tbuckley/cabot-search huggingface dataset:
Abstract A025: Direct <i>in vivo</i> CRISPR screen identifies <i>BAP1</i> and <i>FAT1</i> as potent tumor suppressors in sarcomagenesis
Authors: Jianguo Huang, Xingliang Liu, Warren Floyd, William Haugh, Andrea R Daniel, Zhaoyu Sun, Nerissa T Williams, Melissa J Kasiewicz, Yaping Wu, Diana M Cardona, Brian Piening, John T. Welle, Wesley K Rosales, Venkatesh Rajamanickam, So Young Kim, Eric Xu, Lixia Luo, Yan Ma, Kristianne M Oristian, Omar Lopez, Nicholas E. S. Sibinga, Rutulkumar Patel, Ziqiang Zhang, Alexander J Lazar, Corinne M Linardic, Brady Bernard, William L Redmond, Walter J Urba, David G Kirsch
Journal: Cancer Research (2025)

Abstract Undifferentiated pleomorphic sarcoma (UPS) is among the most common soft tissue sarcomas (STS) in adults. For decades, little therapeutic progress has been made for STSs, including UPSs. Targeted therapies for tumors driven by specific genetic mutations have proven to be more effective than standard chemotherapies. However, the molecular pathogenesis of UPSs remains unknown, hindering the development of targeted therapies for UPSs. Approximately 65% of UPSs harbor TP53 mutations, but somatic mutation of Trp53 alone is insufficient to induce sarcomas in vivo. The addition of Rb1 mutation alongside a Trp53 mutation induces sarcomas in vivo, though with low frequency of tumor onset and slow growth. The role of other genes in facilitating Trp53-driven sarcomas is largely unknown. Through a customized in vivo CRISPR/Cas9 screen of 35 genes commonly mutated in UPSs, followed by individual gene validation in vivo, we discovered that Bap1 knockout cooperates with Trp53 knockout to induce sarcomas in vivo. Furthermore, we demonstrated that Fat1 deletion increased the onset frequency and growth of Trp53 and Rb1-driven sarcomas in a genetically engineered mouse model. Through multiplex immunohistochemistry and flow cytometry, we found that mouse sarcomas induced by Trp53 and Rb1 mutations are significantly enriched with immune cells compared to other mouse sarcomas we generated in vivo. Finally, we show that PARP inhibition may be a potential targeted therapy for RB1-loss STSs and BRD4 inhibition may be a potential targeted therapy for FAT1-loss STSs. Citation Format: Jianguo Huang, Xingliang Liu, Warren Floyd, William Haugh, Andrea R Daniel, Zhaoyu Sun, Nerissa T Williams, Melissa J Kasiewicz, Yaping Wu, Diana M Cardona, Brian Piening, John T. Welle, Wesley K Rosales, Venkatesh Rajamanickam, So Young Kim, Eric Xu, Lixia Luo, Yan Ma, Kristianne M Oristian, Omar Lopez, Nicholas E. S. Sibinga, Rutulkumar Patel, Ziqiang Zhang, Alexander J Lazar, Corinne M Linardic, Brady Bernard, William L Redmond, Walter J Urba, David G Kirsch. Direct in vivo CRISPR screen identifies BAP1 and FAT1 as potent tumor suppressors in sarcomagenesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A025.
Abstract B020: Early detection of colorectal cancer using micronuclei DNA
Authors: Xingyun Yao, Haobo Sun, Yurong Jiao, Chengcheng Liu, Xiangxing Kong, Honghao Liang, Fei Meng, Jun Li, Kefeng Ding, Xiaofei Gao
Journal: Cancer Research (2025)

