tbuckley/cabot-search huggingface dataset:
Abstract 560: Characterizing the role of TIAM1-Rac1 signaling in advanced prostate cancers
Authors: James P. Maine, Masuda Sharifi, Shu Ning, Amy R. Leslie, Zachary A. Schaaf, Wei Lou, Allen C. Gao
Journal: Cancer Research (2025)

Abstract Background: Roughly 20-30% of patients with castration-resistant prostate cancer (CRPC) will progress to neuroendocrine prostate cancer (NEPC) following treatment of androgen receptor signaling inhibitors (ARSIs) such as enzalutamide and abiraterone. NEPC is an aggressive, treatment-resistant form of prostate cancer (PCa) with an average survival time of ∼7 months post-diagnosis. Poor understanding of acquired resistance mechanisms and disease progression prevents the development of efficacious treatments for advanced PCa (NEPC and CRPC). The Rac1-associated guanine nucleotide exchange factor TIAM1—identified as a novel neural lineage signature in enzalutamide-resistant PCa cells—promotes the survival of neuroendocrine small-cell lung cancer. Here, we interrogate how TIAM1 contributes to acquired resistance and disease progression in advanced PCa. Methods: RNA-seq, GEO, and cBioPortal datasets were analyzed to assess the relationships between TIAM1 expression and enzalutamide treatment, patient survival, and androgen receptor dependency. Cell growth assays determined the effects of TIAM1-specific RNA interference and TIAM1 overexpression in CRPC and NEPC-like cell lines. TIAM1 expression was evaluated using real-time quantitative PCR. Results: Analysis of publicly available datasets revealed patients and mice treated with enzalutamide showed increased TIAM1 mRNA expression and that high relative TIAM1 mRNA expression significantly correlated to poor disease-free survival. NEPC and NEPC-like cell lines exhibited higher average TIAM1 mRNA expression than CRPC cells. siRNA TIAM1 depletion in drug-resistant NEPC-like cells showed moderate re-sensitization to the ARSIs enzalutamide and abiraterone. Transient TIAM1 overexpression in CRPC cells conferred partial tolerance to enzalutamide compared to vehicle-treated cells. Conclusions: These results establish the clinical relevancy of TIAM1 in PCa models. Long-term treatment with enzalutamide increased TIAM1 expression in patient and murine samples, possibly contributing to acquired resistance mechanisms as demonstrated by increased ARSI sensitivity upon TIAM1 depletion. Current efforts in our lab focus on elucidating the mechanistic contributions of the TIAM1-Rac1 axis in acquired ARSI resistance to facilitate synergistic treatment of advanced PCa. Citation Format: James P. Maine, Masuda Sharifi, Shu Ning, Amy R. Leslie, Zachary A. Schaaf, Wei Lou, Allen C. Gao. Characterizing the role of TIAM1-Rac1 signaling in advanced prostate cancers [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 560.
Abstract 820: Combined HDAC and ATM inhibition potentiates anticancer effects in glioblastoma preclinical models
Authors: Susan J. Histed, Kaitlyn Chung, Gozde Uzunalli, Elizabeth Hayes, Kyria Kelley-Wolfe, Jordon Fakhoury, Tigran Margaryan, Sonam Patel, Nader Sanai, Artak Tovmasyan, An-Chi Tien, Shwetal Mehta
Journal: Cancer Research (2025)

