tbuckley/cabot-search huggingface dataset:
Abstract 1382: The discovery of a novel antibody, 14G6, as a tool for understanding BAK conformational dynamics and their relationship to venetoclax response in leukemia
Authors: Michelle S. Miller, Hema P. Subas-Satish, Sweta Iyer, Melissa X. Shi, Agnes W. Wong, Karla C. Fischer, Ahmad Z. Wardak, Daisy Lio, Rachel T. Uren, Peter E. Czabotar, Ruth M. Kluck
Journal: Cancer Research (2025)

Abstract Venetoclax, a BCL2-specific inhibitor, is FDA-approved for the treatment of acute myeloid leukemia and chronic lymphocytic leukemia with varying patient responses. Conformation specific antibodies can help unravel the regulation of BCL2 family proteins and its relation to venetoclax response. We used mouse B cell cloning to identify 14G6, the first antibody that is specific for the non-activated, monomeric BAK conformation. The crystal structure of the 14G6 Fab bound to BAK revealed a binding site encompassing both the α1 helix and α5-α6 hinge regions of BAK, the two sites involved in the transition to the active, dimerisation-ready, conformation of BAK. This makes it a useful tool for determining the levels of non-activated, monomeric BAK in cancer cells by blue native PAGE. We found that 14G6 bound the majority of BAK in several leukemia cell lines, and binding decreased following treatment with venetoclax, indicating only minor levels of activated or sequestered BAK in those cells. 14G6 is thus an important new tool to assess BAK status in response to anti-cancer treatments and understand mechanisms of resistance to venetoclax, potentially aiding in the development of more reliable biomarkers to predict patient response. Citation Format: Michelle S. Miller, Hema P. Subas-Satish, Sweta Iyer, Melissa X. Shi, Agnes W. Wong, Karla C. Fischer, Ahmad Z. Wardak, Daisy Lio, Rachel T. Uren, Peter E. Czabotar, Ruth M. Kluck. The discovery of a novel antibody, 14G6, as a tool for understanding BAK conformational dynamics and their relationship to venetoclax response in leukemia [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 1382.
Abstract 6482: Phenoplex™ spatial analysis of whole-slide colon adenocarcinoma imaged with Orion™ 13-plex one-round staining and imaging
Authors: Regan Baird, Fabian Schneider, Edward Lo, Tad George, Joshua Nordberg
Journal: Cancer Research (2025)

Background: The ability to stain and image tissue at high-plex over an entire slide in a single round enables insights into tissue architecture and the molecular mechanisms of immune and disease processes at unprecedented throughput. Here we investigate a whole slide tissue section of high-grade colon adenocarcinoma, a hot tumor that contains prominent clusters of PD-L1 expression scattered throughout, using single-step high-plex staining and imaging at single-cell resolution followed by the analysis of single-cell phenotypes, tissue segmentation and spatial proximity and nearest neighbor analysis. Methods: A standard pathology slide was stained in one round with a 13-plex immune-oncology panel then a 21.7 x 18.5 mm area imaged in one round with the Orion™ spatial biology platform (RareCyte). The panel consisted of Hoechst/nucleus, autofluorescence, Ki-67, CD3e, CD4, CD163, CD8a, PD-L1, PD-1, FOXP3, CD68, CD20, Pan-CK, and Vimentin. Analysis was performed on the resulting OME.TIFF file with Phenoplex™ (Visiopharm) using the following pipeline: tissue segmentation into epithelial, necrotic and stromal regions of interest; cell segmentation using the Visiopharm Blueprint APP for DAPI nuclear detection; and phenotyping and spatial biodistribution analysis using the Guided Highplex Workflow. Results: Data revealed intricate architecture and cellular transitions as tumor cells express varying levels of PAN-CK, with a subset proliferating, and PD-L1 clusters within the lamina propria. Leukocyte clusters are seen interacting with PD-L1+ macrophages and, at higher zoom level, the proximity can be measured of infiltrating T and B cells near the tumor cells. A variety of spatial distance-metric analyses were performed. As an example, neighbor analysis within the stromal ROI showed that PD-L1+ macrophages had a different neighborhood of immune cells within their vicinity compared to PD-L1- macrophages. Conclusions: These data highlight the importance of sufficient plex, resolution and whole slide context to derive reliable spatial biomarkers of potential prognostic value. The ability to generate such rich data in just hours across a whole section with multiplexed biomarker quantitation makes this approach suited to multi-patient clinical studies. Deep-learning based image analysis enables deeper insights into the TME of cancer samples and enables researchers to robustly and accurately quantify and classify tissue samples to understand biology of disease. Citation Format: Regan Baird, Fabian Schneider, Edward Lo, Tad George, Joshua Nordberg. Phenoplex™ spatial analysis of whole-slide colon adenocarcinoma imaged with Orion™ 13-plex one-round staining and imaging [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 6482.
