abstract Macrophages are abundant in the tumor microenvironment of solid tumors like melanoma, and while often pro-tumorigenic, macrophages also possess inherent anti-tumor capabilities. Recent studies have highlighted the potential of CAR-Ms, or chimeric antigen receptor expressing macrophages, to recognize and kill cancer cells. As both phagocytes and antigen-presenting cells, macrophages offer a unique toolset compared to cytotoxic CAR-T cells, potentially improving efficacy in solid tumors. We engineered primary human blood monocyte-derived macrophages to express CAR constructs with an scFV targeting chondroitin sulfate proteoglycan 4 (CSPG4), an antigen commonly overexpressed in solid tumors including melanoma and glioblastoma. Using melanoma as an initial model, we evaluated the impact of CSPG4-targeting CAR-Ms on melanoma growth in vitro and in vivo. We found that CSPG4-targeting CAR-Ms lead to increased phagocytosis of melanoma cells and increased melanoma cytotoxicity compared to control CAR-Ms. Furthermore, CSPG4-targeting CAR-Ms inhibit melanoma spheroid growth in 3D and inhibit melanoma growth in mice. Interestingly, priming CSPG4-targeting CAR-Ms with CSPG4-expressing cancer cells leads to increased phagocytosis and infiltration of melanoma spheroids compared to control CAR-Ms or unprimed CSPG4-targeting macrophages. Together, these results suggest that CSPG4-targeting CAR-M immunotherapy is a promising solid tumor immunotherapy approach for treating melanoma. Citation Format: Daniel Greiner, Minna Roh-Johnson. CSPG4-targeting CAR-macrophages inhibit melanoma growth [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 4818.
Abstract 3081: The multiciliated transcription factor FOXJ1 modulates microtubule dynamics and mediates taxane resistance in prostate cancer
Authors: Ada Gjyrezi, Fang Xie, Daniel E. Fein, Maryam Labaf, Larysa Poluben, Olga Voznesensky, Aniket Gad, Eva Corey, Rupal S. Bhatt, Steven Balk, Paraskevi Giannakakou
Journal: Cancer Research (2025)

Abstract Docetaxel is the first-line chemotherapy for metastatic castration-resistant prostate cancer, but clinically meaningful mechanisms of resistance remain to be established. We generated an in vivo model of docetaxel resistance using castration-resistant patient-derived xenografts and found increased expression of genes that drive development of multiciliated cells, including FOXJ1 and its effector genes, many of which regulate ciliary microtubules. Mechanistically, FOXJ1 overexpression conferred docetaxel resistance in vitro and in vivo, which was associated with decreased docetaxel-mediated microtubule bundling. Overexpression of a microtubule-associated FOXJ1-regulated gene (TPPP3) had similar effects. Conversely, FOXJ1 knockdown impaired basal microtubule function, enhanced taxane binding to microtubules, and increased docetaxel sensitivity. These results establish mechanistic causality between the FOXJ1 signaling axis, microtubule biology, and taxane resistance. Clinically, FOXJ1 gene amplification was increased in taxane-treated prostate cancer patients. Moreover, in the CHAARTED clinical trial of docetaxel combined with androgen deprivation for metastatic prostate cancer, higher baseline FOXJ1 was predictive of decreased survival in prostate cancer patients treated with docetaxel, further supporting clinical relevance. Together these findings identify a previously unrecognized clinically impactful mechanism of taxane resistance whose exploitation could stratify patients that will not benefit from taxane treatment. Citation Format: Ada Gjyrezi, Fang Xie, Daniel E. Fein, Maryam Labaf, Larysa Poluben, Olga Voznesensky, Aniket Gad, Eva Corey, Rupal S. Bhatt, Steven Balk, Paraskevi Giannakakou. The multiciliated transcription factor FOXJ1 modulates microtubule dynamics and mediates taxane resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3081.
Abstract 5138: NRAS overexpression influences EMT in claudin-low triple negative breast cancer
Authors: Jackson Marlon Rodney Thomas, Stephanie Dance-Barnes
Journal: Cancer Research (2025)