Abstract Background: Current development in stool- and cell-free DNA (cfDNA)-based technologies have demonstrated promising potentials in colorectal cancer (CRC) diagnosis. However, the early detection of CRC and advanced adenomas (AA) remains a challenge. Micronuclei (MN) are hallmarks of genomic instabilities. Elevated levels of MN+ erythrocytes have been studied in genotoxicity testing and cancer diagnosis. We utilized previously developed methods to isolate and sequence MN-DNA from erythrocytes in 1-2 mL peripheral blood, revealing significant differences between patients and healthy donors (WO2021/228246 A1). Here, we established an independent cohort to further evaluate the value of MN-DNA in identifying CRC and AA. Methods: We enrolled 1251 samples with complete colonoscopy reports, comprising 360 CRC patients, 330 AA patients, and 561 non-cancer individuals. We collected 1-2 mL of peripheral blood from each enrolled individual, and the MN-DNA was isolated and performed on whole genome sequencing. We used 80% of these samples for the CRC- and AA-associated MN-DNA features identification and model development, while the remaining 20% were designated as the test set to evaluate the model performance and determine the cutoff. Based on the specificity and sensitivity in the test set, we launched a prospective observational case-control clinical trial (NCT05875584), which was used as an independent cohort to validate the model and to perform a comparative analysis with quantitative fecal immunochemical test (qFIT). A total of 598 samples were enrolled in this study (585 were available, including 299 HDs, 206 AAs, and 80 CRCs). Results: The predictive CRC model built on MN-DNA features achieved an AUC of 96% and the detection of AAachieved an AUC of 88% in the independent cohort. Comparing MN-DNA with qFIT, the overall sensitivity was generally consistent (90% vs. 88%), with MN-DNA achieving 91% sensitivity in early-stage (stage I) CRC, significantly higher than 68% in qFIT. Additionally, MN-DNA showed superior sensitivity in detecting AA (70% vs. 18%), with comparable specificity (90% vs. 96%). Conclusions: Our results demonstrate that MN-DNA within erythrocytes from 1-2ml peripheral blood enables accurate detection of AA and early-stage CRC. Research sponsor: Timing Biotech. Citation Format: Xingyun Yao, Haobo Sun, Yurong Jiao, Chengcheng Liu, Xiangxing Kong, Honghao Liang, Fei Meng, Jun Li, Kefeng Ding, Xiaofei Gao. Early detection of colorectal cancer using micronuclei DNA [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B020.
Abstract B041: Predicting T-cell receptor specificity and phenotype using transfer learning models
Authors: Marmar R Moussa
Journal: Cancer Research (2025)

Abstract T-Cell Receptors are at the heart of the immune system's response to antigens. Their vast heterogeneity, encoded via V(D)J recombination allows for recognition of a wide array of pathogens and cancer neoantigens. Several computational challenges arise when tailoring tratments to an individual's unique TCR repretoire, including mapping TCR sequences, especially CDR3b sequences to specific antigens and understanding and modeling the functional implications of TCR diversity, as well as cominging TCR data with other modalities of data, especially in single cell resolution. Here we propose a new algorithm for preditcting and modeling TCR phenotype and specificity to cancer antigens that utilizes a novel approach using transfer learning and large language models. We use antigen and epitope-specific single cell TCR sequencing data of putative cancer neoepitopes presented on MHC-I to extract and engineer CDR3 sequence-based features and train our model for TCR specificity prediction. Our work provides integration with single cell RNA-Seq modality in a comprehensive functional analysis. Citation Format: Marmar R Moussa. Predicting T-cell receptor specificity and phenotype using transfer learning models [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B041.
Abstract A001: AscitesPredict: Validating anti-cancer therapeutic efficacy in gastroesophageal cancer using rapid ex vivo high-dimensional morphology profiling
Authors: Jesse S Boehm, Mushriq Al-Jazrawe, Csaba Molnar, Beth Cimini, Samuel Klempner, Niklas Rindtorff, Steven Blum
Journal: Cancer Research (2025)

