tbuckley/cabot-search huggingface dataset:
Abstract 5047: Identifying genomic features associated with pathologic lymph node metastasis in lung adenocarcinoma patients
Authors: Shijie Wang, Zhiwei Zhou, Song Wang, Rongyun Guo, Zeming Ma, Dachuan Zhao, Liang Wang, Yinan Liu, Yuanyuan Ma, Jianzhi Zhang, Sha Wang, Yedan Chen, Haimeng Tang, Qiuxiang Ou, Jinfeng Chen
Journal: Cancer Research (2024)

Abstract Introduction: Lymph node metastasis evaluation in solid tumors is mainly complicated by the diagnostic yield of standard imaging modalities and tumor size contradictions. Exploring clinical/molecular features that complement the use of radiologic and bronchoscopy findings may provide significant values for a more accurate pathologic determination of nodal metastasis. Methods: We analyzed surgery-resected tumor samples from 72 treatment-naïve lung adenocarcinoma (LUAD) patients via whole-exome sequencing (WES). Mutational profiles of patients categorized based on their pathologic lymph node metastasis (pN) status were assessed, and the association between metastatic-driving features and overall survival (OS) was then explored in both the study cohort and the Cancer Genome Atlas Program (TCGA) external cohort. Results: Among all 72 patients, 41 (56.9%) were pathologically confirmed as positive for lymph node metastasis (pN-positive), while 31 (43.1%) were categorized as pN-negative. The most frequently mutated gene was TP53 in both subgroups (54.8% and 53.7%, respectively), and the aberrant KEAP1-NRF2 signaling pathway was found significantly more enriched in pN-negative patients. Copy-number variant analysis showed that chromosome 7p amplifications (X7p_amp) at the arm level and EGFR amplifications at the focal gene level were more frequently identified in pN-positive patients (P=0.008 and P=0.004, respectively). Importantly, these amplifications were associated with worse OS in both the study cohort and the TCGA external dataset. Consistent with the unfavorable prognosis, pN-positive patients demonstrated a higher chromosome instability score (CIS) (median: 0.32 vs. 0.14, P=0.14) and a lower tumor mutation burden (TMB) (median: 1.83 vs. 3.85 muts/Mb, P=0.048) compared to pN-negative patients. Conclusion: Our findings suggest that X7p_amp, particularly EGFR amplification, might be associated with pathologic involvement of lymph nodes and an unfavorable prognosis in LUAD patients. Our study highlights the importance of integrating clinical and genomic data into conventional radiologic modalities for a more accurate determination of pathologic nodal involvement. Citation Format: Shijie Wang, Zhiwei Zhou, Song Wang, Rongyun Guo, Zeming Ma, Dachuan Zhao, Liang Wang, Yinan Liu, Yuanyuan Ma, Jianzhi Zhang, Sha Wang, Yedan Chen, Haimeng Tang, Qiuxiang Ou, Jinfeng Chen. Identifying genomic features associated with pathologic lymph node metastasis in lung adenocarcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5047.
Abstract 5888: Novel immune-therapeutic target for lung cancer uncovered by SpliceIO™, an innovative platform that identifies disease-specific alternative splicing
Authors: Miguel A. Manzanares, Kendall Anderson, Hasan Zumrut, Sakshi Gera, Nayab Habib, Nicole Williams, Shaleigh Stanton, Taylor Floyd, Sanjana Shah, Devon Trahan, Martin Akerman, Gayatri Arun
Journal: Cancer Research (2024)

