tbuckley/cabot-search huggingface dataset:
Abstract 6308: Dory: a computational method for differential chromatin tracing analysis
Authors: Zhaoxia Ma, Miao Liu, Mengwei Hu, Shengyuan Wang, Siyuan Wang, Chongzhi Zang
Journal: Cancer Research (2025)

Abstract The spatial organization of the genome plays a vital role in maintaining the cell type-specific chromatin structures and regulating gene expression. The three-dimensional (3D) genome structures can be measured by sequencing-based techniques such as Hi-C on the ensemble level or by imaging-based techniques such as chromatin tracing on the single-molecule level. Chromatin tracing is a multiplexed DNA fluorescence in situ hybridization (FISH) technique that can directly trace the 3D positions of genomic loci along individual chromosomes in single cells. By designing the primary probes targeting specific genomic regions and dye-labeled secondary probes to indicate their positions, chromatin tracing can construct the 3D trace of chromatin at high resolution using microscopy. However, few computational tools have been developed for differential analysis of chromatin tracing data. Major challenges include the high variability of chromatin traces and missing values in the 3D coordinates of some loci. Here, we present Dory, a statistical method for identifying differential patterns from two groups of chromatin traces without imputation of missing data. Dory measures the spatial distance between each pair of regions in each chromatin trace and employs multi-level statistical tests to quantify the distance difference between the two groups of chromatin traces. The output of Dory includes the differential score for each region pair comparing chromatin traces between two biological conditions. We applied Dory to chromatin tracing data from six cell types in mouse fetal liver and from a mouse lung cancer progression model. We found that the changes in chromatin structure are associated with A-B compartment alterations and promoter-enhancer interaction alterations that cause differential gene expression. Dory is a user-friendly computational tool that can be applied to multiple types of imaging-based 3D genome data analysis for studying genome functions and gene regulation. Citation Format: Zhaoxia Ma, Miao Liu, Mengwei Hu, Shengyuan Wang, Siyuan Wang, Chongzhi Zang. Dory: a computational method for differential chromatin tracing analysis [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 6308.
Abstract 6293: Developing and deploying the UCSC Xena gene set enrichment analysis appyter
Authors: Cally Lin, Jingchun Zhu, Mary Goldman
Journal: Cancer Research (2025)

Abstract UCSC Xena (https://xena.ucsc.edu) is a popular web-based visual integration and exploration tool for multiomic data and associated clinical and phenotypic annotations. Xena users want to be able to run Gene Set Enrichment Analysis (GSEA) to compare gene expression between their two dynamically created sample subgroups and determine which gene programs are upregulated or downregulated. However, the traditional GSEA implementation was not performant enough to support Xena’s interactive web-based data visualizations. To overcome this challenge, blitzGSEA, a more performant implementation of GSEA developed in 2022 by the Ma’ayan Lab at Mount Sinai, was integrated to be available within the Xena browser using the Appyter framework, a tool also developed by the Ma’ayan lab. Appyter allows users to use Jupyter Notebooks to run bioinformatic methods without having to interact with the code directly and also allows developers to dynamically code inputs, such as the subgroups created by a user. The framework handles users running analyses concurrently and will cache results if two users run the same analysis, such as part of a workshop. Before development, blitzGSEA was rigorously compared to traditional GSEA to confirm that it provided similar, biologically consistent results with efficient memory usage and runtime. The blitzGSEA Appyter was implemented alongside the addition of a Plotly Dash page to provide users with interactive plots and tables of the analysis results. The blitzGSEA Appyter was then deployed on the production Xena Browser using Docker and an AWS EC2 instance. The blitzGSEA Appyter is now publicly available to Xena users for any sample subgroups they create and averages 500 analyses per month around the world. Citation Format: Cally Lin, Jingchun Zhu, Mary Goldman. Developing and deploying the UCSC Xena gene set enrichment analysis appyter [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 6293.
Abstract 1862: Biomimetic poly lactic acid based nanoparticles for tumor targeted delivery of chemotherapeutic drugs
Authors: Harshdeep Kaur, Harpal Singh
Journal: Cancer Research (2025)