Abstract 5671: Development of HTS enzymatic assays for VPS4A and related ATPases
Authors: Anibal Ramos Martinez, Camdon Yemm, Ha Pham, Robert Lowery
Journal: Cancer Research (2025)

VSP4A and VSP4B (Vacuolar Sorting Protein) are members of the meiotic clade ATPases, which function as oligomers and use ATP hydrolysis to drive protein translocation through their central pore. VPS4B is frequently deleted in several cancers, and VPS4A has been shown to be synthetic lethal with VPS4B in cells and animals, causing cell death accompanied by induction of inflammatory cytokines and anti-tumor responses. To accelerate development of selective VPS4A inhibitors while avoiding off target effects with related ATPases, we are assembling a panel of high throughput biochemical assays using the Transcreener ADP2 assay for homogenous detection of ATPase activity with a far-red fluorescence polarization (FP) readout. Here we describe development of assays for VPS4A, VPS4B, as well as Spastin, Katanin and Fidgetin, related meiotic clade ATPases that play important roles in microtubule metabolism. Using purified recombinant enzymes, we established reaction conditions, determined kinetic parameters, and optimized the assays for initial velocity detection of ATPase activity with a Z’ value greater than 0.7, ensuring a sufficient signal window for inhibitor screening and dose response assays. We validated the VPS4A assay for HTS by screening a collection of bioactives (Tocris 2.0) and confirming two hits in dose response mode: BVT948, a PTP inhibitor, and polygodial, an antifungal that has been shown to inhibit a mitochondrial ATPase, both inhibited VPS4A and VPS4B with low micromolar potency. We then profiled BVT948 and polygodial for inhibition of Spastin, Katanin and Fidgetin: both molecules showed modest selectivity (2-5-fold) vs. Katanin and Fidgetin but had similar or greater potency for inhibition of Spastin. These assays will aid efforts to exploit the VPS4A/4B synthetic lethality therapeutically, including screening and SAR-driven hit-to-lead to minimize off-target effects with related ATPases. Citation Format: Anibal Ramos Martinez, Camdon Yemm, Ha Pham, Robert Lowery. Development of HTS enzymatic assays for VPS4A and related ATPases [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 5671.
