tbuckley/cabot-search huggingface dataset:
Abstract 6309: CliPP-on-Web: a dynamic platform for clonal structure identification through penalizing pairwise differences in cancers
Authors: Aaron Wu, Quang Tran, Matthew D. Montierth, Yujie Jiang, Jessica C. Lai, Shuangxi Ji, Wenyi Wang
Journal: Cancer Research (2025)

Background: Intra-tumor heterogeneity plays a crucial role in tumor evolution and response to therapy, highlighting the need to understand mutation clonality and subclonal architecture to drive advancements in precision cancer treatments. However, existing tools for subclonal reconstruction are typically too slow for large cohort analyses, and lack an accessible web-based interface for widespread use. Methods: We developed CliPP-on-Web, an interactive platform built with R Shiny, to streamline subclonal analysis for researchers and clinicians. Its back-end algorithm is based on model-based clustering with regularized maximum likelihood estimation, derived from the core methodology of CliPP. This algorithm models variant allele counts using a binomial distribution, incorporating tumor purity, copy number alterations (CNAs), and cancer cell fractions (CCFs) of somatic mutations. By penalizing pairwise differences in CCFs, it effectively clusters mutations without requiring predefined subclone numbers. Optimization is achieved through the Alternating Direction Method of Multipliers (ADMM), ensuring high computational efficiency. Results: CliPP-on-Web simplifies subclonal analysis by enabling users to process up to 10 samples simultaneously with user-uploaded. Interactive visualization tools, such as Variant Allele Frequency (VAF) and Cellular Prevalence (CP) plots, offer features like zooming, hover details, and adjustable smoothing for enhanced clarity. Pre-loaded integrated datasets from TCGA and PCAWG enable comparative studies, while the Driver Mutation module highlights key cancer mutations with searchable and downloadable results. Capable of processing 100 samples in just30 minutes — far outpacing the ∼3 hours per sample required by tools like PhyloWGS — CliPP-on-Web provides efficient and comprehensive subclonal analysis, advancing cancer genomics research. Conclusions: CliPP-on-Web offers a powerful, accessible platform for analyzing mutation clonality and subclonal architecture across diverse tumor types, facilitating both large-scale studies and individual sample exploration. Citation Format: Aaron Wu, Quang Tran, Matthew D. Montierth, Yujie Jiang, Jessica C. Lai, Shuangxi Ji, Wenyi Wang. CliPP-on-Web: a dynamic platform for clonal structure identification through penalizing pairwise differences in 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 6309.
Abstract 4861: INCA33890 increases CD8+ T-cell effector function compared with pembrolizumab as assessed by single-cell RNA sequencing in human PD-1xTGFβR2 knock-in mouse model
Authors: Michelle Kinder, Jin Lu, Justine Carl, Lifeng Zhang, Paul Collier, Paul Waeltz, Rodrigo Hess, Natalia Pardo, Maria Terradas, Liang-Chuan Wang, Cynthia Timmers
Journal: Cancer Research (2025)

Abstract INCA33890, a novel PD-1xTGFβR2 bispecific Biclonics® antibody, is designed to selectively inhibit TGFβR2 on PD-1+ cells, leveraging a higher binding affinity for PD-1 over TGFβR2. In preclinical studies using the MC38 colorectal tumor model in human PD-1xTGFβR2 Knock-in mice, INCA33890 had a superior antitumor efficacy compared with pembrolizumab, anti-TGFβR2 or isotype control. This study aimed to uncover the differential mechanism of tumor regression by applying single-cell TCR sequencing (scTCRseq) coupled with single-cell RNA sequencing (scRNAseq) on T cells derived from treated MC38 tumor-bearing mice. Intratumoral T cells were enriched and profiled using 10X Genomics scTCRseq and scRNAseq from MC38 tumor-bearing mice treated with INCA33890, pembrolizumab, anti-TGFβR2, or control antibodies. Results revealed that CD8+ T cells in INCA33890-treated mice exhibited a robust increase in RNA transcripts associated with cytotoxicity, proliferation, and T-cell exhaustion compared with pembrolizumab or control antibody treatments, signifying a potent effector response within the tumor microenvironment. Sub-grouping of CD8+ T cells into 13 distinct clusters based on marker expression and gene enrichment analysis demonstrated a notable expansion of proliferating, activated, and cytotoxic CD8+ T cell populations following INCA33890 treatment—an outcome not observed with pembrolizumab or control treatments. INCA33890 treatment also reduced the proportion of intratumoral-naïve CD8+ T cells, transforming their gene expression profile toward an effector-like phenotype. In intratumoral CD4+ T cells, treatment with INCA33890 resulted in signatures of enhanced activation, proliferation, and exhaustion compared with pembrolizumab and control treatments, suggesting broad engagement of the adaptive immune response. scTCRseq demonstrated a marked increase in the clonality of intratumoral T cells, further underscoring the impactful immune modulation induced by INCA033890. In summary, bispecific Biclonics® targeting of TGFβR2 and PD-1 with INCA33890 promotes the expansion and activation of effector CD8+ T-cell populations within the tumor microenvironment, driving enhanced antitumor activity in vivo. Citation Format: Michelle Kinder, Jin Lu, Justine Carl, Lifeng Zhang, Paul Collier, Paul Waeltz, Rodrigo Hess, Natalia Pardo, Maria Terradas, Liang-Chuan Wang, Cynthia Timmers. INCA33890 increases CD8 T-cell effector function compared with pembrolizumab as assessed by single-cell RNA sequencing in human PD-1xTGFβR2 knock-in mouse model [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 4861.
Abstract 1448: An evolutionarily conserved chromatin remodeling factor, FACT, in regulation of chromatin, gene expression and cancer
Authors: Priyanka Barman, Sukesh Bhaumik
Journal: Cancer Research (2025)