Abstract Global cancer burden is increasing day by day and to mitigate this situation, chemotherapy is widely used as systemic treatment modality. Along with many pros, chemotherapy does have various cons such as: systemic toxicity, faster degradation in physiological conditions hence low bioavailability and poor tumor accumulation. To overcome these shortcomings, nano-drug delivery systems are used. The nanoparticles can be tailor made according to physiological conditions of the tumor microenvironment. Herein, the redox responsive polymer has been synthesized by introducing the disulphide linkage in the polymer. The chemo-drug Pirarubicin has been encapsulated by double emulsion method in the nanoparticles prepared with redox-responsive polymer. The drug release profile indicated the release of the drug is more efficient in presence of 10mM Dithiothreitol (reducing agent for disulphide linkage) when compared to 0mM dithiothreitol, hence suggesting the successful synthesis of stimulus responsive drug delivery system. In this context, this study investigates the therapeutic efficacy of Pirarubicin encapsulated in polylactic acid based redox responsive nanoparticle(NP) whose surface have been modified with tumor and macrophage cell membranes. The coated cell membrane provides advantages such as immune escape, long blood circulation time, specific molecular recognition and tumor cell targeting. The prepared nanoparticles have a hydrodynamic size in nano-range with high negative zeta potential. The cellular internalization studies of free drug vs the cell membrane coated NPs (CMNPs) were done and it was confirmed with fluorescence microscopy as well as flow cytometry that CMNPs were internalized more efficiently in one hour drug incubation study. The same was confirmed when cancer cell proliferation inhibition assay was done, and half maximal inhibitory concentration was highest in case of uncoated NP, then that of free a drug, and lowest in case of CMNPs. This study provides the synthesis and characterization of redox responsive polymer, preparation of cell membrane coated nanoparticles and in-vitro studies for the same. This study has a future scope in the field of personalized medicine at much cheaper price when compared to active targeting methods by antibodies, CART, proteins etc. Citation Format: Harshdeep Kaur, Harpal Singh. Biomimetic poly lactic acid based nanoparticles for tumor targeted delivery of chemotherapeutic drugs [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 1862.
Abstract 1746: FGFR3 inhibition is a highly effective therapy in MTAP-deficient, FGFR3 altered urothelial carcinoma
Authors: Yu-Yi Chu, Jianfeng Chen, Cindy Y. Jiang, Ying Mei, Yuxue Zhang, Arlene Siefker-Radtke, Jianjun Gao
Journal: Cancer Research (2025)

Abstract FGFR3 alterations are observed in more than 15% of metastatic urothelial cancers. In 2019, erdafitinib was the first FGFR inhibitor approved by the FDA for treatment of FGFR3-altered metastatic urothelial cancer with an objective response rate of 40%. However, a high percentage of patients with FGFR3 alterations still do not respond to erdafitinib. Thus, it is critical to identify additional biomarkers to stratify patients and increase the therapeutic efficacy of FGFR inhibitors. Our previous study identified that FGFR3 was more frequently altered in methylthioadenosine phosphorylase (MTAP)-deficient tumors (MTAP-deficient: 31% vs MTAP-proficient: 8%), which raises our interest to investigate whether MTAP deficiency leads to enhanced dependency on FGFR3 activity and increases tumor treatment response to FGFR inhibitors. Here, we report that IC50 of FGFR inhibitors is significantly lower in MTAP-deficient tumors compared to MTAP-proficient tumors. Notably, an MTAP enzyme, which was developed to deplete its substrate, MTA [a known inhibitor of protein arginine methyltransferase 5 (PRMT5)], significantly increases the PRMT5 activity and results in resistance to FGFR inhibitors in MTAP-deficient tumors. Moreover, our data demonstrate that PRMT5 inhibition sensitizes MTAP-proficient tumors to FGFR inhibitors, suggesting that inhibition of PRMT5 activity by MTA contributes to tumor response to FGFR inhibitors in MTAP-deficient tumors. Taken together, our current findings suggest that: 1) MTAP deficiency could serve as a rational biomarker to predict response of FGFR inhibitors and; 2) FGFR inhibitors may be highly effective therapies for patients with MTAP-deficient, FGFR3 altered urothelial cancer. Citation Format: Yu-Yi Chu, Jianfeng Chen, Cindy Y. Jiang, Ying Mei, Yuxue Zhang, Arlene Siefker-Radtke, Jianjun Gao. FGFR3 inhibition is a highly effective therapy in MTAP-deficient, FGFR3 altered urothelial carcinoma [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 1746.
Abstract 4461: Utilizing steered molecular dynamics simulations for enhanced virtual screening: Active pharmacophore search by dynamic corrections to target MKK3-MYC interactions
Authors: Muhammet Eren Ulug, Saima Ikram, Ehsan Sayyah, Serdar DURDAGI
Journal: Cancer Research (2025)

