tbuckley/cabot-search huggingface dataset:
Abstract 991: PARADIGM: an embeddings-based multimodal learning framework with foundation models and graph neural networks
Authors: Asim Waqas, Aakash Tripathi, Mia Naeini, Paul A. Stewart, Matthew B. Schabath, Ghulam Rasool
Journal: Cancer Research (2025)

Abstract Introduction: Cancer research faces significant challenges in integrating heterogeneous data across varying spatial and temporal scales, limiting the ability to gain a comprehensive understanding of the disease. PARADIGM(Pan-Cancer Embeddings Representation using Advanced Multimodal Learning with Graph-based Modeling) addresses this challenge by providing a framework leveraging foundation models (FMs) and Graph Neural Networks (GNN). PARADIGM framework generates embeddings from multi-resolution datasets using modality-specific FMs, aggregates sample embeddings, fuses them into a unified graph representation, and uses GNNs for survival prediction. Methods: We applied PARADIGM for survival analysis of five squamous cell carcinomas; head and neck (527), lung (496), bladder (408), cervical (294), and esophageal (184) cancers, and five adenocarcinomas; colon (393), lung (549), prostate (490), rectum (157), and stomach (406) cancers. Additionally, we validated using lung squamous cell data from Moffitt Cancer Center (103 patients). Multimodal data for training and evaluation included EHR data (e.g., age, gender, and smoking status), whole slide images (WSIs), pathology reports, and molecular data (e.g., gene expression, miRNA, and protein expression). Model performance was assessed using concordance index (C-index) for survival prediction, with 7-fold cross-validation ensuring robustness. Results &amp; Conclusions: PARADIGM demonstrated significant improvements in survival prediction compared to unimodal and multimodal approaches such as multilayer perceptron, Transformers, and XGBoost (Table 1). Our findings indicate that integrating diverse data modalities into a cohesive representation yields more accurate and insightful predictions. This approach highlights the potential of embeddings-based multimodal learning to foster improved outcome predictions and provide actionable insights for personalized treatment strategies. Citation Format: Asim Waqas, Aakash Tripathi, Mia Naeini, Paul A. Stewart, Matthew B. Schabath, Ghulam Rasool. PARADIGM: an embeddings-based multimodal learning framework with foundation models and graph neural networks [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 991.
Abstract 1371: ChemoNETosis is associated with chemotherapy resistance in pancreatic cancer
Authors: Shohei Nogi, Shunsuke Kagawa, Atsuki Taniguchi, Nobuhiko Kanaya, Yoshihiko Kakiuchi, Kazuya Yasui, Satoru Kikuchi, Shinji Kuroda, Hiroshi Tazawa, Toshiyoshi Fujiwara
Journal: Cancer Research (2025)

Abstract Background: Chemotherapy resistance is a major contributor of the poor prognosis of pancreatic cancer, yet its underlying mechanisms remain poorly understood. Neutrophil Extracellular Traps (NETs), a form of neutrophil-specific cell death, have been reported to be associated with poor prognosis in various cancers because they act to suppress tumor immunity and promote metastasis. Recently, chemotherapy-stimulated NETs, termed “ChemoNETosis”, were reported to contribute to chemotherapy resistance in breast cancer (Mousset A, Cancer cell. 2023). Therefore, we investigated the role of NETs in resistance to cytotoxic chemotherapy in pancreatic cancer. Methods: The abundance of NETs in the tumor microenvironment was analyzed in relation to chemotherapy efficacy using immunohistochemical staining of resected specimens from pancreatic cancer patients treated with neoadjuvant chemotherapy. The ability of pancreatic cancer cells to induce NETs was assessed with and without gemcitabine stimulation by extracellular DNA staining in vitro and by immunohistochemical analysis in vivo. Finally, the efficacy of the combined anti-NETs treatment and gemcitabine was examined in a mouse subcutaneous tumor model. Results: NETs were more abundant in unresponsive tumors compared to responsive tumors in clinical sample. Gemcitabine-treated pancreatic cancer cells induced significantly higher levels of NETs than untreated cells in vitro as well as in vivo tumor models. This “ChemoNETosis” was effectively inhibited by Navarixin, a CXCR2 inhibitor. Combination therapy with Navarixin and gemcitabine achieved greater tumor reduction compared to gemcitabine alone with, a complete response (CR) rate of 28.6% (2/7) vs 0% (0/7). Conclusion: NETs may play a key role in chemotherapy resistance in pancreatic cancer. Targeting NETs could provide a novel approach to enhancing the efficacy of chemotherapy in preclinical models and warrants further investigation. Citation Format: Shohei Nogi, Shunsuke Kagawa, Atsuki Taniguchi, Nobuhiko Kanaya, Yoshihiko Kakiuchi, Kazuya Yasui, Satoru Kikuchi, Shinji Kuroda, Hiroshi Tazawa, Toshiyoshi Fujiwara. ChemoNETosis is associated with chemotherapy resistance in pancreatic 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 1371.
Abstract 5509: Mechanisms regulating resistance to KRAS inhibitor driven by DNp63/YAP regulation of tissue stiffness and metabolic alterations in lung adenocarcinoma
Authors: Santanu Adhikary, Marco Napoli, Suehelay Acevedo, Christina L. Carr, Jaden R. Baldwin, Nicole Hackel, Hitendra S. Solanki, Yaakov E. Stern, Laxmi Swetha Karanam, Duy T. Nguyen, Eric B. Haura, Elsa R. Flores
Journal: Cancer Research (2025)