Abstract Eukaryotic genome is packed in the form of chromatin that is an array of nucleosomes. Such nucleosomal organization acts as a barrier for gene regulatory factors to access DNA for transcription. Importantly, cells have evolved with mechanisms for nucleosomal disassembly and reassembly for transcription to occur through chromatin. A heterodimeric chromatin remodeling factor, FACT (Facilitates chromatin transcription), plays a key role in nucleosomal disassembly and reassembly to promote transcription. Intriguingly, FACT is upregulated in breast and other cancers, and FACT upregulation induces oncogenesis. Thus, the upstream regulatory pathways/factors of FACT can emerge as cancer biomarkers which can be targeted for an effective cancer therapy. Further, FACT is found to be downregulated and/or mutated in various cancers including breast cancer. Thus, it is crucial to understand regulatory mechanisms lying upstream of FACT with downstream functions in regulation of chromatin to orchestrate gene expression towards understanding cancer pathogenesis with targeted therapeutic potential. In this conference, we will present our recent work on FACT regulation and functions in controlling chromatin and gene expression with implication in cancer. Citation Format: Priyanka Barman, Sukesh Bhaumik. An evolutionarily conserved chromatin remodeling factor, FACT, in regulation of chromatin, gene expression and 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 1448.
Abstract 1896: Spatial proteomics and tumor-immune phenotyping identifies a diverse immune landscape in syngeneic murine tumor models
Authors: Arindam Bose, Emily Quann Alonzo, Sophie Struble, Jeremy Fisher, Richard A. Heil-Chapdelaine, Natasha F. Diaz Granados, Vasundhara Agrawal
Journal: Cancer Research (2025)

Abstract Syngeneic mouse models have a functionally intact immune system, and therefore, serve as a crucial tool for evaluation of the immune response to tumors and pre-clinical evaluation of immunotherapeutic strategies. However, the immune response varies between different syngeneic models. Identification and selection of appropriate models for pre-clinical evaluation is challenging. To understand the dynamic interplay between the tumor and immune system, we implemented multiplexed spatial proteomics across various syngeneic tumor models. Spatial mapping of multiple tumor and immune markers in untreated tumor provides an overview of the tumor immune architecture. This information can be applied to identify optimal models for preclinical immunotherapy approaches, to understand the response to therapies at the preclinical stage, and to identify potential biomarkers for clinical evaluation. The Cell DIVE Multiplexed Imaging Solution, in combination with IHC-validated antibody conjugates from Cell Signaling Technology (CST), enables profiling of immune cell populations in the context of human and mouse tumor tissue. Here, we demonstrate multiplexed Cell DIVE imaging of syngeneic mouse tumor models using a novel CST® panel of mouse-reactive antibodies. We apply segmentation and clustering analysis to identify spatially co-localized populations of cells and discuss the complexities of immune cells and their interactions. Cell type specific markers combined with multiplexed tissue imaging and spatial mapping is an approach that enables a better understanding of the anti-tumor immune response, which can be applied to address challenges associated with developing immune-based therapies. The study highlights the importance of simultaneously observing multiple immune cell types and tumor characteristics in spatial context. Citation Format: Arindam Bose, Emily Quann Alonzo, Sophie Struble, Jeremy Fisher, Richard A. Heil-Chapdelaine, Natasha F. Diaz Granados, Vasundhara Agrawal. Spatial proteomics and tumor-immune phenotyping identifies a diverse immune landscape in syngeneic murine tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1896.
Abstract 4470: Development of a nanoparticle formulation of an MMP-activated, tumor-specific prodrug with an enhanced therapeutic index for the treatment of breast cancer
Authors: Zubeda Khatoon, Hannah L. Spencer, Huw S. Jones, Goreti R. Morais, Amalia R. Estrada, Robert A. Falconer
Journal: Cancer Research (2025)