Abstract The complex interplay between mitogen-activated protein kinase 3 (MKK3) and the MYC proto-oncogene protein is critical for cancer progression, especially in triple negative breast cancer (TNBC). Despite substantial advancements, effective MYC-targeted drug discovery remains a challenge, underscoring the need for innovative approaches to manage MYC-dependent malignancies. One promising strategy involves disrupting the protein-protein interactions (PPIs) between MKK3 and MYC, as MKK3-mediated activation of MYC is pivotal in multiple cell types, highlighting a new target for therapeutic interventions in MYC-driven cancers. In this study, we employed a novel in silico approach to screen small molecule libraries targeting the MKK3-MYC interaction. Dynamic structure-based pharmacophore models were created to screen these libraries, identifying compounds that effectively aligned with the specified pharmacophore features. Physics-based simulations were then conducted on the selected hits. Steered molecular dynamics (sMD) simulations were employed to evaluate the correlation between the force required to dissociate the candidate ligands from the binding pocket and their corresponding average binding free energies. Comparative analysis of the average binding free energies of these identified hits, relative to the reference compound SGI-1027, indicates that the selected molecules have promising predicted binding affinities. These findings may represent a significant step forward in our ability to modulate MYC activation for cancer therapy. Citation Format: Muhammet Eren Ulug, Saima Ikram, Ehsan Sayyah, Serdar DURDAGI. Utilizing steered molecular dynamics simulations for enhanced virtual screening: Active pharmacophore search by dynamic corrections to target MKK3-MYC interactions [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 4461.
Abstract 6277: A time-series mouse model identifies an early post-treatment effective liquid biomarker of ICB response in human head and neck cancer
Authors: Binbin Wang, Robert Saddawi-konefka, Lauren M. Clubb, Shiqi Tang, Di Wu, Sumit Mukherjee, Sahil Sahni, Saugato Rahman Dhruba, Kun Wang, J. Silvio Gutkind, Eytan Ruppin
Journal: Cancer Research (2025)

Abstract Background &amp; Approach: Immune checkpoint blockade (ICB) therapy has shown promise for head and neck squamous cell carcinoma (HNSCC); however, response rates remain limited, with only a subset of patients exhibiting significant clinical benefits. Identifying non-invasive liquid biomarkers to predict ICB response is crucial for optimizing patient selection and treatment strategies. In this study, we generate and analyze time-series RNA and T-cell receptor (TCR) sequencing data from blood in a murine HNSCC model treated with anti-PD-1 therapy to identify potential liquid biomarkers predictive of ICB response Results: Our analysis reveals significant differences in the clonal expansion and temporal dynamics of effector T cells (Teff) and B cells between responders and non-responders, indicating distinct immune profiles associated with therapeutic outcomes. Notably, these immunological changes are most prominent at early post-treatment timepoints, suggesting that this period is optimal for assessing ICB efficacy and for the potential identification of predictive biomarkers. Importantly, the Teff and B cell transcriptomic gene signatures identified at these early post-treatment timepoints predict ICB treatment responses in HNSCC patient cohorts without the need for additional training, underscoring their potential clinical utility. Further time-series ligand-receptor interaction analyses uncover potential immune cell communication pathways that may mediate ICB outcomes, offering insights into mechanisms underlying ICB resistance. Conclusions: Our findings highlight the importance of early post-treatment timepoints for assessing ICB response and suggest blood-based Teff and B cell signatures as effective biomarkers for predicting ICB treatment outcomes in HNSCC patients. This study provides a potential framework for translating findings from murine models to human clinical practice, facilitating the development of personalized immunotherapeutic strategies. Citation Format: Binbin Wang, Robert Saddawi-konefka, Lauren M. Clubb, Shiqi Tang, Di Wu, Sumit Mukherjee, Sahil Sahni, Saugato Rahman Dhruba, Kun Wang, J. Silvio Gutkind, Eytan Ruppin. A time-series mouse model identifies an early post-treatment effective liquid biomarker of ICB response in human head and neck 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 6277.
Abstract 6290: sc2DAT: workflow for targeting tumor subpopulations of single cells
Authors: Giacomo B. Marino, Nasheath Ahmed, Daniel J. Clarke, Avi Ma'ayan
Journal: Cancer Research (2025)