Abstract Alternative splicing (AS) plays a critical role in generating tumor-specific neoantigens targetable through an arsenal of immunotherapeutic modalities. Previous studies have demonstrated tumor-promoting activity of deregulated AS isoforms and mutated splicing factors, both of which increase the yield of neoantigen-encoding AS isoforms. Therefore, the identification of AS isoforms has the potential to produce novel therapeutic targets, especially in lung tumors where splicing deregulation is frequent. Envisagenics has developed SpliceIO, a proprietary software platform for AS-derived neoantigen discovery. SpliceIO uses RNA-seq data to uncover extracellular neoantigens encoded by transmembrane proteins. This predictive ensemble maximizes the value of RNA-seq data to predict fundamental aspects of neoantigen activity, such as protein localization, epitope accessibility, and cancer pathway relevance. Here, we summarize the discovery and validation of novel AS-derived neoantigens identified using SpliceIO in non-small cell lung cancer (NSCLC). Our novel SpliceIO-identified neoantigens in NSCLC were validated following our well-established experimental pipeline. We have confirmed RNA expression of the neoantigen-expressing transcripts in lung cancer cell lines and patient samples using a combination of RT-PCR as well as RNA-ISH. Further, we have validated the membrane-bound extracellular localization of neoantigen-containing isoforms at the protein level using Western blotting, GFP and c-Myc tagged isoform generation, eukaryotic cells transfection, and microscopy. Our top target showed high tumor specificity, heterogeneous distribution in tumor samples, high prevalence, confirmed novel extracellular N-terminal domain, and strong biological relevance in lung cancer. This demonstrates the potential of utilizing RNA splicing for identifying many more membrane associated proteins for tumor specific immunotherapeutic targeting. The combination of computational and experimental approaches to neoantigen identification using SpliceIO allows for novel target discovery amenable for targeted immunotherapeutic development for lung cancer treatment and other indications driven by deregulated AS. Citation Format: Miguel A. Manzanares, Kendall Anderson, Hasan Zumrut, Sakshi Gera, Nayab Habib, Nicole Williams, Shaleigh Stanton, Taylor Floyd, Sanjana Shah, Devon Trahan, Martin Akerman, Gayatri Arun. Novel immune-therapeutic target for lung cancer uncovered by SpliceIO™, an innovative platform that identifies disease-specific alternative splicing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5888.
Abstract 4648: Metabolic vulnerabilities of drug-resistant melanoma with therapeutic potential
Authors: Yanlin Yu, Lei Huang, Weiping Chen, Glenn Merlino
Journal: Cancer Research (2024)

Abstract Melanoma has been at the center of revolutions in both targeted BRAF therapy and immune therapy. However, the resistance to current therapeutic drugs has been a formidable obstacle to continuing benefit to patients. Overcoming resistance and new therapeutic agents and strategies are the primary goals of current cancer research. We currently found that metabolic pathways altered significantly in BRAFi-resistant melanoma. We hypothesized that BRAFi-resistant melanoma rewires its metabolic routes to reach its needs in energy and biosynthetic precursors, both essential for escaping the BRAFi attack. We found that five amino acids transporters and metabolic enzymes (ASNS, slc7a11, slc7a5, slc3a2, slc4a7) were the significant increase in resistant melanoma. Knockdown by shRNA or knockout by crispr/cas9 of these amino acids transporters or/and metabolic enzymes enhanced the sensitivity of BRAFi resistant melanoma to BRAFi. In contrast, overexpression of these amino acid transporters or/and metabolic enzymes promoted the ability of resistance of BRAFi in parent melanoma cells. Moreover, the inhibition of these amino acid transporters and metabolic enzymes by small molecular inhibitors significantly attenuated the resistance of the BRAFi-resistant melanoma whereas less affected the parent melanoma. Notably, we confirmed that blocking these amino acid transporters and metabolic enzymes by shRNA and/or small molecular inhibitors could rescue the sensitivity of resistant melanoma cells and inhibit resistant-melanoma cell growth in the preclinical mouse model in vivo. Importantly, we found that overexpression of slc7a11, slc7a5 and slc3a2 correlated with worse survival in melanoma in SK-TCGA data. Our findings uncovered the mechanism of how metabolic reprogramming fueled melanoma cell growth and proliferation for escaping drug attacks and offered a rational strategy to guide clinical treatment. The identified novel molecular proteins represented a promising therapeutic target for BRAF mutant melanoma patients with resistance to current therapy. Citation Format: Yanlin Yu, Lei Huang, Weiping Chen, Glenn Merlino. Metabolic vulnerabilities of drug-resistant melanoma with therapeutic potential [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4648.
Abstract 432: The noncanonical mechanism of metabolic enzyme LDHA in cancer progression
Authors: Juan Liu, Wenwei Hu, Zhaohui Feng
Journal: Cancer Research (2024)