Targeted therapies to the KRAS oncogene have shown significant success in treatment of lung adenocarcinoma (LuAD). Challenges emerge when tumors acquire resistance to these targeted KRAS inhibitors (KRASi). Recent studies have reported several mechanistic pathways associated with the development of resistance which includes nuclear localization of YAP. TP53 mutations are the predominant genetic changes responsible for inducing resistance to targeted therapies and chemotherapy drugs. Mutations in TP53 lead to the inhibition of the tumor and metastasis suppressor TAp63 and the activation of the oncogenic isoform ΔNp63. We have previously shown that loss of ΔNp63 in KRAS driven LuAD results in fewer tumors indicating an oncogenic role for ∆Np63 in LuAD. Here, we demonstrate that cells and tumors resistant to KRAS G12C inhibitors (KRASiR) exhibit increased expression of ∆Np63 while the sensitive cells express lower levels of ∆Np63. The KRASiR cells showed increased total and nuclear localization of YAP/TAZ along with increased expression of ∆Np63 in the nucleus. KRASiR resistant cells also had increased proliferation, mitochondrial membrane potential and mitochondrial fusion, promoting oxidative phosphorylation in KRASiR LUAD cells. We further found that ΔNp63 is crucial for driving resistance to KRAS G12C inhibitor in vivo using genetically engineered mouse models and patient derived xenografts. Therefore, ΔNp63 is an ideal target to overcome acquired resistance to KRAS inhibitors. Additionally, using atomic force microscopy (AFM), we found that KRASiR cells are stiffer, and that tissue stiffness regulated by YAP/∆Np63 can also result in KRASi resistance. ChIP-seq analysis for ∆Np63 and YAP bound targets are revealing the molecular basis of the mechanisms driving resistance to KRAS G12C inhibitors. Citation Format: Santanu Adhikary, Marco Napoli, Suehelay Acevedo, Christina L. Carr, Jaden R. Baldwin, Nicole Hackel, Hitendra S. Solanki, Yaakov E. Stern, Laxmi Swetha Karanam, Duy T. Nguyen, Eric B. Haura, Elsa R. Flores. Mechanisms regulating resistance to KRAS inhibitor driven by DNp63/YAP regulation of tissue stiffness and metabolic alterations in lung adenocarcinoma [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 5509.
Abstract 1048: Unraveling cancer disparities in African Americans: Socioeconomic, healthcare, and environmental contributions in UChicago and Baylor catchment areas
Authors: Ahmed Fadiel, Saleh Fadel, W. Butt, K.D. Eichenbaum, M. Abbasi, A. Elbialy, Kunle Odunsi
Journal: Cancer Research (2025)