Abstract 4023: ACCESS: Advancing childhood cancer experience, science and survivorship in Canada
Authors: Stephanie A. Grover, Christine J. Williams, Adrienne Co-Dyre, David Malkin, James A. Whitlock
Journal: Cancer Research (2025)

In Canada, roughly 1,500 children and adolescents are diagnosed with cancer each year. Advocacy for enhanced childhood cancer research and care in Canada by patients, families and the academic community led to a $23M investment through the Canadian Institutes of Health Research to establish a national pediatric cancer consortium (termed ‘ACCESS’). ACCESS’ mission is to ensure every child with cancer in Canada has access to the latest scientific advances, diagnostic tools, therapies, and supportive care leading to better outcomes and quality of life. ACCESS is a unique collective of scientists, healthcare providers, industry leaders, partner organizations, advocates, patients, and their families who are conducting research, changing policy, and developing new tools to ensure better lives for children who experience cancer in Canada and for their loved ones. The goal is to implement transformative change in the delivery of fair, fast, effective, and safe cancer care for all children. ACCESS is driven and led by people with lived experience of pediatric cancer and framed by the patient journey. To date, ACCESS has unified a national community. It has: connected a community of more than 750 people and stimulated a culture of open communication in which diverse viewpoints, including those of people with lived experience of cancer, are sought and valued; built productive and effective partnerships to connect and leverage the work of organizations working to improve childhood cancer; initiated more than 20 new innovative pan-Canadian research studies that impact all aspects of the patient journey, including new Canadian-led clinical trials; developed an educational hub for all ACCESS members, and produced accessible communications materials such as webinars, a newsletter and a comprehensive website; developed national best practice standards and tools for research and care; started to address the complex policy, regulatory and practical barriers that prevent equitable access to cancer diagnosis and treatment for all children in Canada. Future priorities include achieving organizational sustainability, supporting collaborations and inclusivity, overcoming barriers that affect the access of children to diagnostics and treatment, enhancing data connectivity and sharing, and developing and implementing a national strategy for pediatric cancer. Citation Format: Stephanie A. Grover, Christine J. Williams, Adrienne Co-Dyre, David Malkin, James A. Whitlock, on behalf of the ACCESS network. ACCESS: Advancing childhood cancer experience, science and survivorship in Canada [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 4023.
Abstract 1802: Exosomes-mediated oral gene delivery to treat lung cancer
Authors: Raghuram Kandimalla, Margaret Wallen, Disha N. Moholkar, Jeyaprakash Jeyabalan, Wendy Spencer, Farrukh Aqil, Ramesh C. Gupta
Journal: Cancer Research (2025)

Abstract Gene therapy is an emerging field in cancer therapeutics that targets specific proteins to control cancer cell proliferation. In recent years, several attempts to treat lung cancer using gene therapy have shown promise, but clinical translatability remains a significant challenge. Factors such as immunogenicity, toxicity, inflammatory responses, and cost-effectiveness hinder the widespread use of gene delivery vectors. Oral delivery of genes could potentially address these challenges; however, achieving therapeutic dosages at the targeted site is difficult due to the degradation of nucleic acids in the gastrointestinal tract before reaching systemic circulation. In the current study, we report a novel exosome-polyethyleneimine (PEI) matrix (EPM) for the oral delivery of nucleic acid therapeutics (siRNA) to treat lung cancer. Exosomes were isolated from bovine colostrum powder by rehydration and differential centrifugation. The tumor-targeting ligand folic acid (FA) was covalently attached to the exosome surface via click chemistry, while PEI was conjugated through ionic interaction to form FA-EPM. The siRNA entrapment efficiency by EPM was found to be more than 90% of the supplied siRNA (up to 20 μg). The transfection efficiency of EPM-siRNA was assessed in vitro via western blot analysis, determining KRAS and NRF2 knockdown in human lung cancer cells (A549). Results demonstrated that EPM-siKRAS and EPM-siNRF2 suppressed KRAS and NRF2 expression by 70-80% in A549 cells in a dose-dependent manner. The therapeutic efficacy of orally administered EPM-siNRF2 and FA-EPM-siKRAS was tested in subcutaneous and orthotopic lung tumor xenografts generated in nude and nod scid mice, respectively. The EPM-siNRF2 formulation inhibited subcutaneous lung tumor growth by 59% compared to control animals (p &amp;lt; 0.01), matching the tumor inhibition by the same formulation administered intravenously. Additionally, orally administered FA-EPM-siKRAS inhibited orthotopic lung tumor growth by 74% (p &amp;lt; 0.01) accompanied with &amp;gt;80% downregulation of the tumor KRAS expression level. This study demonstrated that colostrum exosome-based EPM technology effectively delivers siRNA to tumor sites when administered orally, achieving significant gene knockdown and lung tumor suppression. These findings suggest a simple and effective exosome-based oral gene delivery strategy for cancer therapeutics. Citation Format: Raghuram Kandimalla, Margaret Wallen, Disha N. Moholkar, Jeyaprakash Jeyabalan, Wendy Spencer, Farrukh Aqil, Ramesh C. Gupta. Exosomes-mediated oral gene delivery to treat 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 1802.
