tbuckley/cabot-search huggingface dataset:
Abstract 5967: Real-world outcomes of renal cell carcinoma and intracranial metastatic disease
Authors: Madison Sherman, Karim Hafazalla, Arjun Sahgal, Georg Bjarnason, Sunit Das
Journal: Cancer Research (2025)

Introduction: Intracranial metastatic disease (IMD) is a serious complication of renal cell carcinoma (RCC). However, large-scale data on its clinical characteristics, survival outcomes, and treatment strategies are limited, especially at the population level. Objective: To examine the clinical features, survival outcomes, and treatment patterns of RCC patients with IMD in Ontario, Canada, and provide insights to optimize patient management. Methods: This population-based retrospective cohort study included RCC patients diagnosed between 2010 and 2019 in Ontario. Demographics, treatments, and survival data were obtained from provincial healthcare records. Kaplan-Meier and Cox regression analyses assessed overall survival (OS). Propensity score matching (PSM) was used to compare survival outcomes between treatment groups. Results: Among 13,353 RCC patients (mean age: 62 years), 4.6% developed IMD (71% metachronous, 29% synchronous), with a median time to IMD of 8.3 months [Interquartile Range: 1.3, 25.6]. Median OS was significantly shorter for patients with IMD (20.9 months) versus those without IMD (125.4 months; p &amp;lt; 0.001). Synchronous IMD (HR: 2.58) was linked to worse OS. Those without metastases at diagnosis had the longest OS (127.0 months), compared to patients with extracranial metastases alone (13.6 months; HR: 6.89) or synchronous IMD (4.8 months; HR: 14.71). Patients with stage 4 disease at diagnosis who developed metachronous IMD had better OS than those who never developed IMD (17.7 vs. 12.0 months). In patients with IMD, systemic therapy was associated with improved survival (HR: 0.47). Stereotactic radiosurgery (SRS) and/or neurosurgery was associated with improved survival, compared to whole-brain radiotherapy (WBRT) or no IMD-directed treatment (HR: 0.47). Propensity-matched analyses showed that receipt of SRS/neurosurgery was associated with improved OS, compared to WBRT or no IMD-directed treatment (25.9 vs. 13.1 months; HR: 0.55). Conclusion: This study provides large-scale, population-based insights into the impact of IMD in RCC. Our findings show that SRS/neurosurgery is protective in all subgroups of RCC patients with IMD, informing clinical decision-making and offering valuable guidance for optimizing patient outcomes and resource allocation. Additionally, these findings highlight the need for routine brain imaging in RCC to enable early detection and improve management strategies. Citation Format: Madison Sherman, Karim Hafazalla, Arjun Sahgal, Georg Bjarnason, Sunit Das. Real-world outcomes of renal cell carcinoma and intracranial metastatic disease [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 5967.
Abstract 1380: Role of cytokine-induced cell death on efficacy of teclistamab-mediated T cell killing of multiple myeloma cells
Authors: Allison Carr, Adrian Ting
Journal: Cancer Research (2025)