Abstract Background: Cancer incidence rates are disproportionately high among African Americans for several cancers, including breast and prostate cancer. Reasons for these disparities may take root from a complex set of social, economic, and environmental factors. This study examines disparities in cancer incidence among African Americans between the University of Chicago and Baylor College of Medicine catchment areas, focusing on identifying modifiable factors. Methods: Data were obtained from SEER, CDC WONDER, ACS, and Policy Map. We used our intelligent Catchment Analysis Tool, or iCAT, to examine the incidence of cancers with demographic, socioeconomic, and healthcare utilization variables, environmental factors, pollution, and water quality. iCAT helped precisely delineate catchment areas to analyze referral patterns of hospitals and population density. Statistical analysis using multivariate logistic regression and spatial analysis enabled us to identify clusters of disparities. Data visualizations were developed to illustrate relationships, including geographic heatmaps and scatter plots. Results: Our findings demonstrated that cancer incidence rates were dependent on socioeconomic and environmental inequalities, with distinct differences in patterns at U. Chicago and Baylor catchment areas. Communities characterized by higher poverty levels, lower educational attainment, and limited access to healthcare showed increased cancer incidence rates. Environmental factors, especially air quality, further accentuated these disparities. Conclusions: The findings underscore the urgent need for multilevel interventions to target socioeconomic inequities, improve healthcare access, and reduce environmental risks to decrease the cancer burden among African Americans. This study provides a basis for working toward tailored public health strategies in the U. Chicago and Baylor catchment areas, contributing to health equity and improved cancer outcomes. Citation Format: Ahmed Fadiel, Saleh Fadel, W. Butt, K.D. Eichenbaum, M. Abbasi, A. Elbialy, Kunle Odunsi. Unraveling cancer disparities in African Americans: Socioeconomic, healthcare, and environmental contributions in 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 1048.
Abstract 1860: Development of novel AXL inhibitor-loaded PLGA nanoparticles for targeted therapy in triple negative breast cancer
Authors: Fatma Kazdal, Nermin Kahraman, Bulent Ozpolat
Journal: Cancer Research (2025)

Triple Negative Breast Cancer (TNBC) is the most aggressive and heterogeneous subtype of breast cancer with the highest mortality rates. TNBC is characterized by a lack of Estrogen (ER), PR, and HER2 receptors and currently, there is no effective targeted therapy for TNBC patients. AXL, a receptor tyrosine kinase (AXL-RTK), is overexpressed in TNBC cells and patient tumors and has been linked to poor prognosis. Despite its potential as a therapeutic target, there are currently no FDA-approved inhibitors for AXL in TNBC. In this study, we aimed to develop AXL- inhibitor-based targeted therapy and evaluate its therapeutic potential for TNBC using a PLGA (poly-lactic-co-glycolic acid)) nanoparticle delivery system. We formulated it into PLGA nanoparticles to improve bioavailability and enable targeted delivery to TNBC tumors. Various dosages of AXL inhibitor-loaded PLGA nanoparticles were tested on MDA-MB-231 and MDA-MB-436 human TNBC cell lines, and significant inhibition of cell growth and colony formation was observed, with a half-maximal inhibitory concentration (IC50) of 5 μM. The size and morphology of the nanoparticles were characterized using Atomic Force Microscopy (AFM) and Scanning Electron Microscopy (SEM), which revealed nanoparticle sizes ranging from 63-99.9 nm. Western blot analysis showed that the AXL inhibitor-loaded PLGA nanoparticles effectively inhibited AXL protein expression and its downstream signaling pathways, leading to superior anti-proliferative effects compared to free AXL inhibitors. These results suggest that AXL inhibitor-loaded PLGA nanoparticles offer a promising strategy for enhancing the therapeutic efficacy of AXL inhibitors in TNBC. In vivo, efficacy studies are currently underway to evaluate their potential for targeted therapy in both primary and metastatic TNBC models. Citation Format: Fatma Kazdal, Nermin Kahraman, Bulent Ozpolat. Development of novel AXL inhibitor-loaded PLGA nanoparticles for targeted therapy in 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 1860.
Abstract 5518: Targeting FAK by Ifebemtinib synergizes with Pan RAS inhibitors in treating RAS mutant cancers
Authors: Baoyuan Zhang, Ran Pang, Jiaming Gao, Jingwen Cheng, Ping Zhang, Natasha Qin, Leo Liu, Zaiqi Wang
Journal: Cancer Research (2025)

