tbuckley/cabot-search huggingface dataset:
Abstract A002: Immunotherapy responses in liver cancer: How TERT and TP53 mutations affect outcomes
Authors: Ebtesam Al-Najjar, Bayan Khasawneh, Waseem Abdelrahim, Abdullah Esmail, Ala Abudayyeh
Journal: Cancer Research (2025)

Abstract Background: Genomic profiling has revolutionized therapeutic approaches and clinical management for liver cancer. However, the pathogenetic mechanisms, molecular drivers of recurrence, and predictive biomarkers remain only partially understood. An analysis of the United States Hepatocellular Carcinoma (HCC) cohort from The Cancer Genome Atlas showed that common mutations are mainly located in the TERT promoter region, TP53, and CTNNB1 genes. Recent studies on smaller Chinese have also identified TP53, TERT, and CTNNB1 as the most frequently mutated genes among Chinese HCC patients. Our study further explores the correlation between specific genomic mutations (TERT, TP53), and immunotherapy response in HCC cases. Methods: The cBioPorta was used for genomic profiling in multiple cohort studies of hepatobiliary cancer cases. Only HCC cases with TERT and TP53 mutation, and patients who had received immunotherapy, were included. Cases involving cholangiocarcinoma (CCA), HCC with CCA, other genetic mutations, or patients treated with chemotherapy were excluded from this study. Kaplan-Meier survival curves were created to assess the median overall survival (OS) based on immunotherapy response, and we calculated pooled 95% confidence intervals (CIs) to determine the reliability and precision of our result. The log-rank P-value was used to assess differences in OS between mutated genes. Results: The total cases were 1915 of hepatobiliary cancer after excluding 873 cases remaining with HCC among them, 400 patients (45.8%) had mutations in TERT, and 403 patients (46.2%) had mutations in TP53. The finalized number was 65 (64.4%) with TERT and 43 (42.4%) with TP53 who received immunotherapy. The median OS differed substantially across mutation types: 42 months for TERT mutations, 37 months for TP53 mutations, and 58 months for cases with both mutations (p=0.5). Conclusion: Our study observed improved OS in patients with both TERT and TP53 mutations. Although patients with only TERT mutations had better OS compared to those with TP53 mutations alone. Further research is required to clarify the specific associations between TERT mutations and treatment outcomes. Citation Format: Ebtesam Al-Najjar, Bayan Khasawneh, Waseem Abdelrahim, Abdullah Esmail, Ala Abudayyeh. Immunotherapy responses in liver cancer: How TERT and TP53 mutations affect outcomes [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 A002.
Abstract A022: Decoding aneuploidy: Identifying drivers and therapeutic targets in recurrent breast cancer copy number alterations
Authors: Khalid N Al-Zahrani, Ellen R Langille, Andreea Obersterescu, Christopher Lowden, Katie Teng, Lauren Caldwell, David Cook, Miguel Pérez-Castro, Cynthia Chiu, Alexander Bahcheli, Ricky Tsai, Jacob Berman, Kin Chan, Linkang Zhang, K.W. Annie Bang, Michael Parsons, Adele Lopes, Jocelyn Nurtanto, E. Idil Temel, Iosifina Fotiadou, Julien Dessapt, Hartland Jackson, Sean Egan, Jüri Reimand, Jeffrey Wrana, Daniel Schramek
Journal: Cancer Research (2025)