Abstract Multiple myeloma (MM) is the second most common hematologic malignancy among US adults, characterized by high rates of relapse and refractory disease. Anti-Myeloma T cell immunotherapies, such as chimeric antigen receptors (CAR-Ts) and bispecific T cell engagers (BiTEs), have been able to induce deep responses in the clinic and extending survival for many. However, even these responses are not durable and majority of patients still relapse. MM cell signaling in response to cytokines released by these T cells, such as Tumor Necrosis Factor (TNF) Alpha, and Interferon gamma (IFNγ), may offer additional insight into mechanisms of relapse and resistance as well as avenues of therapeutic manipulation. To evaluate the effects of TNF and IFNγ on MM cell death and proliferation, we obtained human MM cell lines (MMCLs) and stably transduced them with a GFP-NLS reporter. We then monitored these cell lines in the presence of TNF, IFNγ, or TNF+IFNγ and tracked their cell death and growth kinetics over time using DiYO-3 incorporation and GFP count, respectively, via IncuCyteS3 live cell imaging. We next utilized Teclistamab, a B cell maturation antigen (BCMA)-directed BiTE, to co-culture MMCLs with healthy donor derived T cells at various effector to target (E:T) ratios and monitored for T cell mediated death again via IncuCyteS3 live cell imaging. While all MMCLs were able to be killed at high E:T ratios (1:1), only cytokine-sensitive lines remained susceptible to T cell killing at lower E:T ratios (1:10). The addition of TNF and/or IFNγ blocking antibodies confirmed that the increased sensitivity of these lines to T cell killing was indeed mediated by the two cytokines. In summary, were able to show an in vitro model of differential MM cell response to Teclistamab mediated T cell killing, and that this difference in response was predicated on the MM cells’ baseline sensitivity to cytokine mediated cell death via TNF and IFNγ. Thus, further dissecting mechanisms underlying resistance or sensitivity of MM cells to cytokine induced death could suggest therapeutic targets with the potential to enhance the efficacy of anti-MM T cell immunotherapies. Citation Format: Allison Carr, Adrian Ting. Role of cytokine-induced cell death on efficacy of teclistamab-mediated T cell killing of multiple myeloma 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 1380.
Abstract 2495: Does single-cell gene expression reflect RNA abundance?
Authors: Christie Jay Lau, Liliane Cabral-Fernandes, Yadong Wang, Sumaiyah K. Rehman, Geoffrey Liu, Catherine A. O'Brien, Gregory W. Schwartz
Journal: Cancer Research (2025)

Abstract Transcriptional dysregulation is a hallmark of cancer that is often studied using single-cell RNA sequencing (scRNA-seq) to capture the transcriptomic profile of individual cells. However, these measurements are not directly representative of gene expression levels due to biased transcript detection which can lead to dramatic misinterpretations of the underlying biology. To demonstrate this phenomenon, we profiled baseline and drug-tolerant persister cells from a patient-derived colorectal cancer xenograft model. Although persister cells are known to be globally hypotranscriptive and exhibit lower total RNA and housekeeping expression by cell number-normalized (CNN) quantitative PCR (qPCR), significantly more transcripts and genes were detected by single-nuclei RNA-seq as compared to baseline. Additionally, we identified this trend in two independent lung adenocarcinoma persister scRNA-seq experiments and noticed an association with higher sequencing read depth per transcript. In all three cases, transcript over-detection could not be ameliorated through filtering, read subsampling, batch correction, or normalizations specifically developed to address read depth bias. As such, we developed a novel computational approach to correct the effects of sequencing read depth bias on scRNA-seq data and recover the relative expression of cells across samples. To benchmark the validity of our approach, we identified five genes predicted to be significantly upregulated from raw and conventionally-normalized counts but downregulated from our depth-normalized counts. Using CNN qPCR, we found decreased abundance of all five targets in colorectal cancer persister cells, in agreement with the depth-normalized analysis approach and results. Beyond the context of persister models, we also examined single-cell ATAC+RNA-seq and spatial transcriptomic data from lymphoma and prostate cancer specimens and demonstrate how depth normalization can be helpful for addressing technical anomalies, such as transcript under-detection due to tissue edge effects. Altogether, sequencing read depth normalization allows us to move beyond the current approach of scaling all cells to the same expression level and achieve more biologically accurate inference from scRNA-seq data. Citation Format: Christie Jay Lau, 1 Liliane Cabral-Fernandes, 1 Yadong Wang, 2 Sumaiyah K. Rehman, 2 Geoffrey Liu, 2 Catherine A. O'Brien, 2 Gregory W. Schwartz2. Does single-cell gene expression reflect RNA abundance [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 2495.
Abstract 6888: Targeting melanoma cells through G-quadruplex formation: mechanism and enhanced efficacy of T-oligo in combination therapy
Authors: Rose Bahari, Stephanie M. Lopez, Archit Agnihotri, Hyatt Alaraj, Lawrence Miller, Neelu Puri
Journal: Cancer Research (2025)