Abstract Overcoming cancer drug resistance is a major unmet clinical need as it remains challenging to accurately predict therapeutic sensitivity from baseline tumor and immune profiling. While biopsies from refractory disease are challenging to routinely obtain for research, upwards of 40% of gastroesophageal and 70% ovarian patients develop peritoneal carcinomatosis and ascites, a plentiful, heterogenous and molecularly representative sample format that is easily accessible since routine drains occur. However, in standard clinical practice this material is only subjected to cytology to detect malignant cells and then discarded. Bulk profiling technologies are challenging to deploy due to the highly variable single cell heterogeneity of ascites. To address these challenges, we have developed the first generation of AscitesPredict, an ‘ex vivo tumor biosensor’ technology using single cell technologies to measure cell identities and therapeutic sensitivities during a 5 day period in which viability is preserved via media supplementation with patient-matched ascites fluid. AscitesPredict utilizes high dimensional single cell image-based morphological profiling and machine learning applied to brightfield microscopy. Thus far, we have profiled over 35 GEA ascites samples, made initial assessments of technological reproducibility, and have optimized initial workflows against a diversity panel of 20 therapeutics. Our ultimate goal is to harden the technology to facilitate deployment by a wide diversity of researchers and clinicians for two driving use cases: (1) supporting preclinical drug development and (2) eventually as a functional diagnostic. Citation Format: Jesse S Boehm, Mushriq Al-Jazrawe, Csaba Molnar, Beth Cimini, Samuel Klempner, Niklas Rindtorff, Steven Blum. AscitesPredict: Validating anti-cancer therapeutic efficacy in gastroesophageal cancer using rapid ex vivo high-dimensional morphology profiling [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A001.
Abstract B021: Saturation mutational scanning uncovers druggability of all FGFR kinase point mutations
Authors: Carla Tangermann, Avantika Ghosh, Martin Ziegler, Francesco Facchinetti, Jannis Stappenbeck, Marisa Riester, Luise Carmina Viardot, Tobias Zundel, Luc Friboulet, Antoine Hollebecque, José Naveja Romero, Angela Wanninger, Maria Elena Hess, Tilman Brummer, Melanie Börries, Sonja Loges, Yohann Loriot, Lena Illert, Sven Diedrichs
Journal: Cancer Research (2025)

Abstract Variants of unknown significance represent one of the biggest challenges for genomics-based precision oncology. High throughput functional genomics is thus essential to characterize the vast number of cancer mutations and tailor the most promising treatment accordingly. Aberrantly activated fibroblast growth factor receptors (FGFRs) frequently drive tumorigenesis with a variety of genetic aberrations across a wide range of tumor entities. Approved selective inhibitors (FGFRis) are available. However, it remains largely unknown which of the many different point mutations affecting FGFR1, FGFR2, FGFR3 or FGFR4 are druggable, i.e. activating FGFR signaling while not mediating FGFRi resistance thereby substantially limiting the therapeutic potential of approved FGFRis. Here, we implemented a saturation mutational scanning platform to screen all 11520 possible point mutations covering the kinase domains of FGFR1-4. In pooled positive selection screens, we identified 474 activating mutations and 738 resistance-mediating mutations to the FGFR inhibitors pemigatinib and/or futibatinib - with many clustered in particular structural elements. Combining these comprehensive datasets revealed 301 druggable FGFR point mutations analogous to a strong PS3/BS3 evidence level. Notably, mutations in the same codon or the corresponding mutations in different FGFRs could strongly differ in their impact, thus underlining the necessity for a saturation approach to study each mutation individually. The screens also identified loss-of-function mutations and FGFR2-specific activating nonsense mutations. Importantly, the functional screens identified 97% of acquired resistance mutations in a clinical trial. In summary, we provide a comprehensive and clinically highly relevant catalog of every single druggable point mutations in the FGFR kinase domains which is readily available for clinical decision support to select the optimal cancer therapy and to push the boundaries of approved inhibitor applications. Citation Format: Carla Tangermann, Avantika Ghosh, Martin Ziegler, Francesco Facchinetti, Jannis Stappenbeck, Marisa Riester, Luise Carmina Viardot, Tobias Zundel, Luc Friboulet, Antoine Hollebecque, José Naveja Romero, Angela Wanninger, Maria Elena Hess, Tilman Brummer, Melanie Börries, Sonja Loges, Yohann Loriot, Lena Illert, Sven Diedrichs. Saturation mutational scanning uncovers druggability of all FGFR kinase point mutations [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B021.
Abstract A039: Dynamic change of plasma circulating extracellular vesicles PD-L2 as a predictor of immune response in melanoma patients receiving anti-PD-1 therapy
Authors: Jie Dai, Linzi Sun, Xiaoting Wei, Lili Mao, Qian Zhao, Junjie Gu, Caili Li, Jun Guo, Lu Si
Journal: Cancer Research (2025)