Abstract Background: Brain penetrant histone deacetylase inhibitors (HDACi) are promising radiosensitizing agents for glioblastoma (GBM). In addition to suppression of HDAC activity, the antiproliferative effect of HDACi includes downregulation of DNA damage repair (DDR) pathway and persistent DNA damage. Here, we evaluated synergistic effect of combining HDAC and DNA repair enzyme, ataxia telangiectasia mutated (ATM) inhibitors, quisinostat (QST) and AZD1390 to broaden therapeutic window for GBM treatment. Methods: In vitro dose-response assays were performed in patient-derived xenograft (PDX)-derived glioma stem cells (GSCs) with both QST and AZD1390 with or without radiation treatment to assess synergy. Immunoblotting and immunofluorescence assays were performed for histone acetylation, DNA damage (pH2AX), pRAD50, pATM and cleaved caspase 3 to assess pharmacodynamic responses. Quantitative PCR analysis was performed to examine changes in gene expression of key DNA damage pathway genes. Results: Combined treatment with QST and AZD1390 synergistically inhibit GBM growth across multiple GBM GSC models in combination with radiation. HDACi treatment dampens the DDR response pathway via suppression of key DDR pathway genes resulting in persistent unrepaired DNA damage. Conclusions: Our data indicate that QST and AZD1390 act synergistically to radiosensitize GBM cells and increase the therapeutic window for treatment. In vivo experiments are under way to examine efficacy of this combination using orthotopic PDX GBM models. Keywords: glioblastoma, ATM, HDAC, DNA damage repair Citation Format: Susan J. Histed, Kaitlyn Chung, Gozde Uzunalli, Elizabeth Hayes, Kyria Kelley-Wolfe, Jordon Fakhoury, Tigran Margaryan, Sonam Patel, Nader Sanai, Artak Tovmasyan, An-Chi Tien, Shwetal Mehta. Combined HDAC and ATM inhibition potentiates anticancer effects in glioblastoma preclinical models [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 820.
Abstract 1217: Modelling GBM-vasculature interaction on chip
Authors: Promise Emeh, Kevin Jimenez-Cowell, Martine Lamfers, Clemens Dirven, Nick Saites, Todd Burton, Karla Queiroz
Journal: Cancer Research (2025)

Abstract The tumor microenvironment (TME) in glioblastoma (GBM) is remarkably intricate, characterized by its dynamic nature and high heterogeneity that significantly influence tumor progression and treatment resistance. The heterogeneous TME comprises of blood vessels, immune cells, neurons, and the blood-brain barrier (BBB) presenting distinct tumor compartments that influence the tumor behavior. A recent classification based on the heterogeneous TME identified three distinct subtypes TMELow, TMEMed, and TMEHigh distinguished by varying endothelial and immune cell populations. This study explores the complex interactions between glioblastoma (GBM) and its tumor microenvironment (TME), focusing specifically on the blood-brain barrier (BBB) and vascular compartment. To evaluate GBM's impact on the BBB, a compartmentalized model was developed that prevents direct cell-to-cell contact, allowing the observation of paracrine signaling. Using this model, distinct effects were identified across different GBM cell lines: one cell line caused significant BBB permeability with low transendothelial electrical resistance (TEER) values, while another had minimal impact on barrier integrity. To further investigate GBM-BBB interactions, a vascular network model incorporating brain endothelial cells, stromal cells and GBM cells within an extracellular matrix was developed. This model revealed consistent differences between the cell lines, aligning with the initial findings and reflected in endothelial cell morphology and vascular network density. Analysis of cytokines secreted by the GBM cell lines provided further insights into the observed changes in vascular organization. Ongoing investigation aims to use patient derived cells in this model to pick up interpatient variability and specifically look at the differences between the TME subtypes. This approach allows for the in vitro modelling and characterization of GBM TME subtypes and potentially the identification of novel druggable targets in the GBM TME. Citation Format: Promise Emeh, Kevin Jimenez-Cowell, Martine Lamfers, Clemens Dirven, Nick Saites, Todd Burton, Karla Queiroz. Modelling GBM-vasculature interaction on chip [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 1217.
Abstract 1079: L2S2: Chemical perturbation and CRISPR KO LINCS L1000 signature search engine
Authors: Giacomo B. Marino, John E. Evangelista, Daniel J. Clarke, Avi Ma'ayan
Journal: Cancer Research (2025)