Abstract Melanoma is one of the deadliest skin cancers in the world, estimated to cause 7, 990 deaths annually. Telomerase binds to the 3' overhang of the telomere, causing telomere elongation and cell survival. Treatment against melanoma aims at targeting the 3' telomere overhang using T-oligo, which is a guanine-rich oligonucleotide homologous to the telomere overhang, preventing the growth of melanoma cells by inducing apoptosis. As a guanine-rich oligonucleotide, T-oligo can form G-quadruplexes (G4), secondary structures of nucleic acids, which we aim to detect using FRET microscopy in melanoma cells. Currently, vemurafenib and trametinib are agents that are used to treat melanoma. We were also interested in studying the combinational treatment of T-oligo with vemurafenib/trametinib to determine if it improves the efficacy of these drugs as compared to monotherapy in melanoma cells. We hypothesize that T-oligo forms G-quadruplexes in the nucleus of melanoma cells, and combination therapy of vemurafenib/Trametinib with T-oligo would be efficacious compared to monotherapy. Citation Format: Rose Bahari, Stephanie M. Lopez, Archit Agnihotri, Hyatt Alaraj, Lawrence Miller, Neelu Puri. Targeting melanoma cells through G-quadruplex formation: mechanism and enhanced efficacy of T-oligo in combination 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 6888.
Abstract 4771: A novel immunotherapy for metastatic prostate cancer: A monoclonal antibody that can bind both STEAP1 and STEAP2
Authors: Minzhi Sheng, Boyang Su, Amanda Sparkes, Gobi Thillainadesan, Esther Matus, Jessica Wright, Stanley Liu, Jean Gariepy, Hon S. Leong
Journal: Cancer Research (2025)

Prostate cancer (PCa) is the most common cancer among Canadian men, with metastatic PCa (mPCa) patients having a 5-year survival rate of only 30%. However, the prostate-specific membrane antigen, a key target in PCa therapy, is expressed in many normal tissues and shows heterogeneity among PCa patients. Recently, Six Transmembrane Epithelial Antigens of the Prostate 1 and 2 (STEAP1 and STEAP2) have gained attention as promising therapeutic targets due to their high expression in most PCa cases compared to normal tissues and essential organs. This study aimed to develop a novel immunotherapy targeting STEAP1/2 to elicit PCa-specific immune responses in cellular and animal mPCa models. Monoclonal antibodies were generated against the extracellular region of STEAP1, which shares 60% sequence similarity with STEAP2 but has minimal homology with other human proteins. The specificity and binding strength of these antibodies were validated through techniques such as immunofluorescence, flow cytometry, immunoprecipitation, and ELISA. Results from immunofluorescence and flow cytometry using STEAP1 overexpression and knockdown PCa cell lines demonstrated the specificity of certain clones for human STEAP1. Furthermore, one antibody clone successfully pulled down STEAP2 in immunoprecipitation-mass spectrometry experiments and showed binding to STEAP2 in cell lines overexpressing the antigen. ELISA results revealed binding affinities in the low nanomolar range for STEAP1 and the low micromolar range for STEAP2.These findings highlight the potential of the monoclonal STEAP1/2 antibody developed in this study, providing a promising platform for future immunotherapy strategies and expanding treatment options for mPCa patients. Citation Format: Minzhi Sheng, Boyang Su, Amanda Sparkes, Gobi Thillainadesan, Esther Matus, Jessica Wright, Stanley Liu, Jean Gariepy, Hon S. Leong. A novel immunotherapy for metastatic prostate cancer: A monoclonal antibody that can bind both STEAP1 and STEAP2 [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 4771.
Abstract 4052: Biological Variations in NRF2 Hotspot Mutants
Authors: Syed A. Ashraf, Anh Thi Thai, Jinghai Wu, McKenzie Kreamer, Katarina Benejova, Terry M. Williams, Martin Benej, Ioanna Papandreou, Nicholas C. Denko
Journal: Cancer Research (2025)