Abstract Chromosome instability is highly prevalent in cancer and drives large scale chromosomal imbalances, known as aneuploidies. However, how aneuploidy contributes to tumorigenesis remains difficult to study due to the vast numbers of genes affected. To address these limitations, we have developed a CRISPR-Knock Out and Activation Linked Assay (CRISPR-KOALA), which enables systematic high-throughput bidirectional genetic screens in immune-competent mouse models of cancer. Using CRISPR-KOALA we screened the mouse orthologs of all 3,752 genes residing on the ten most frequently altered human chromosome arms in basal-like breast cancer (BLBC), which to date is the largest bidirectional screen performed in vivo. Our screen identified 90 cancer driver genes, the vast majority of which have hitherto unknown functions in cancer. These genes drive distinct signalling pathways, reflecting the high degree of BLBC heterogeneity. Individual manipulation of the identified cancer driver genes completely overcomes the need for copy number alterations (CNAs) in p53-mutant BLBC mouse models. Mechanistically, we uncover PLGRKT as a potent oncogene and show that its tumor-promoting activity is associated with the creation of highly stress-resistant mitochondria that promote tumor cell survival, rather than through its canonical role of regulating the extracellular matrix. Overall, our work reveals that arm-level CNAs can function to select specific driver genes to promote heterogenous biological processes. Citation Format: Khalid N Al-Zahrani, Ellen R Langille, Andreea Obersterescu, Christopher Lowden, Katie Teng, Lauren Caldwell, David Cook, Miguel Pérez-Castro, Cynthia Chiu, Alexander Bahcheli2, Ricky Tsai, Jacob Berman, Kin Chan, Linkang Zhang, K.W. Annie Bang, Michael Parsons, Adele Lopes, Jocelyn Nurtanto, E. Idil Temel, Iosifina Fotiadou, Julien Dessapt, Hartland Jackson, Sean Egan, Jüri Reimand, Jeffrey Wrana, Daniel Schramek. Decoding aneuploidy: Identifying drivers and therapeutic targets in recurrent breast cancer copy number alterations [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 A022.
Abstract A012: Mutation analysis of SCLC patients with distant metastases
Authors: Yin Liu, Yuezhu Wang, Ralph D’Agostino, Jimmy Ruiz, Lance D Miller, Wencheng Li, Michael D Chan, Liang Liu, Fei Xing
Journal: Cancer Research (2025)

Abstract Small cell lung cancer (SCLC) is a highly proliferative and aggressive type of lung cancer, accounting for 10–15% of all lung cancer cases. SCLC is characterized by early metastasis, with more than half of the cases presenting with metastases at the time of diagnosis. While comprehensive genomic studies have been performed for SCLC, metastasis-associated mutations have not been fully characterized. In this study, 57 SCLC samples from the Wake Forest Baptist Comprehensive Cancer Center (WFBCCC), profiled by either FoundationOne CDx or Guardant360 CDx between 2013 and 2022, were analyzed. The most common metastatic sites were identified as the brain (54.3%), liver (45.6%), and bone (33.3%). Associations between clinical features and distant metastases were examined, with no significant differences observed in age, sex, race, or smoking status among the metastatic groups. To explore the relationship between gene mutation rates and distant metastatic sites, we collected somatically altered genes from these patients. Stratified by metastatic site, Cox proportional hazards regression analysis was performed to identify mutations associated with the progression of metastases. BRCA2 and APC alterations were significantly associated with brain metastases, while PDGFRA mutations were linked to liver metastases. No mutations were found to be associated with bone metastases. Our findings suggest the potential efficacy of PARP inhibitors for treating brain metastases and PDGFRA inhibitors for addressing liver metastases in SCLC. Validation in SCLC animal model is under investigation. This study reveals specific mutations associated with metastatic progression to the brain and liver. These findings underscore the importance of precision medicine approaches in tailoring treatments based on the genetic profile of tumors, offering the potential to improve outcomes for patients with this aggressive cancer. Citation Format: Yin Liu, Yuezhu Wang, Ralph D’Agostino, Jimmy Ruiz, Lance D Miller, Wencheng Li, Michael D Chan, Liang Liu, Fei Xing. Mutation analysis of SCLC patients with distant metastases [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 A012.
Abstract B033: Patient-derived 3D organoids for drug screening in cutaneous neurofibroma: A personalized approach to treatment discovery
Authors: Huyen Thi Lam Nguyen, Alberto Mendoza Valderrey, Summer Norris, Andre Panossian, Sara Gosline, Paul Piehowski, Hutchinson Chelsea, Alice Soragni
Journal: Cancer Research (2025)