The Library of Integrated Network-Based Cellular Signatures (LINCS) Common Fund program was established to construct a reference database of human cancer cell lines responses to diverse multi-omics and phenotypic perturbations. As part of the LINCS initiative, 248 cell lines were profiled with the L1000 transcriptomics assay to measure the response to 33,621 small molecules and 7,508 single gene CRISPR knockouts (KOs). From this massive dataset, we computed sets of up- and down-regulated genes. These gene sets are served for search by the LINCS L1000 Signature Search (L2S2) platform. L2S2 provides instant results when searching across over 1.678 million chemical perturbations and CRISPR KO signatures. The platform includes filters for FDA-approved drugs and signature directionality. With the L2S2 search engine, users can identify small molecules and single gene CRISPR KOs that produce gene expression profiles similar or opposite to their submitted gene sets. Significant CRISPR KO signatures can reveal potential driver genes and drug targets. Similarly, approved drugs and preclinical small molecule signatures that might reverse or mimic a desired expression pattern can provide hypotheses for preclinical experimental validation studies. L2S2 also includes a consensus search feature which ranks specific perturbations across cellular contexts, time points, and concentrations. L2S2 was systematically applied to the CPTAC3 cohort to prioritize potential targets, approved drugs, and preclinical compounds for all previously identified multi-omic cancer cohort subtypes. Overall, L2S2 provides cancer researchers with a powerful tool to further understand and personalize treatments for cancer subtypes. L2S2 is available from: https://l2s2.maayanlab.cloud. Citation Format: Giacomo B. Marino, John E. Evangelista, Daniel J. Clarke, Avi Ma'ayan. L2S2: Chemical perturbation and CRISPR KO LINCS L1000 signature search engine [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 1079.
Abstract 2631: Trop-2 is expressed in tumor budding cells and drives colon cancer cell migration and invasion through a β-catenin, CDC42, PKCα, Akt signaling network
Authors: Saverio Alberti, Valeria Barresi, Rossano Lattanzio, Marco Trerotola, Emanuela Guerra, Martina Ceci, Roberta Di Pietro, Donato F. Altomare, Raffaella Depalo, Arcangelo Picciariello, Laura Antolini, Federica M. Previtera
Journal: Cancer Research (2025)

Abstract TROP2 was previously shown to drive metastatic diffusion of colorectal cancer (CRC), upon proteolytic activation by ADAM10. Trop-2 activation was shown to lead to cleavage of E-cadherin, with release from the scaffolding cytoskeleton and disruption of cell-cell junctions. This suggested that Trop-2-driven loss of cell adhesion is pivotal for the acquisition of invasion capacity in CRC. Tumor budding was shown to play a role in CRC invasion at the tumor/stroma interface and to impact on disease outcome. We thus investigated whether Trop-2 is associated with CRC cell budding. Our findings show that essentially all CRC buds express Trop-2. Trop-2-positive tumor cell buds and poorly differentiated clusters associated with metastatic relapse in CRC patients in independent CRC case series. Trop-2 was shown to drive cell migration and matrix invasion upon induction of β-catenin signaling, via expression of CDC42, phosphorylation/activation of PKCα at Ser657 and of Akt at Thr308. The highest impact on CRC patient prognosis was jointly shown by Trop-2, CDC42 and phosphorylated PKCα, supporting a model of Trop-2-driven CRC progression through induction of migration and invasion of tumor budding cells. Citation Format: Saverio Alberti, Valeria Barresi, Rossano Lattanzio, Marco Trerotola, Emanuela Guerra, Martina Ceci, Roberta Di Pietro, Donato F. Altomare, Raffaella Depalo, Arcangelo Picciariello, Laura Antolini, Federica M. Previtera. Trop-2 is expressed in tumor budding cells and drives colon cancer cell migration and invasion through a β-catenin, CDC42, PKCα, Akt signaling network [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 2631.
Abstract 1034: Sleep disturbances and obesity-related cancer risk: Results from the Health Examinees Study
Authors: Sinyoung Cho, Sukhong Min, Hyobin Lee, Daehee Kang
Journal: Cancer Research (2025)