Pan-RAS inhibitors have been developed for the treatment of RAS-mutant cancers. Despite the challenges in achieving clinical benefits, targeting Pan-RAS represents a novel strategy for treating these previously considered untargetable malignancies. Previous studies have demonstrated that targeting FAK enhances the therapeutic efficacy of KRAS G12C inhibition in clinical settings, as hyperactivated FAK signaling is a major mechanism of acquired resistance following KRAS G12C inhibition. In the present study, we observed that Pan-RAS inhibitors can induce acquired hyperactivity of FAK, potentially rendering cancer cells resistant to Pan-RAS inhibition. Co-administration of a clinical-stage FAK inhibitor, Ifebemtinib (also known as Ifebe, IN10018), with RMC6236, a Pan-RAS inhibitor, exhibited synergistic cytotoxic effects in multiple RAS-mutant cancer cell lines. Furthermore, we evaluated the dual regimen in KRAS-mutant and NRAS-mutant animal models, where the combination therapy demonstrated superior tumor growth inhibition compared to monotherapy. Our previous findings indicated that FAK inhibition in conjunction with KRAS G12C/G12D inhibition enhances the anti-cancer effects of PD-1 blockade. Here, we confirmed that the combination of Ifebe and RMC6236 also augments the anti-tumor efficacy of PD-1 antibody therapy, suggesting that this treatment enhancement is independent of the specific RAS mutation type. In summary, our study reveals that the combination of FAK inhibitor Ifebe with Pan-RAS inhibitor exhibits synergistic anti-cancer effects and further improves the outcomes of PD-1 blockade therapy. These preclinical results support the need for further clinical investigation. Citation Format: Baoyuan Zhang, Ran Pang, Jiaming Gao, Jingwen Cheng, Ping Zhang, Natasha Qin, Leo Liu, Zaiqi Wang. Targeting FAK by Ifebemtinib synergizes with Pan RAS inhibitors in treating RAS mutant 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 5518.
Abstract 4324: Inhibition of ERK reactivation by FGTI-2734: A strategy to overcome sotorasib resistance in KRAS G12C lung cancer
Authors: Aslamuzzaman Kazi, Hitesh Kumar Kantilal Vasiyan, Deblina Ghosh, Dipankar Bandyopadhyay, Rachit D. Shah, Vignesh Vudatha, Jose Trevino, Said M. Sebti
Journal: Cancer Research (2025)

Abstract Discovery of sotorasib is a major breakthrough for KRAS G12C targeted therapies. However, overall response rates of patients with KRAS G12C lung cancer treated with sotorasib are modest due to resistance mediated by adaptive reactivation of ERK, which requires wild-type (WT) RAS membrane localization. In this study, we demonstrate that the dual farnesyltransferase (FT) and geranylgeranyltransferase-1 (GGT-1) inhibitor FGTI-2734 inhibits WT RAS membrane localization, and overcomes sotorasib adaptive resistance through inhibition of sotorasib-induced ERK feedback reactivation. The combination of FGTI-2734 and sotorasib is synergistic at inhibiting the viability and inducing apoptosis of lung cancer cell lines with KRAS G12C mutation, including those that are highly resistant to sotorasib. Anti-tumor activity of sotorasib is enhanced by FGTI-2734, leading to significant tumor regression of a patient-derived xenograft (PDX) from a KRAS G12C lung cancer patient as well as several xenografts from highly sotorasib-resistant KRAS G12C human lung cancer cells. Importantly, in vivo, FGTI-2734 inhibited sotorasib-induced ERK reactivation in the KRAS G12C PDX, and combinations of FGTI-2734 and sotorasib were also significantly more effective at suppressing the levels of P-ERK in sotorasib-resistant human KRAS G12C lung cancer xenografts. This study provides a rational strategy for overcoming sotorasib resistance in KRAS G12C lung cancer. Citation Format: Aslamuzzaman Kazi, Hitesh Kumar Kantilal Vasiyan, Deblina Ghosh, Dipankar Bandyopadhyay, Rachit D. Shah, Vignesh Vudatha, Jose Trevino, Said M. Sebti. Inhibition of ERK reactivation by FGTI-2734: A strategy to overcome sotorasib resistance in KRAS G12C lung 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 4324.
Abstract 5486: Bioluminescent assays for antibody-drug conjugate development: internalization and Fc-mediated functions
Authors: Julia K. Gilden, Christopher Eggers, Yitong Li, Rod Flemming, Nicholas Hess, Gopal B. Krishnan, Frank Fan, Brock Binkowski, Marjeta Uhr, Mei Cong
Journal: Cancer Research (2025)