Abstract Neurofibromatosis type 1 (NF1) is a common genetic disorder, affecting approximately 1 in 3,500 individuals worldwide. Mutations in the NF1 gene impair the function of the tumor suppressor protein neurofibromin, which plays a crucial role in regulating cell proliferation and differentiation. Alterations of NF1 lead to dysregulation of the RAS signaling pathway and uncontrolled cell proliferation. Approximately 90% of NF1 patients develop cutaneous neurofibromas (cNFs)—benign skin tumors Although benign, cNFs cause substantial morbidity and quality of life deterioration for affected individuals. No approved therapies for cNFs currently exist, with surgery as the only non-curative treatment option. Drug development for cNFs is complicated by a lack of models that recapitulate the complexity of their composition. We have developed a platform to rapidly establish and screen patient-derived 3D cNF organoids. By mirroring key characteristics of the original tumors, including cellular complexity and heterogeneity, cNF organoids match patient tumor’s characteristics at the cellular and molecular level. We are conducting drug screenings on individual tumor from every patient to identify compounds that inhibit cNF tumor cell proliferation, and identifying biomarkers predictive of drug response. We have enrolled 22 NF1 patients undergoing cNF removal as part of their clinical care. Preliminary drug screening results indicate variable drug sensitivities among patients, with notable dose-dependent responses to Onalespib (an Hsp90 inhibitor) and Digoxin (a Na+/K+ ATPase inhibitor). By integrating drug response data with proteogenomic profiles, we aim to leverage a machine learning-based biomarker discovery pipeline, to identify specific transcripts, proteins, and phosphosites associated with drug sensitivities. Citation Format: Huyen Thi Lam Nguyen, Alberto Mendoza Valderrey, Summer Norris, Andre Panossian, Sara Gosline, Paul Piehowski, Hutchinson Chelsea, Alice Soragni. Patient-derived 3D organoids for drug screening in cutaneous neurofibroma: A personalized approach to treatment discovery [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 B033.
Abstract A023: Zebrafish personalized medicine models of fusion-driven rhabdomyosarcoma
Authors: Lisa Hall, Madison Kouche, Emma Harrison, Kareesma Parbhoo, Elaine Mardis, Genevieve Kendall
Journal: Cancer Research (2025)

Abstract Clinical sequencing efforts have revolutionized our approaches to categorizing pediatric cancers in real time. This has dramatically improved our ability to profile pediatric tumors and in some circumstances to identify actionable vulnerabilities and personalize clinical care. Unfortunately, many of the fusion positive pediatric sarcomas are driven by oncogenic fusions that have unclear mechanisms of transformation and lack therapeutic targets. Many of these fusion-oncogenes have no cell, patient derived xenograft (PDX), or animal model to understand the biology of the human disease. This makes identifying potential new targeted therapies challenging. Our group has developed a strategy to model novel rhabdomyosarcoma fusion-oncogenes in vertebrate zebrafish systems. We have shown success with this precision functional genomics approach for alveolar and infantile rhabdomyosarcoma, including the PAX3::FOXO1 and VGLL2::NCOA2 oncogenic fusions. We found that human fusion-oncogenes generated tumors in zebrafish that histologically and transcriptionally recapitulate the human disease. We are now collaborating with the NCI-COG-NCH Molecular Characterization Initiative to identify novel rhabdomyosarcoma fusion-oncogenes, with no existing animal models, to incorporate into this precision medicine approach. This model uses a Tol2 transposon-based system to integrate the human fusion-oncogene coding sequence into the zebrafish genome. We track tumor formation in the fish by linking the fusion-oncogene to a viral 2A GFP sequence, which functions as a visual proxy for expression in vivo. Here, we present SRF::NCOA2, a fusion of transcriptional coactivators found in human spindle-cell rhabdomyosarcoma, that is transforming in multiple promoter contexts. The SRF::NCOA2 injected zebrafish in our model develop tumors before six months of age. We are now validating fidelity with the human disease using histology and bulk RNA sequencing to identify shared transcriptional signatures. Broadly, we see this as a high throughput strategy in vertebrate models to mechanistically study novel fusion oncogenes. We anticipate our modeling strategies will support targeted therapy development to improve patient treatment and outcomes. Citation Format: Lisa Hall, Madison Kouche, Emma Harrison, Kareesma Parbhoo, Elaine Mardis, Genevieve Kendall. Zebrafish personalized medicine models of fusion-driven rhabdomyosarcoma [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 A023.
Abstract IA031: AI and implementation of personalized medicine
Authors: Casey S Greene
Journal: Cancer Research (2025)