Abstract Background: Relationships of sleep duration, chronotype, snoring, and insomnia (initiation difficulties, fragmentation, and daytime fatigue) with obesity-related cancer risk have not been comprehensively investigated. We aimed to examine the association between sleep disturbances and obesity-related cancer risk. Methods: Participants were recruited between 2004 and 2013 and followed up through December 31, 2018. A total of 70,061 participants (2,543 incident obesity-related cancer) from the Health Examinees-Gem study were included in the present study. Cox proportional hazard models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of sleep duration, chronotype, snoring, and insomnia with obesity-related cancer risk. Joint effect analyses were conducted between sleep duration and other disturbances (chronotype, snoring, and insomnia). Furthermore, nonlinear associations between sleep duration and incidence of obesity-related cancer were evaluated in restricted cubic spline analysis. Results: The median follow-up time for this study was 8 years (range, 1-11 years). Short sleep duration (&amp;lt;6 hours) was associated with a higher risk of obesity-related cancer in males compared to reference sleep duration (7-8 hours; adjusted HR 1.30 [95% CI 1.02-1.64]). Short sleep duration was significantly associated with obesity-related cancer risk in participants with a BMI ≥25kg/m2 (adjusted HR 1.27 [95% CI 1.02-1.57]). Joint effects were observed between short sleep duration and non-conventional chronotype (adjusted HR: 1.52, 95% CI: 1.14-2.01). Adjusted restricted cubic spline analysis demonstrated statistically significant nonlinear relationships between sleep duration and obesity-related cancer risk (P &amp;lt;0.001). Conclusions: Short sleep duration may serve as a risk factor for obesity-related cancer. Non-linear relationships should be further investigated. Citation Format: Sinyoung Cho, Sukhong Min, Hyobin Lee, Daehee Kang. Sleep disturbances and obesity-related cancer risk: Results from the Health Examinees 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 1034.
Abstract 1050: Geographic disparities in the incidence of breast and prostate cancers among African Americans: A comparative analysis between the UChicago and Baylor catchment areas
Authors: Ahmed Fadiel, A. Fadiel, S. Fadel, A. Oluyomi, O. Rosales, K.D. Eichenbaum, M. Abbasi, A. Elbialy, None an, None kunle Odunsi, Saleh Fadel
Journal: Cancer Research (2025)

Abstract Background: Cancer disparities continue to be a significant challenge for public health across the nation, especially among African Americans. Causes include socioeconomic factors, environmental conditions, and limited healthcare access. We are exploring data-driven studies of geographic disparities in the incidence rates for breast and prostate cancers across African American populations in catchment areas around the University of Chicago and Baylor College of Medicine. Methods: Catchment areas were identified using our intelligent Catchment Analysis Tool, or iCAT, to map physical boundaries, referral patterns, distances, and population densities. Data were extracted from the SEER Program, CDC WONDER, and the American Community Survey (ACS). The variables analyzed included cancer incidence rates, demographic and socioeconomic factors, healthcare access and utilization, and environmental exposures, including air pollution and water quality. Chi-square tests, t-tests, logistic regression, and multivariate analysis were also performed to identify key drivers of disparities. The results were displayed on geographic maps, charts, and graphs, highlighting spatial clusters and relationships between cancer incidence and contributing factors. Results: Our preliminary findings indicate large disparities in cancer incidence rates between the two catchment areas. We investigate associations between socioeconomic inequality, healthcare access, and environmental exposures. African Americans living in areas of the lowest socioeconomic status and decreased healthcare access demonstrated higher incidence rates. Conclusions: This study can catalyze a focus on systemic inequity in socioeconomic conditions, healthcare accessibility, and environmental quality that influence cancer disparities among African Americans. These findings suggest actionable insights toward targeted interventions and policymaking within the UChicago and Baylor catchment areas. Citation Format: Ahmed Fadiel, Fadiel A., Fadel S. , Oluyomi A. , Rosales O. , Eichenbaum K.D. , Abbasi M. 1, Elbialy A. , an, kunle Odunsi, Saleh Fadel. Geographic disparities in the incidence of breast and prostate cancers among African Americans: A comparative analysis between the UChicago and Baylor catchment areas [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 1050.
Abstract 555: ERBB4 upregulation in a taxol-resistant triple-negative breast cancer cell line
Authors: Ling-Huei Yih, Hsiao-Hui Kuo, Tsai-Ming Lu
Journal: Cancer Research (2025)