Abstract Triple-negative breast cancer accounts for 20% of all breast cancer cases and has a poor prognosis due to the lack of targetable expression of specific hormone and growth factor receptors. Therefore, systemic chemotherapy is one of the main therapeutic options. However, a lack of tumor specificity results in systemic toxicity. A tumor-selective prodrug, such as ICT25881, could enhance the therapeutic index of the active drug. ICT2588 comprises a colchicine analogue as the active drug, which is conjugated to an MMP14-specific peptide sequence and an endcap to prevent non-specific degradation. MMP14 is widely expressed and functionally active in the tumor tissues and neo vasculature compared to healthy tissues where it is largely absent, thereby facilitating specific release of the active drug within the tumor microenvironment. Despite the therapeutic potential of ICT2588, a lack of aqueous solubility is a limitation. In this study we aim to optimize a nanoparticle formulation of ICT2588 using a lactic and glycolic acid (PLGA) based approach, to increase the aqueous solubility of ICT2588, while offering a controlled release system without additional toxicity.2 ICT2588 was synthesized and purified by semi-preparative HPLC. Nanoparticles were synthesized via nanoprecipitation and the formulations were optimized in terms of hydrodynamic diameter, zeta potential, and encapsulation efficiency. The evaluation of the ICT2588-PLGA formulations in an MDA-MB-231 triple negative breast cancer model will be reported, with the MMP14 overexpression validated by SDS PAGE and western blotting. The improvements in aqueous solubility will increase the therapeutic potential of ICT2588 and facilitate its translation towards clinical evaluation. 1.Atkinson JM, Falconer RA, Edwards DR, et al. Development of a novel tumor-targeted vascular disrupting agent activated by membrane-type matrix metalloproteinases. Cancer Research 2010;70(17):6902-6912, doi:10.1158/0008-5472.CAN-10-1440 2.Alsaab HO, Alharbi FD, Alhibs AS, et al. PLGA-Based Nanomedicine: History of Advancement and Development in Clinical Applications of Multiple Diseases. Pharmaceutics 2022;14(12):2728, doi:10.3390/pharmaceutics14122728 Citation Format: Zubeda Khatoon, Hannah L. Spencer, Huw S. Jones, Goreti R. Morais, Amalia R. Estrada, Robert A. Falconer. Development of a nanoparticle formulation of an MMP-activated, tumor-specific prodrug with an enhanced therapeutic index for the treatment of 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 4470.
Abstract 4144: PTPTF negatively regulates c-Src kinase through the dephosphorylation of the activation loop
Authors: Haley Stanczyk, Carolina Galeano-Naranjo, Tianyan Gao
Journal: Cancer Research (2025)