Abstract Personalized medicine is often viewed as limited by our ability to gather and integrate data to predict the best treatment options for each patient. Multi-omic and multi-modal precision medicine reflect attempts to bring all available data to bear on this challenge. I'll discuss lessons learned from within our lab on modeling efforts in this space. I'll also discuss how other underrecognized barriers are, in my experience, more limiting than modeling challenges in implementing personalized or precision medicine. Citation Format: Casey S Greene. AI and implementation of personalized medicine [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 IA031.
Abstract A014: Blocking the HHLA2 immune checkpoint alters transcriptomic signature in specific subsets of NK cells
Authors: Nahuel Perrot, Nikolaos Kalavros, Deepthi Chowbene, Shoushuo Wang, Yered Pita-Juarez, Antonella Arruda de amaral, David McDermott, Gordon Freeman, Ioannis Vlachos, Kathleen Mahoney
Journal: Cancer Research (2025)

Abstract Background: Determining how immune checkpoint inhibitors (ICI) alter functional characteristics of lymphocytes can improve our understanding of these treatments. HERV-H LTR-associating 2 (HHLA2, B7-H7) is an immune checkpoint expressed by many tumors. HHLA2 has an activating receptor, TMIDG2, and an inhibitory receptor, KIR3DL3. The KIR family of receptors is expressed in NK cells as well as T cells. We developed a series of monoclonal antibodies that block the inhibitory HHLA2:KIR3DL3 interaction. HHLA2:KIR3DL3 blocking antibodies in Phase I clinical trials are currently enrolling cancer patients (NCT05958199, NCT06240728). Method : We performed single-cell RNA sequencing on co-cultures of NK cells isolated from peripheral blood cells with or without the presence of K562 cells expressing HHLA2, which are NK cells target, to assess the effects of HHLA2 antibodies blocking HHLA2:KIR3LD3. Co-cultured cells were treated with different HHLA2 blocking antibodies or isotype control. Results : We found different subsets of NK cells in the cocultures delineated by different marker sets, including the XCL2 and CCL4 chemokines, further differentiated TXNIP positive NK cells and BCL2 positive subsets. Additionally, we observed differential abundance between the interaction blocking conditions as compared to isotypes controls. Furthermore, differential gene expression analysis after non-selective HHLA2 blockade was more pronounced in the XCL2+ subset, followed by the CCL4+ subset, and included genes implicated in phagocytosis, regulation of macrophages and chemotaxis, signaling detection, cytokine secretion, and the humoral immune response respectively for each subset. Finally, by iteratively sub-clustering our subsets based on known NK cell markers, we have discovered clusters reflecting a milieu of NK cell states and activity profiles. We will explore whether these subsets of NK cells, specifically XCL2 and+ CCL4+ subsets, are expressed in tumors and characterize the interaction in greater depth. Conclusion : Better understanding of how blocking the HHLA2:KIR3DL3 pathway affects lymphocyte function could determine which patients may best benefit from targeting this pathway. Citation Format: Nahuel Perrot, Nikolaos Kalavros, Deepthi Chowbene, Shoushuo Wang, Yered Pita-Juarez, Antonella Arruda de amaral, David McDermott, Gordon Freeman, Ioannis Vlachos, Kathleen Mahoney. Blocking the HHLA2 immune checkpoint alters transcriptomic signature in specific subsets of NK cells [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 A014.
Specific targeting of the 5‐hydroxytryptamine <scp>2B</scp> receptor (5‐<scp>HT<sub>2B</sub>R</scp>) demonstrates antifibrotic effects in murine models and ex vivo models of scleroderma skin
Authors: Thuong Trinh‐Minh, Cuong Tran‐Manh, Andrea‐Hermina Györfi, Nicholas Dickel, Christoph Liebel, Xiang Zhou, Jiucun Wang, Meik Kunz, Helena Arozenius, Lars Pettersson, Sam Lindgren, Christina Wenglén, Jörg H.W. Distler
Journal: Arthritis & Rheumatology (2025)