Abstract Immune checkpoint inhibitors (ICIs) have provided new hope for melanoma patients, however, not all patients benefit. Furthermore, ICI-related therapies cause significant immune-related adverse events that adversely affect patient outcomes. Therefore, there is a pressing need for reliable biomarkers to identify patients most likely to benefit from these treatments. In this study, we employed an extracellular vesicles (EVs) protein expression array to explore the longitudinal membrane protein profiles of plasma-derived EVs from 33 melanoma patients receiving anti-PD-1 and anti-angiogenesis therapy at baseline and early treatment. We found that changes in PD-L2 levels on the EV membrane were associated with patient outcomes. The role of EV PD-L2 as an indication of disease progression and treatment efficacy was validated in an independent cohort of melanoma patients treated with anti-PD-1 monotherapy. Plasma-derived PD-L2+ EVs from patients with mucosal melanoma significantly reduced the frequency of granzyme B+ CD8 T cells within the peripheral blood mononuclear cells (PBMCs) of healthy individuals. The inhibitory effect of PD-L2+ EVs on CD8 T cells was further validated using human melanoma cell lines and the B16-F10 mouse model. Although intratumoral injection of PD-L2+ EVs could promote melanoma growth in vivo, tumors with PD-L2+ EVs showed a higher response to anti-PD-1 than those without PD-L2+ EVs. Collectively, our study demonstrates that PD-L2+ EVs inhibit CD8 T cell activation and promote melanoma growth, and changes in PD-L2 on circulating EVs during early treatment could serve as a biomarker for ICI-based therapy. Citation Format: Jie Dai, Linzi Sun, Xiaoting Wei, Lili Mao, Qian Zhao, Junjie Gu, Caili Li, Jun Guo, Lu Si. Dynamic change of plasma circulating extracellular vesicles PD-L2 as a predictor of immune response in melanoma patients receiving anti-PD-1 therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A039.
Abstract A029: Highly-resolved integrated single cell atlas of human breast cancer enables hypothesis-driven analysis of tumor heterogeneity
Authors: Andrew D Chen, Lina Kroehling, Christina Ennis, Gerald Denis, Stefano Monti
Journal: Cancer Research (2025)

Abstract Single cell transcriptomics (scRNAseq) remains the method of choice to quantify and annotate cellular heterogeneity in the tumor and its microenvironment (TME), yet most studies are under-powered to associate changes in tumor heterogeneity with phenotypes such as tumor subtype, grade, and patient age, among others. In this study, we created an integrated atlas of human breast cancer (BC), the largest resource of its kind, totaling &amp;gt; 700,000 cells across 145 patients, and optimized computational methods to benchmark integration performance, and robustly perform hierarchical cell type annotation. By combining single profiles, a higher-resolution annotation of immune, stromal, and epithelial cell types was achieved. Further, using this integrated atlas, differential abundance analyses identified significant changes in immune and stromal cell type composition associated with tumor grade. These changes in TME heterogeneity were not discernible or had effects in the opposite direction when the analysis was limited to individual BC studies, highlighting the need for atlas-based mega-analysis approaches. This highly-resolved integrated scRNAseq BC atlas will be a valuable resource for hypothesis-driven analyses of tumor heterogeneity including our own ongoing analysis of comorbidities in BC. Citation Format: Andrew D Chen, Lina Kroehling, Christina Ennis, Gerald Denis, Stefano Monti. Highly-resolved integrated single cell atlas of human breast cancer enables hypothesis-driven analysis of tumor heterogeneity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A029.
Abstract B010: Exploring the synthetic lethal interactions between mRNA methyl-5-cytocine at sites of R-loops and mismatch repair deficiency in solid tumor
Authors: Li Lan
Journal: Cancer Research (2025)