Abstract 4884: Reversing immune desertification for effective cancer therapy
Authors: Alessandra Araujo, Max Rodnick-Smith, Ranya Al-Khaledy, Mark Badeaux, Everett Stone
Journal: Cancer Research (2025)

Abstract Patients with tumors that have a “cold, or “immune desert” phenotype typically have poor outcomes on immune checkpoint therapy (ICT). Aberrant sphingosine-1-phosphate (S1P) signaling in tumors and in their draining lymph nodes (TDLN) appears to causes a common form of immune desertification by disabling or stalling lymphocyte egress from the TDLN, ultimately restricting immune trafficking to tumors. Clinically, tumor expression levels of the S1P producing enzyme sphingosine kinase 1 (SPHK1) strongly and negatively correlate with survival of patients after immune checkpoint inhibitor (ICI) therapy) and pre-clinically correlate with reduced tumor infiltrating lymphocytes (TILs). While there are five known S1P receptors (S1PR1-5), the expression of S1PR1 is required for lymphocyte egress from lymphatic organs. Abnormal S1P signaling or S1PR1 agonists functionally downregulate S1PR1 levels, trapping lymphocytes in the lymph node and is the mechanism of action of certain immunosuppressants (e.g., fingolimod) used to treat autoimmune diseases such as multiple sclerosis. In preliminary studies we have demonstrated in murine cancer models treated with pharmacologically optimized S1P degrading enzymes (SGPL1), that depleting extracellular S1P dramatically increases the trafficking of lymphocytes out of TDLNs, increases tumor T cell infiltration and strongly or completely inhibits tumor growth when administered as a single agent. Data from our lab suggests that deeply lowering extracellular S1P without eliminating internal stores of S1P needed for lymphatic egress is a powerful modality for increasing the level of S1PR1 on lymphocytes, releasing tumor specific T cells from TDLNs, and ultimately increasing tumor immune infiltration. Essentially the exact opposite mechanism as observed with immunosuppressants such as fingolimod. Current small molecule inhibitors of S1P production can only lower extracellular S1P levels by ∼ 50% via decreasing intracellular pools and only show limited anti-cancer activity. A cold tumor microenvironment is a common phenomenon that limits ICT efficacy and therapeutics that could enhance lymphocyte trafficking to the tumor would represent a significant advance for improving patient outcomes. Citation Format: Alessandra Araujo, Max Rodnick-Smith, Ranya Al-Khaledy, Mark Badeaux, Everett Stone. Reversing immune desertification for effective cancer therapy [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 4884.
Abstract 4903: Short chain per- and polyfluoroalkyl substances associate with elevated alanine aminotransferase: cross-sectional analysis results from the STRIVE cohort
Authors: Bojung Seo, Hongxu Wang, Rachel Maguire, Yukun Liu, Beatrice Smith, Kristin Haller, David Conti, Heinz-Josef Lenz, Antonio Planchart, Giorgio Roccaro, Lesley S. Miller, Andrew Muir, Susan K. Murphy, Andrew Moon, Melissa Troester, Cynthia A. Moylan, Joellen Schildkraut, Cathrine Hoyo, Jesse A. Goodrich
Journal: Cancer Research (2025)

Abstract Background: Although long chain, high molecular weight per- and polyfluoroalkyl substances (PFAS) (≥8 and ≥6 carbons for carboxylic and sulfonic acids; molecular weight &amp;gt;400 g/mol) have been associated with elevated ALT, the association of short chain, low molecular weight PFAS with elevated ALT or cirrhosis, a risk factor for hepatocellular carcinoma, remains unclear. Objectives: To examine associations of short or long chain PFAS mixtures with elevated ALT or cirrhosis and baseline factors related to PFAS. Methods: We included 349 adults aged 40-75 years from the Southern Liver Health Study (STRIVE), an ongoing longitudinal observational study. At enrollment, 135 out of 196 participants had a confirmed diagnosis of cirrhosis. We used logistic regression to examine associations between individual PFAS serum levels and elevated ALT or cirrhosis, at baseline. Quantile g-computation