Abstract Single-cell RNA sequencing (scRNA-seq) provides enhanced insights into the cellular composition of human tissues. In cancer, normal proportions of single cells are aberrantly dysregulated, and thus targeting subpopulations of cells within a tumor might be more effective than targeting all cells of a tumor. Here we present Single Cells to Drugs And Targets (sc2DAT), a unique workflow for the analysis of bulk and single cell RNA-seq datasets collected from tumors of the Clinical Proteomic Tumor Analysis Consortium (CPTAC). sc2DAT can take in as input single cell or bulk RNA profiles from one or two conditions. When processing scRNA-seq samples, sc2DAT first clusters the single cell vectors of expression to identify cell type subpopulations. It then bulkifies the vectors of expression in each cluster of single cells. For bulk RNA-seq, sc2DAT applies deconvolution with BayesPrism to infer cell-type-specific expression profiles for each identified subpopulation within a tumor. The sc2DAT platform currently has over 20 precomputed single-cell reference datasets derived from human and mouse studies. The expression vectors in each cluster of single cells are analyzed to discover genes that give rise to cell-surface proteins that are highly expressed in the tumor’s subpopulation, but lowly expressed across all human healthy cell types and tissues. These identified cell-surface proteins can become immunotherapy targets for selectively elimination of subpopulation of single cells within a tumor. In addition, sc2DAT integrates the LINCS L1000 perturbational gene expression dataset to predict drugs and preclinical compounds that could induce a healthy phenotype in subpopulations of single cells within a tumor. Once datasets are uploaded to sc2DAT, the results are presented in a comprehensive report with an abstract, introduction, methods, results, conclusions, and references sections. The reports have many figures and tables, and it can be exported and shared in several formats including a PDF file. We applied sc2DAT to several CPTAC3 and CPTAC4 datasets to identify cell-type-specific subpopulation targets and reverser compounds, uncovering many potential personalized therapeutic strategies for immunotherapy and small-molecule interventions. sc2DAT is available from: https://sc2dat.maayanlab.cloud. Citation Format: Giacomo B. Marino, Nasheath Ahmed, Daniel J. Clarke, Avi Ma'ayan. sc2DAT: workflow for targeting tumor subpopulations of single 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 6290.
Abstract 4289: Discovery of potent RAD51 inhibitors with anticancer activity in preclinical models of non-small cell lung cancer
Authors: Yifan Yu, Morgan Black, Nikolina Radulovich, Peter Ferguson, James Koropatnick, Ming Tsao, Mark D. Vincent, Geoffrey Liu, Samir H. Barghout
Journal: Cancer Research (2025)