Systemic sclerosis (SSc) is a connective tissue disease with fibrotic remodeling of the skin and various internal organs. SSc is associated with the highest case-specific mortality of all rheumatic autoimmune diseases with limited antifibrotic treatment options. Here, we evaluated the therapeutic effects of the highly selective 5-hydroxytryptamine 2B receptor (5-HT2BR) inhibitor AM1476. The antifibrotic effects of AM1476 were evaluated in the mouse models of bleomycin-induced pulmonary fibrosis, in tight-skin-1 (Tsk-1) mice and in mice with sclerodermatous chronic graft-versus-host disease (cGvHD). For further validation, the antifibrotic effects of AM1476 were analyzed in precision cut skin (PCS) slices from SSc patients. AM1476 demonstrated high selectivity for 5-HT2BR over more than 200 other receptors including other 5-HT receptors in vitro. AM1476 reduced accumulation of hydroxyproline and fibrotic tissue remodeling of skin and/or lung in all three mouse models at well tolerated doses with a comparable efficacy to that of Nintedanib. In PCS of SSc skin, treatment with AM1476 reduced the expression of SSc-specific signature genes. AM1476 demonstrated more pronounced regulation of terms related to fibroblast activation and fibrotic remodeling than mycophenolate mofetil (MMF). We describe AM1476 as a highly selective inhibitor of 5-HT2BR. Treatment with AM1476 ameliorated fibrosis in three mouse models of SSc and normalized the expression of fibrosis-related genes directly in SSc skin. As AM1476 also demonstrated good tolerability in a phase I trial, further clinical trials with AM1476 are currently in the planning stage.
Abstract A034: Cancer neutrophil encyclopedia: A deep dive into antigen-presenting warriors
Authors: Yingcheng Wu
Journal: Cancer Research (2025)

Abstract Neutrophils, the most efficient defenders against pathogens, are essential for tumor microenvironment balance and homeostasis. However, given their plasticity and short half-life which made them too fragile to be profiled, it poses complex challenges regarding how neutrophils are imprinted and adapt specific fates across cancers. Here we designed a one-two-punch sorting strategy, generated the neutrophil atlas from 225 samples of 144 patients from 17 cancer types, and further developed a computational pipeline to recover both shared and specific transcriptional programs. Unexpectedly, neutrophils harbored extraordinary complexity composed of 10 cell states and showed sharp tissue or phenotypic specialty. We observed and verified that cancer neutrophils are dramatically arranged along tumor-specific terminal differentiation paths such as inflammation, angiogenesis and antigen-presenting. In particular, the antigen-presenting program was associated with better patient outcomes in the majority of cancers. Such a program can be evoked by leucine metabolism and is dependent on mitochondrial remodeling, acetyl-CoA generation, and preferable epigenetic histone H3K27ac modification. Functionally, antigen-presenting neutrophils invoked expanded T cell response and neoantigen-specific reactiveness. We finally designed the antigen-presenting neutrophil immunotherapy (adoptive transferring and leucine diet) which fine-tunes the microenvironment balance and fuels anti-PD-1 immunotherapy. In summary, these data not only lay the groundwork for future neutrophil research, and open the black box of neutrophil state divergence across cancers, but also unravel minimally invasive therapeutic opportunities including adoptive transferring antigen-presenting neutrophils. Citation Format: Yingcheng Wu. Cancer neutrophil encyclopedia: A deep dive into antigen-presenting warriors [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 A034.
Abstract IA012: Panel Discussion 1: Regulatory and Non-Regulatory Challenges to the Wide Adoption of Precision Diagnostics
Authors: Anthony Letai
Journal: Cancer Research (2025)

Abstract While in recent years, genomic and functional precision medicine have overcome many technical and scientific challenges, widespread adoption is often limited by factors that go well beyond the laboratory or clinic. In this session, the panel will discuss important practical and logistical challenges that continue to limit patient access to precision medicine tools in cancer. Topics will include governmental regulation, reimbursement, tissue custody, and awareness. Citation Format: Anthony Letai. Panel Discussion 1: Regulatory and Non-Regulatory Challenges to the Wide Adoption of Precision Diagnostics [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 IA012.