was used to test the associations of short or long chain PFAS mixtures with the outcomes. Linear regression examined baseline factors associated with PFAS. Results: Increasing all short chain PFAS by one quartile was associated with higher odds of elevated ALT (odds ratio: 2.20 [1.32-3.67]); no association was observed with the long chain PFAS mixture. Perfluoroheptanoate, a short-chain PFAS, was associated with both elevated ALT and cirrhosis (odds ratios: 1.53 [1.01-2.33]; 1.51 [1.01-2.27], respectively) at unadjusted P. Long chain PFAS were higher in males and linked to higher reported levels of alcohol consumption. Both long and short chain PFAS were lower in bottled water users, non-water drinkers, and current smokers compared. Perfluoropentanoic acid, a short chain PFAS, was higher in females. Conclusions: In the STRIVE cohort, higher short-chain PFAS mixture concentrations were significantly associated with elevated ALT and varied by sex and lifestyle behaviors. Citation Format: Bojung Seo, Hongxu Wang, Rachel Maguire, Yukun Liu, Beatrice Smith, Kristin Haller, David Conti, Heinz-Josef Lenz, Antonio Planchart, Giorgio Roccaro, Lesley S. Miller, Andrew Muir, Susan K. Murphy, Andrew Moon, Melissa Troester, Cynthia A. Moylan, Joellen Schildkraut, Cathrine Hoyo, Jesse A. Goodrich. Short chain per- and polyfluoroalkyl substances associate with elevated alanine aminotransferase: cross-sectional analysis results from the STRIVE cohort [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 4903.
Abstract 6850: A new syngeneic lung cancer model with KRAS and LKB double mutations for evaluating the efficacy of combined KRAS mutation targeted therapy and immunotherapy
Authors: Lei Ci, Derek Reznik, Kai Zhou, Minghui Sun, Yi Li, Qin Huang, Ruilin Sun
Journal: Cancer Research (2025)

Abstract Background: Lung cancer, particularly non-small cell lung cancer (NSCLC), remains the leading cause of cancer-related deaths globally. Genetically engineered mouse models are vital for replicating the genetic and histopathological characteristics of NSCLC, enabling precise manipulation of tumor suppressors and oncogenes. These models facilitate the development of autochthonous tumors within their natural tissue environment. Mutations in LKB1 and KRAS, which frequently co-occur, are associated with resistance to immune checkpoint inhibitors (ICIs) in NSCLC. However, challenges in detecting and quantifying spontaneous lung tumors in mouse models persist. Therefore, there is a critical need for preclinical models with intact immune systems that allow for effective detection and quantification of spontaneous lung cancers. Such models are essential for evaluating the efficacy of therapies targeting KRAS and LKB1 double-mutant NSCLC. Methods: We developed a novel mouse model (KLL mouse) on the C57BL/6 background, incorporating the KRAS(G12D) mutation, LKB1 deficiency, and firefly luciferase expression. Spontaneous lung cancer was initiated via intranasal delivery of an adeno-associated virus (AAV)-based Cre recombinase system. Tumor progression was monitored longitudinally using micro-CT imaging. From this model, we derived the 279# tumor cell line from spontaneous lung tumors in one mouse (279#). This cell line was used to establish both subcutaneous and orthotopic lung tumor models for therapeutic efficacy studies. Conclusion: We successfully established a comprehensive preclinical platform for studying NSCLC with KRAS and LKB1 dual mutations. This platform includes a spontaneous lung cancer mouse model, a derived KLL cell line, and associated subcutaneous and orthotopic tumor models. These resources provide valuable tools for investigating optimal treatment strategies for NSCLC, particularly the combination of targeted therapies and immunotherapies. Citation Format: Lei Ci, Derek Reznik, Kai Zhou, Minghui Sun, Yi Li, Qin Huang, Ruilin Sun. A new syngeneic lung cancer model with KRAS and LKB double mutations for evaluating the efficacy of combined KRAS mutation targeted therapy and immunotherapy [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 6850.