RAD51 is a protein that plays a key, canonical role in double-strand break (DSB) repair through homologous recombination (HR) and is biologically important for maintaining genome stability. Given its additional, non-canonical role in mitigating the replication stress characteristic of tumor cells, RAD51 has emerged as an attractive therapeutic target in several malignancies including non-small cell lung cancer (NSCLC). Nonetheless, drug discovery endeavors for developing direct RAD51 inhibitors have had limited success. Here, we describe a series of novel RAD51 inhibitors and their cytotoxic activity in preclinical models of NSCLC. We accessed and improved upon a previously discovered series of phenylsulfonyl indolyl isoquinoline derivatives that bind to the hydrophobic pocket of RAD51 preventing its multimerization and interaction with BRCA2. Of these, JKYN-1 and its mesylate salt (patent application # CA3204011A1) displayed potent and selective RAD51 inhibition in cell-free assays. Given the biological importance of replication stress in a subset of NSCLC, we assessed the cytotoxicity of these RAD51 inhibitors in preclinical models of NSCLC. Using the CellTiter-Glo assay, JKYN-1 displayed cytotoxicity in A549 and H1975 cell lines with lower IC50 values compared to the classical RAD51 inhibitor B02 (A549, 4.9 vs &amp;gt;10 μM; H1975, 3.2 vs 8.3 μM). We subsequently assessed the cytotoxicity in a panel of 7 patient-derived organoids (PDOs) of NSCLC with diverse molecular, genetic, and clinical profiles (LPTO308, XDO137, LPTO357, LPTO318, LPTO366, LPTO362, LPTO221). In these models, JKYN-1 and JKYN-1-mesylate displayed a highly potent cytotoxicity with sub-micromolar IC50 values between 0.1-0.87 μM as opposed to B02 that had IC50 values between 3.7 to &amp;gt;10 μM. In conclusion, our data identify JKYN-1 and its mesylate salt as potent and selective RAD51 inhibitors with superior cytotoxic activity compared to classical inhibitors such as B02. These findings highlight the potential of these novel compounds as promising therapeutic agents in a subset of NSCLC. Citation Format: Yifan Yu, Morgan Black, Nikolina Radulovich, Peter Ferguson, James Koropatnick, Ming Tsao, Mark D. Vincent, Geoffrey Liu, Samir H. Barghout. Discovery of potent RAD51 inhibitors with anticancer activity in preclinical models of non-small cell 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 4289.
Abstract 6131: Temozolomide induces innate immune responses via the production of double-stranded RNAs in glioblastoma cells
Authors: Natsuki Koide, Tatsunori Nishimura, Miho Suzuki, Keiko Shinjo, Yutaka Kondo
Journal: Cancer Research (2025)

Immunotherapy using immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment by enhancing T cell-mediated anti-tumor immunity. However, its efficacy in glioblastoma (GBM) remains limited, as demonstrated by unsuccessful clinical trials. The primary challenge is the low abundance of tumor-infiltrating lymphocytes (TILs) within the GBM tumor microenvironment (TME), which fosters an "immune-cold" or "immune-suppressive" state, rendering the tumor resistant to immunotherapy. The first-line treatment for GBM is temozolomide (TMZ), and several studies have examined whether TMZ improves patient outcomes when combined with ICIs. However, one such trial, Ipi-Glio, did not demonstrate improved outcomes with the addition of ipilimumab to TMZ. In contrast, the MAYA study in metastatic colon cancer patients showed clinical benefits when patients were treated with TMZ followed by low-dose ICIs. As a result, it remains unclear whether TMZ has synergistic effects with ICIs in GBM treatment. To address this question, we consider the following: Does TMZ increase the abundance of TILs within the GBM TME? The recruitment and activation of TILs depend on pro-inflammatory cytokines, including type I interferons (IFN-I), which bridge innate and acquired immunity. Thus, we further investigate: Does TMZ stimulate IFN-I production to enhance TIL infiltration?When the U251 GBM cell line was treated with TMZ, the cells expressed IFNB1, a type of IFN-I, as well as interferon-stimulated genes (ISGs). We also aimed to clarify the pathway through which IFN-I is induced. Several pathways are known to activate IFN-I, so we knocked down the expression of key intermediates in these pathways and treated the cells with TMZ. As a result, the upregulation of IFNB1 and ISGs induced by TMZ was diminished when RIG-I was knocked down. RIG-I is a pattern recognition receptor that detects double-stranded RNA (dsRNA). This finding suggests that the IFN-I induction observed in TMZ-treated GBM cells is linked to the presence of dsRNA within the tumor cells. In this presentation, we will discuss the origins of the dsRNAs and whether TMZ-induced IFN-I is sufficiently strong to transform the "immune-cold" or "immune-suppressive" GBM TME into an "immune-hot" state. Citation Format: Natsuki Koide, Tatsunori Nishimura, Miho Suzuki, Keiko Shinjo, Yutaka Kondo. Temozolomide induces innate immune responses via the production of double-stranded RNAs in glioblastoma 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 6131.