Abstract Resistance to chemotherapy remains an unfavorable obstacle to effective cancer treatment. Although paclitaxel is one of commonly used chemotherapeutic agents in the treatment of triple-negative breast cancer (TNBC), resistance mechanisms are not fully understood. In this study, we found that ErbB2 Receptor Tyrosine Kinase 4 (ERBB4) was substantially upregulated in T50RN, a paclitaxel-resistant cell clone established from the human TNBC cell line MDA-MD-231. We thus aimed to explore whether and how ERBB4 may modulate T50RN cell resistance to paclitaxel. The T50RN cell was obtained by exposing human TNBC cell line MDA-MB-231 to stepwise escalating paclitaxel concentration from 0.5 to 50 nM and then the resistant cell line T50RN was selected and expanded. The IC50 of paclitaxel was 2 and &amp;gt;100 nM in MDA-MB-231 and T50RN cells respectively. Treatment of the cells with ERBB inhibitors, sfatinib, allitinib, or PF299804, in sub-lethal concentration only induced a small additive effect on paclitaxel cytotoxicity in MDA-MB-231 cells, but dramatically enhanced paclitaxel cytotoxicity in T50RN cells. Since only the expression of ERBB4 was significantly upregulated in T50RN cells, the expression of EGFR1 was equally high in MDA-MB-231 and T50RN cells, and ERBB2 and ERBB3 were low in both cells, ERBB4 might play a critical role on the effect of the three ERBB inhibitors. In addition, the three inhibitors also significantly enhanced paclitaxel-induced spindle abnormalities in T50RN cells but had no effect in MDA-MB-231 cells. Depletion of ERBB4 with shRNA also significantly reduced the cell growth ability of T50RN but not MDA-MB-231 on soft agar. These results suggest that ERBB4 may play a critical role in paclitaxel resistance in T50RN cells. Further elucidation of how ERBB4 is induced in T50RN cells and how ERBB4 regulates cell resistance might provide leads to overcome paclitaxel resistance. Citation Format: Ling-Huei Yih, Hsiao-Hui Kuo, Tsai-Ming Lu. ERBB4 upregulation in a taxol-resistant triple-negative breast cancer cell line [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 555.
Abstract 522: One drug- Two targets in osteosarcoma
Authors: Marina Curcic, Sanjay K. Srivastava
Journal: Cancer Research (2025)

Osteosarcoma, the most common primary malignant bone tumor, mostly affects adolescents and older adults, with limited therapeutic advances leading to poor survival rates for metastatic or recurrent cases. Current treatments often fail due to high mutational burdens and chemoresistance, necessitating new targeted therapies. In this study, we investigated the potential of PCT, a kinase inhibitor recently approved for hematological malignancies, for its anticancer effect against osteosarcoma. Our comprehensive in vitro analysis demonstrated that PCT inhibits cell viability, induces apoptosis, and causes G2/M arrest in multiple osteosarcoma cells. Gene expression analysis indicated that at very low micromolar concentrations, PCT inhibits the expression of AXL, β-Catenin and key players of the pathway at protein and mRNA level. Molecular docking analysis indicated PCT’s high binding affinity to AXL confirming our observations that PCT suppresses AXL/β-Catenin expression and transcriptional activity. Oral administration of PCT significantly reduced osteosarcoma tumor growth in murine models without any observable toxicity. The tumors of PCT treated mice exhibited inhibition of AXL and β-Catenin signalling axis and induction of apoptosis. Our findings suggest PCT as a dual inhibitor of AXL and β-catenin, directly affecting osteosarcoma progression. This research highlights PCT’s potential as a targeted therapeutic for osteosarcoma, offering new avenues to improve outcomes for patients with this aggressive malignancy. Citation Format: Marina Curcic, Sanjay K. Srivastava. One drug- Two targets in osteosarcoma [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 522.