Kinases and phosphatases play a dynamic role in the regulation of signaling propagation. c-Src is an oncogenic kinase that plays multifunctional roles in the initiation and progression of many cancers, including breast, colorectal and lung cancers. The activity of c-Src kinase is tightly regulated by the phosphorylation status of two key tyrosine residues (Tyr419 and Tyr530 in human c-Src) that controls its propensity for entering an active conformation. Phosphorylation of Tyr530 at the C-terminus of c-Src locks the kinase in an inactive confirmation whereas phosphorylation of Tyr419 in the activation loop is required to activate c-Src. A number of tyrosine phosphatases have been identified to activate c-Src by dephosphorylating Tyr530. However, the phosphatases controlling the Tyr419 site remain elusive. In this study, we investigated the role of protein tyrosine phosphatase receptor type F (PTPRF) in regulating the phosphorylation of c-Src. PTPRF is characterized by an extracellular domain, a single transmembrane motif, and two tandem intracellular phosphatase domains (including a catalytically active D1 domain and a catalytically inactive D2 domain). We show that overexpression of PTPRF, but not a phosphatase inactive mutant, results in a decrease in Tyr419 phosphorylation of both wild-type and Y530F constitutively active c-Src in 293T cells. On the other hand, CRISPR-mediated knockout of PTPRF increases the phosphorylation of c-Src and signaling downstream. Co-immunoprecipitation experiments indicate that PTPRF interacts with c-Src through its D2 pseudo phosphatase domain. Consistent with the notion that the kinase activation reduces c-Src protein stability, we find that the expression of c-Src is increased when co-expressed with PTPRF, suggesting that PTPRF-mediated dephosphorylation stabilizes c-Src protein. Taken together, this study identifies PTPRF as a novel phosphatase that negatively regulates c-Src kinase activity through the dephosphorylation of Tyr419 in the activation loop. Citation Format: Haley Stanczyk, Carolina Galeano-Naranjo, Tianyan Gao. PTPTF negatively regulates c-Src kinase through the dephosphorylation of the activation loop [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 4144.
Abstract 4222: N-acetyl-L-cysteine (NAC) sensitizes psammaplin A induced DNA damage in malignant hematologic cells by enhancing HDAC inhibition
Authors: Yu Bao, Yumei He, Dan Liu, Ping Gong, Samuel Waxman, Yongkui Jing
Journal: Cancer Research (2025)

Abstract Psammaplin A (PsA) is a symmetrical bromotyrosine-derived disulfide dimer isolated from the Psammaplysilla sponge. PsA is a selective natural Class I HDAC inhibitor, that requires reduction into monomer with glutathione (GSH). Cell growth inhibition and apoptosis was determined in 12 malignant hematologic cell lines revealed 8 lines sensitive (more than 50% inhibition at 1 μM) and 4 lines insensitive (less than 20% inhibition at 1 μM). PsA induces acetylation of H3 and DNA damage detected with γ-H2A.X in the sensitive lines, but not in the four insensitive cell lines. The sensitivity of PsA in these lines correlates with HDAC inhibition and reduced GSH levels. The insensitive cell lines have lower GSH levels without HDAC inhibition. N-acetyl-L-cysteine (NAC) acts as a precursor of GSH synthesis and is used as an antioxidant. Pretreatment with 5 mM NAC following by PsA enhances cell growth inhibition 10 fold. NAC plus PsA is more effective than the HDAC inhibitor SAHA, which is not enhanced by NAC, to inhibit cell growth in vitro. Western blot analysis shows that NAC sensitizes PsA effect by increasing HDAC inhibition as measured by acetylated H3 and by DNA damage marker γ-H2A.X with upregulation of GSH. Chemical studies reveal that GSH, but not NAC, reduces PsA into a monomer. PsA is enhanced by NAC to inhibit tumor growth in MOML13 xenograft models without causing toxicity. These data support that NAC enhances PsA effect by increasing intracellular GSH which reduces PsA into a HDAC inhibiting monomer with increased cancer cell growth inhibition. Citation Format: Yu Bao, Yumei He, Dan Liu, Ping Gong, Samuel Waxman, Yongkui Jing. N-acetyl-L-cysteine (NAC) sensitizes psammaplin A induced DNA damage in malignant hematologic cells by enhancing HDAC inhibition [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 4222.
Abstract 2994: Co-targeting the HER family and mutant KRAS is efficacious in colorectal cancer
Authors: Mary Kate Kilroy, Cecilia Wischmeier, Briley SoYoung Park, Rosalin Mishra, Wasim Feroz, Joan T. Garrett
Journal: Cancer Research (2025)