Abstract This study investigates Nras-mediated Ras-Mapk in epithelial-mesenchymal transition and the therapeutic potential of RAS-MAPK inhibitors in Claudin-low(CL) triple-negative breast cancer (TNBC). The K14TRT line represents a potential model for CL and metastatic TNBC research due to its genomic similarities to human CL, TNBC. Research at the Perou Lab indicated that the K14TRT cell line exhibited great expression of the NRAS gene, which may influence the EMT characteristics of the cell line. NRAS influences EMT by altering the expression of signaling proteins involving stem-cell characteristics, cell-to-cell attachment, and cell growth regulators. Subsequent knockout of NRAS via siRNA transfection and use of the MEK inhibitor Trametinib were used to observe changes in transcriptome expression. These changes in the transcriptome will then be analyzed to identify future vulnerabilities in the K14TRT cell line using significance analysis of microarray (SAM) in R-Studio. TNBC lacks targeted treatments that other subtypes of breast cancer have, leading to significant disparities in the 5-year survival rate of breast cancer (78.0% for TNBC vs. 91.2% AVG). In addition, triple-negative breast cancer disproportionately affects young Black American and pre-menopausal women. This study highlights the potential influence of NRAS-mediated RAS-MAPK on EMT in Claudin-low, TNBC. Highlighting the RAS-MAPK pathway for its potential use as a primary target in CL, TNBC. Citation Format: Jackson Marlon Rodney Thomas, Stephanie Dance-Barnes. NRAS overexpression influences EMT in claudin-low 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 5138.
Abstract 6716: Effect of ZFHX3 in endometrial cancer progression
Authors: Sanjeev Ganesh, Areebah Qazi, Swornalata Pukhrambam, Sophia Agrusa, Jessica Long, Katherine Gurdziel, Michael Wilson
Journal: Cancer Research (2025)

Abstract Endometrial cancer (EC) is the most prevalent gynecological cancer and the 4th most common cancer in women globally. The frequency of EC is increasing in contrast to other prevalent cancers driven by lifestyle choices and metabolic conditions. Currently, research is focused on molecular mechanisms of tumor initiation and tumor microenvironment. ZFHX3 (ATBF1), is a transcription factor that has roles in embryogenesis steroid hormone regulation. It has been identified as a tumor suppressor gene in multiple cancer types. ZFHX3 mutations have been observed in normal endometrium and reports suggest it is mutated in about 20% of EC cases. Despite these frequent mutations, very few studies fully comprehend the molecular mechanisms behind ZHFX3 inactivation and its subsequent role in initiating EC. Our study aims to find the role of ZFHX3 in initiating EC. We knocked down ZFHX3 in 12Z cells via siRNA, followed by mRNA-seq, to examine its function in the endometrial epithelium. Our preliminary data suggests that ZFHX3 regulates c-MyB, a proto-oncogene, suggesting its role as a tumor suppressor gene in EC. We performed transcriptomic analysis on endometrial cells following the knockdown of ZFHX3 and identified differential expression of cell cycle and cell adhesion-related genes, suggesting important roles for ZFHX3 in oncogenic processes. We also overexpressed ZFHX3 expression in Ishikawa cells and treated them with estrogen and progesterone. These cells were subjected to RNA-seq analysis to identify the different signaling pathways affected by the presence of progesterone. Comparing the 2 RNA-seq data, we found EGR1 to be a common gene. We also investigated the effects of ZFHX3 knockdown in the endometrial epithelium in vivo and found an increase in the Ki67 expression and endometrial gland number, indicating endometrial hyperplasia. Future studies will focus on the relation between ZFHX3 and EGR1, its subsequent signaling pathways, and elucidating its role as a tumor suppressor. Citation Format: Sanjeev Ganesh, Areebah Qazi, Swornalata Pukhrambam, Sophia Agrusa, Jessica Long, Katherine Gurdziel, Michael Wilson. Effect of ZFHX3 in endometrial cancer progression [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 6716.