Abstract Background: NRF2 is a transcription factor that is a master regulator for the cell’s antioxidant response. Under normal conditions, NRF2 is rapidly degraded by cytoplasmic association with KEAP1 and subsequent ubiquitination and proteasomal degradation. Activating mutations in NRF2 contribute to lung cancer transformation. D29H, R34G, and E79Q are the most common mutations found in lung squamous cell carcinoma. Methods: H520 lung cancer cells harbor an intact NRF2/KEAP system. H520 mutant cell lines were generated using lentivirus transduction of either WT or mutant NRF2 and confirmed by Western blot. Immunofluorescence was used to examine the effect of mutations on NRF2 levels and subcellular localization. Cells were tested for ROS levels by DCFFA fluorescence and subcellular NRF2 localization before and after treatment with tert-butyl hydroperoxide. Colony forming ability was tested after radiation with 0, 2, 4, or 6 Gy. Results: D29H and R34G mutations result in increased NRF2 levels and stress-independent translocation to the nucleus compared to wild type NRF2. These mutant cells also showed higher expression of the NRF2 target gene G6PD. E79Q has little difference compared to wild type. All mutants showed decreased DCF fluorescence. With regards to colony formation ability, mutant cell lines were not statistically different from WT cells. Conclusion: Our findings identified D29H and R34G as having increased nuclear levels and transactivation compared to WT cells. Despite the increased activity of NRF2 in these two mutations, there was little evidence for increased radiation resistance. These results indicate differential biological response of common NRF2 mutations. Citation Format: Syed A. Ashraf, Anh Thi Thai, Jinghai Wu, McKenzie Kreamer, Katarina Benejova, Terry M. Williams, Martin Benej, Ioanna Papandreou, Nicholas C. Denko. Biological Variations in NRF2 Hotspot Mutants [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 4052.
Abstract 1776: Investigation into the enhancement of 20S proteasome-mediated proteolysis as a therapeutic for HPV-associated cervical cancer
Authors: Shannon M. Cartwright, Linh Le, Kate Hartnett, Jetze J. Tepe
Journal: Cancer Research (2025)

Abstract Human papillomaviruses (HPVs) are one of the most common sexually transmitted infections (STIs) in the world. HPVs can be divided into two main categories, low-risk and high-risk. Low-risk HPVs do not cause cancer and can often be cleared by the infected person’s immune system. However, high-risk HPVs are responsible for approximately 5% of cancers worldwide - most commonly cervical cancer, and there is currently no cure once infection occurs. While prophylactic vaccines exist that can successfully prevent the infection of many high-risk HPVs, vaccination rates worldwide are low. After infection, the virus incorporates its genome into the host cell genome, and the cell begins to produce HPV proteins. In high-risk HPVs, two of these proteins, HPV E6 and E7, are oncoproteins with partially disordered structures. E6 and E7 proteins have many functions impacting cancer development, including inducing the degradation of tumor suppressor proteins p52 and pRB, respectively, through the ubiquitin-26S proteasome system (UPS). The removal of these cell cycle progression checkpoints allows for uncontrolled cell growth, which can promote cancer. The Tepe lab works on the development of small molecules which can increase the protein degradation capacity of the 20S proteasome, a protease that specifically degrades disordered proteins in a ubiquitin-independent manner. This project works to establish if the 20S proteasome can degrade HPV E6 and E7 proteins, and if the use of 20S proteasome enhancing small molecules can deplete levels in HPV+ cervical cancer cells. We have discovered that treatment with two of these compounds decreases E6 and E7 levels in a HPV18+ cervical cancer cell line and work is ongoing to determine if this impact is through 20S proteasome activation. Additionally, we are investigating if this decrease is enough to inhibit the out-of-control cell growth caused by E6 and E7. The goal of this project is to understand if 20S proteasome activators can be used as a therapy for HPV-mediated cervical cancer. Citation Format: Shannon M. Cartwright, Linh Le, Kate Hartnett, Jetze J. Tepe. Investigation into the enhancement of 20S proteasome-mediated proteolysis as a therapeutic for HPV-associated cervical 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 1776.
Abstract 2498: PharmaRonNet: integrating multi-omics data to reveal key biological pathways
Authors: Kaiqiang Hu, Wanyu Tao, Yunyang Zhang, Pengwei Pan, Fang He
Journal: Cancer Research (2025)