We are investigating the role of naturally co-occurring HER3 and KRAS mutations in colorectal cancer, as about 6% of all colorectal cancers contain a HER3 mutation and 41% contain a KRAS mutation. After investigating the frequency of co-occurring mutations in publicly available data sets, we observed that there is a statistically significant co-occurrence of HER3 in KRAS mutations while there is mutual exclusivity with mutations in the other members of the HER family (EGFR, HER2, HER4) and mutant KRAS. We have found that there is a striking increase in total HER3 levels in SNU-407, LS180, LS513 cells and 572918-348-R and 172845-121-B patient derived organoids (PDOs) when treated with the KRASG12D inhibitorsMRTX1133 and RMC9805, creating an adaptive response that could limit the efficacy of a KRAS inhibitor as a single agent. We next aimed to determine if this was biologically meaningful by genetically knocked down HER3, KRAS or the combination in SNU-407 and LS-513 cells. We have found that genetic knockdown of both KRAS and HER3 with siRNA targeting KRAS and HER3 in the CRC cell lines SNU-407 (HER3V104M,KRASG12D) and LS513 (HER3WT, KRASG12D) results in a statistical reduction in cell proliferation in comparison to genetic knockdown with only KRAS or HER3. Next, we examined HER3 binding partners in a panel of CRC and observed HER3 bound to EGFR in SNU-407 cells and HER3 bound to MET in LS513 cells. Co-targeting EGFR and mutant KRAS resulted in a slight synergistic effect in KRASG12D mutant cell lines usingMRTX1133 in combination with sapitinib, afatinib or peltinib. Currently, we are assessing if there is a synergistic effect directly targeting HER3 with a HER3 antibody-drug-conjugate in combination with a KRAS inhibitor in CRC cells. Our findings may present a new paradigm for targeted combination therapies in colorectal cancer with the eventual goal of increased overall patient survival. Citation Format: Mary Kate Kilroy, Cecilia Wischmeier, Briley SoYoung Park, Rosalin Mishra, Wasim Feroz, Joan T. Garrett. Co-targeting the HER family and mutant KRAS is efficacious in colorectal 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 2994.
Abstract 3004: Preclinical characterization of CGT6297, a novel PI3Kα H1047R mutant-selective inhibitor
Authors: Aaron C. Smith, Ben Arwood-Levine, Abiezer Blandon, Alexandra Born, Richard Brizendine, Payal Chatterjee, Mark J. Chicarelli, Michael L. Conner, Brad Fell, Jennifer Fulton, Anna Guarnieri, Hannah Hubert, Ravi Jalluri, Hailey Knox, Keith Koch, Daniel Krischlunas, Vijay Kumar, Sara Kuzbiel, Matt McDonald, Colin McHugh, Brent Mclean, Kelsey W. Nassar, Paul Larsen, Brad Newhouse, Scott Niman, Rob Rieger, John Robinson, Marelí Rodriguez, Leah Salituro, Vinny Scarato, Lee Stunkard, Francis Sullivan, Patrick Sutter, Roy Turton, Rob Van Gulick, Brooklynn Venteicher, Logan Vine, Shannon Winski, Shannon Winski, Hannah Work, Yeyun Zhou
Journal: Cancer Research (2025)

Abstract PIK3CA encodes the p110α catalytic subunit of PI3-kinase alpha (PI3Kα) and is the most frequently mutated kinase in human cancer with common mutations occurring in the kinase domain (H1047R) and helical domain (E542K/E545K). The approved PI3Kα inhibitor, alpelisib, shows promise for this targeted class of agents with improvements in progression-free survival in ER+/Her2- breast cancer patients in combination with fulvestrant. However, toxicities attributed to the inhibition of wild-type PI3Kα, such as hyperglycemia, gastrointestinal issues, and skin reactions, lead to sub-optimal target engagement due to requisite dosing modifications. A PI3K mutant inhibitor that spares WT PI3K is predicted to be better tolerated, require fewer dosing modifications, and therefore, have the potential to provide improved clinical benefit. Herein, we present the preclinical characterization of CGT6297, a wild type sparing PI3Kα H1047R inhibitor. Citation Format: Aaron C. Smith, Ben Arwood-Levine, Abiezer Blandon, Alexandra Born, Richard Brizendine, Payal Chatterjee, Mark J. Chicarelli, Michael L. Conner, Brad Fell, Jennifer Fulton, Anna Guarnieri, Hannah Hubert, Ravi Jalluri, Hailey Knox, Keith Koch, Daniel Krischlunas, Vijay Kumar, Sara Kuzbiel, Matt McDonald, Colin McHugh, Brent Mclean, Kelsey W. Nassar, Paul Larsen, Brad Newhouse, Scott Niman, Rob Rieger, John Robinson, Marelí Rodriguez, Leah Salituro, Vinny Scarato, Lee Stunkard, Francis Sullivan, Patrick Sutter, Roy Turton, Rob Van Gulick, Brooklynn Venteicher, Logan Vine, Shannon Winski, Shannon Winski, Hannah Work, Yeyun Zhou. Preclinical characterization of CGT6297, a novel PI3Kα H1047R mutant-selective inhibitor [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 3004.