Abstract The RNA methyltransferase TRDMT1 generates 5-methyl Cytosine (m5C) at R-loops which promotes transcription coupled homologous recombination (TC-HR) and thus impedes cellular sensitivity to R-loop induced DNA double-strand breaks (DSBs) at transcribing regions of the genome. We performed TRDMT1 inhibitor based drug screening approach in 300 cancer cell lines and identifies key factors associated with DNA mismatch repair (MMR) pathway especially in solid tumors. The R-loop accumulation correlated to severe replication stress and generated more transcription replication conflicts (TRCs) in TRDMT1 and MMR deficient background. Our study revealed synthetic lethal interactions between TRDMT1 and MMR which can provide a promising future strategy for improving treatment of solid tumors. Citation Format: Li Lan. Exploring the synthetic lethal interactions between mRNA methyl-5-cytocine at sites of R-loops and mismatch repair deficiency in solid tumor [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B010.
Abstract B014: Characterizing two emerging entities in the kidney: Eosinophilic vacuolated tumor (EVT) and low-grade oncocytic tumor (LOT)
Authors: Brenda Mai, Phuoc Christie-Nguyen, Rania Moin
Journal: Cancer Research (2025)

Abstract Context: Oncocytomas are rare benign renal tumors that encompass two emerging entities of eosinophilic vacuolated tumor (EVT) and low-grade oncocytic tumor (LOT). EVT is characterized by a solid growth of eosinophilic cells with cytoplasmic vacuolation, prominent nucleoli, and only very focal CK7 expression. LOT is a neoplasm with bland low-grade nuclei, diffuse strong CK7 labelling, and negative (CD117) expression. This study aims to characterize the immunohistochemistry of EVT and LOT through investigation of additional markers.Methodology: A retrospective review was conducted on renal oncocytic tumors (LOT and EVT) diagnosed at Memorial Hermann TMC between 2014 and 2024. Patient data, including age, gender, and tumor characteristics, were extracted from EMR. Specimens were examined for immunohistochemical markers such as CK7, CD117, GATA3, E-cadherin, and PAX8. The study posed minimal risk and was IRB-approved, with all data de-identified and securely stored.Results: Four patients with LOT were identified, comprising 2 females and 2 males, aged between 62 and 88 years, with a median age of 77 years. Histologically, the tumors were well-circumscribed, consisting of sheets and nests of monomorphic oncocytic cells with round to oval nuclei. Immunohistochemical analysis showed cells were diffusely and strongly positive for CK7 and negative for CD117, distinguishing these tumors from oncocytomas. LOT tumor cells were also found to be positive for GATA3, E-cadherin, PAX8, and Succinate dehydrogenase B (SDHB), while negative for vimentin, renal cell carcinoma (RCC), Carbonic anhydrase 9 (CAIX), CD10, and AMACR (P504s). Proliferation index by Ki-67 was low at 1-2%.Conclusion: The study provided detailed insights into the immunohistochemical profile and distinguishing features of LOT. LOT was found to be positive for GATA3 and BerEp4, which are distinct immunohistochemical characteristics compared to other renal oncocytic tumors. which aids in accurate diagnosis and enhances understanding of these emerging entities. Citation Format: Brenda Mai, Phuoc Christie-Nguyen, Rania Moin. Characterizing two emerging entities in the kidney: Eosinophilic vacuolated tumor (EVT) and low-grade oncocytic tumor (LOT) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B014.