Abstract In this study, we present PharmaRonNet, a new bioinformatics tool based on the ResponseNet algorithm. PharmaRonNet constructs weighted networks from either single-omics or multi-omics data, revealing key pathways and mediators involved in specific biological or pathological processes. To validate PharmaRonNet’s functionality, a case study was conducted using a public transcriptomics dataset of the liver cancer cell line HepG2 treated with insulin. PharmaRonNet successfully identified several insulin-response-related genes as key factors, outperforming standard methods such as differentially expressed genes (DEGs) analysis and other gene network-building tools. Subsequently, PharmaRonNet was used to investigate the mechanisms leading to resistance to the selective CDK4/6 inhibitor, Palbociclib, in hormone receptor (HR)-positive breast cancer. With WES, transcriptome, and proteome data from the Palbociclib-resistant MCF7 breast cancer cell line, PharmaRonNet revealed the involvement of tyrosine phosphorylation and cyclic nucleotide-mediated signaling along with cell growth regulation. Within these pathways, certain "core" genes were identified with the most linkages within the PharmaRonNet. Synergy effect tests were then performed to validate the roles of these key factors in mediating Palbociclib resistance. Overall, PharmaRonNet helps link different layers of omics data, enabling the discovery of hidden mechanisms often overlooked by canonical bioinformatics analysis, and enhancing our understanding of complex biological phenomena. These insights pave the way for developing novel strategies to combat drug resistance in cancers. Citation Format: Kaiqiang Hu, Wanyu Tao, Yunyang Zhang, Pengwei Pan, Fang He. PharmaRonNet: integrating multi-omics data to reveal key biological pathways [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 2498.
Abstract 6471: Spatial multiomics reveals T-cell activation and exhaustion states in the tumor microenvironment
Authors: Steve Zhou, Yifan Wang, Debia Wakhloo, Anushka Dikshit, Li-Chong Wang, Maithreyan Srinivasan
Journal: Cancer Research (2025)

Abstract Spatial Multiomics allows for context-based study of the tumor microenvironment (TME). TME consists of diverse cells that collectively influence tumor progression, therapeutic response, and immune activation. CD8 T-cells, essential for antitumor immunity, often become exhausted in the TME. Recent studies show that PD1+ TCF1+ stem-like CD8 T-cells retain differentiation potential and can be rejuvenated through cytokine signaling and immune checkpoint modulation. This detailed spatial profiling of RNA and protein expression in the TME is crucial to understanding immune cell function, activation, and differentiation. Here we introduce a protease-free workflow for RNAscope™ Multiplex Fluorescent v2 assay combining RNA in-situ hybridization (ISH) and protein immunofluorescence to study cell marker proteins (CD8, PD1) with RNA targets (TNFA, TCF7, IFNG) in a tumor microarray (TMA). The Manual Multiplex Protease-Free workflow enables simultaneous RNA and protein visualization without enzymatic disruption, preserving antigen integrity and tissue morphology. Using this Multiomics assay we can study CD8 T-cell differentiation and activation. Co-detection of TNFA, TCF7, and IFNG transcripts with CD8 and PD1 proteins provides insights into specific T cell phenotypes and their activation/exhaustion status. Data reveal robust co-expression patterns of these targets, particularly in the tumor-cell neighboring stromal and immune cells in breast, cervical and stomach cancers, reflecting immune activation and exhaustion across distinct TME niches. This methodology lays a foundation for refining immunotherapeutic strategies targeting PD1+ TCF7+ CD8 T-cells, enhancing effector functions, and advancing precision oncology interventions. Citation Format: Steve Zhou, Yifan Wang, Debia Wakhloo, Anushka Dikshit, Li-Chong Wang, Maithreyan Srinivasan. Spatial multiomics reveals T-cell activation and exhaustion states in the tumor microenvironment [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 6471.