Abstract Antibody-drug conjugates (ADCs) combine targeted delivery with potent cytotoxic payloads, utilizing multiple mechanisms of action (MoA). These include direct cytotoxicity following internalization of the ADC by antigen-expressing cells, killing of bystander cells through cleaved payloads, antigen function blockade, and immune-mediated cytotoxicity (e.g. Antibody-Dependent Cellular Cytotoxicity and Antibody-Dependent Cellular Phagocytosis) driven by the antibody Fc region. Comprehensive characterization and potency testing of ADCs require assays that capture each MoA. To address this need, we developed bioluminescent tools to streamline ADC evaluation, focusing on antibody internalization, Fc-mediated effector functions, and bystander killing. Studying bystander killing is particularly important in immunotherapy strategies for cancer, as it allows ADCs to target heterogenous tumors where not all cells express the antigen. The internalization assay employs luciferase-labeled Fab fragments with a quenching mechanism to measure intracellular antibody localization. The assay was validated using HER2-expressing SKOV3 cells with anti-HER2 monoclonal antibodies as model systems. It shows strong time- and antigen-dependent luminescence, achieving over 100-fold signal increases compared to controls, enabling quantitative ADC screening. Additional assays include Fc receptor (FcR) binding assays and cell-based reporter bioassays for ADCC and ADCP activities. The HiBiT technology is a luminescent tagging system that enables precise and sensitive detection of protein interactions and cellular events, making it a powerful tool for evaluating Target Cell Killing (TCK) by effectors and cytotoxic payloads carried by antibodies. To assess payload efficacy, a HiBiT-enabled bystander killing assay was developed, distinguishing ADCs with varying payload properties. Taken together, the internalization assay, bystander killing assay, and Fc effector bioassays, all based on bioluminescent platforms, offer a comprehensive and high-throughput solution for evaluating ADC functionality. With exceptional sensitivity, broad dynamic range, and efficient workflows, these tools enable precise optimization of therapeutic efficacy, delivering significant value for preclinical ADC development. Citation Format: Julia K. Gilden, Christopher Eggers, Yitong Li, Rod Flemming, Nicholas Hess, Gopal B. Krishnan, Frank Fan, Brock Binkowski, Marjeta Uhr, Mei Cong. Bioluminescent assays for antibody-drug conjugate development: internalization and Fc-mediated functions [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 5486.
Abstract 1693: Elraglusib (9-ING-41), a glycogen synthase kinase-3β inhibitor in combination with imipridones for treatment of solid cancer
Authors: Maryam Ghandali, None leiqing Zhang, Benedito A. Carneiro, Wafik S. El-Deiry
Journal: Cancer Research (2025)

Abstract Glycogen Synthase Kinase-3 (GSK-3) is a serine/threonine kinase with multiple biological roles, including cancer progression, therapeutic resistance and immune regulation. The GSK3β inhibitor elraglusib has shown promising preclinical and clinical activity in multiple tumor types. Previous studies demonstrated that GSK3 inhibitors can sensitize cancer cells to TRAIL-mediated apoptosis and downregulate the NF-κB pathway. Imipridones are a family of small molecule compounds that induce Death Receptor 5 and tumor necrosis factor (TNF)-related-apoptosis inducing ligand (TRAIL), causing cell death in multiple cancer models; the compounds can also inhibit the NF-κB pathway. We hypothesized that combining these two compounds would enhance anti-tumor activity. Ovarian, GBM, pancreatic, and colorectal cancer cell lines were treated with the novel drug combination of elraglusib and imipridone ONC206. CellTiter-Glo viability assays were performed after 72 hours to investigate the combinational treatment synergy. The combination treatment showed synergy in ovarian cancer (TOV21G, A2780, SKOV3), glioblastoma (SNB19, U251, LN229), pancreatic cancer (Capan-1), and colorectal cancer (HCT116) cell lines. In pancreatic and colorectal cancer cell lines, synergy was also investigated and observed between elraglusib and imipridone ONC212. Western blot analysis was performed to investigate the combinatorial effects. Single and combination treatments showed decreased expression of NF-κB p65 , anti-apoptotic proteins MCL-1 and survivin in cancer cells. Our ongoing studies are exploring other potential mechanisms of synergy and effects on immune-mediated killing of cancer cells. Our results show a potentially effective new combination of Elraglusib and Imipridones that can be further developed for cancer treatment. Citation Format: Maryam Ghandali, leiqing Zhang, Benedito A. Carneiro, Wafik S. El-Deiry. Elraglusib (9-ING-41), a glycogen synthase kinase-3β inhibitor in combination with imipridones for treatment of solid 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 1693.