Abstract Metabolic reprogramming is a hallmark of cancer cells and a key contributor to cancer progression, which is a promising target for cancer therapies. The enhanced glycolysis, also known as the Warburg effect, represents the most widely recognized metabolic alteration in cancer, wherein the majority of cancer cells undergoes reprogramming to heavily rely on glycolysis for their accelerated growth and proliferation. The glycolytic enzyme lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate in the final stage of glycolysis. LDHA is frequently overexpressed in cancers, which plays a critical role in promoting glycolysis and cancer progression. To deepen our understanding of the oncogenic mechanism of LDHA, we screened for LDHA-interacting proteins in human breast cancer cells by liquid chromatography mass spectrometry (LC/MS) analysis. Through this strategy, small GTPase Rac1 was identified as an LDHA-interacting protein. LDHA interacted with the active form of Rac1, Rac1-GTP, and impaired the interaction of Rac1-GTP with its negative regulators, GTPase-activating proteins, leading to Rac1 activation independently of the glycolytic enzyme activity of LDHA. In addition, LDHA overexpression was significantly associated with increased Rac1 activity in clinical breast cancer specimens. Inhibiting Rac1 significantly attenuated the oncogenic effect of LDHA. Combining small-molecule inhibitors targeting LDHA enzyme activity and Rac1 activity displayed a synergistic inhibitory effect on breast cancers with LDHA overexpression in mouse models. Thus, our results revealed a novel and critical noncanonical mechanism of LDHA in promoting cancer progression through its direct interaction and activation of Rac1. Given that LDHA is frequently overexpressed in cancer, LDHA overexpression constitutes an important mechanism contributing to aberrant Rac1 activation in cancer. Importantly, our findings also suggest that pharmacologically targeting LDHA enzyme activity and Rac1 activity simultaneously is a promising strategy to treat breast cancers with LDHA overexpression. Citation Format: Juan Liu, Wenwei Hu, Zhaohui Feng. The noncanonical mechanism of metabolic enzyme LDHA in cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 432.
Abstract 6740: Next-generation LNPs induce effective anti-tumor T cell responses
Authors: Douglas G. Millar, Matthew J. Gold, Kirsten Olsen, Yu Wu, Yury Karpov, Robert Nechanitzky, Haritha Menon, Rajesh Krishnan, Robert Georgantas, Pamela Ohashi, Natalia Martin-Orozco
Journal: Cancer Research (2024)

Abstract mRNA immunotherapies have gained interest for the treatment of tumors from various origins, however, their ability to provide long -term durable tumor control has been underwhelming. Here we report that novel mRNA lipid nanoparticle (LNP) vaccinations induce robust expansion of antigen-specific T cells, although this does not always correlate with their ability to infiltrate and kill solid tumors. Using a portfolio of novel ionizable lipids and a robust in vivo model that reliably identifies LNPs with prominent anti-tissue T cell activity we have identified a putative LNP candidate that provides long term tumor control in a murine syngeneic tumor model. We utilized the model antigen glycoprotein (Gp), from the lymphocytic choriomeningitis virus (LCMV), and produced mRNA encoding the immunodominant epitopes gp3333-41, gp6161-80 and gp276276-286 (3GP-mRNA). This mRNA was encapsulated in various novel LNP formulations and administered i.m. into naïve C57Bl/6 mice to track the induction of a robust CD8+ T cell response identified using tetramers to gp33 and gp276. Successful candidate LNPs were then tested in the RIPgp model of autoimmune diabetes. RIPgp transgenic mice express LCMV-Gp in the pancreatic β cells and offer a robust assay for the ability to induce antigen-specific T cells capable of breaking self-tolerance and infiltrating and killing target tissue. Utilizing the RIPgp model to screen LNP candidates we identified a lead candidate, C2-5A, that both induced a robust expansion of antigen-specific T cells and tissue destruction. When utilized in a colon adenocarcinoma model expressing the LCMV-Gp antigen (MC38-Gp), therapeutic dosing of LNP C2-5A as a monotherapy lead to long term tumor clearance in 40% of the treated animals. We believe this screening platform allows the selection of LNP candidates capable of breaking self-tolerance, and one such candidate C2-5A provides a potent vehicle and adjuvant for mRNA based cancer vaccines. Citation Format: Douglas G. Millar, Matthew J. Gold, Kirsten Olsen, Yu Wu, Yury Karpov, Robert Nechanitzky, Haritha Menon, Rajesh Krishnan, Robert Georgantas, Pamela Ohashi, Natalia Martin-Orozco. Next-generation LNPs induce effective anti-tumor T cell responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6740.
Abstract 4616: TBK1 and GSK3 mediated TRAF2 phosphorylation confers resistance to PI3K-AKT inhibition in breast cancer cells
Authors: Hasem Habelhah, Laiqun Zhang
Journal: Cancer Research (2024)

Abstract Breast cancer (BC) is the most frequently diagnosed malignancy and the second leading cause of cancer mortality in Western women. As is the case for most other solid tumors, metastasis and drug resistance are the main causes of death. In ~80% of BC cases, the PI3K-AKT pathway is aberrantly activated, due to the alterations in genes encoding the pathway components, such as Ras, Her2, PTEN, PIK3C and AKT. Consequently, over 100 clinical trials are currently underway worldwide to evaluate the therapeutic efficacy of PI3K and AKT inhibitors in BC; however, initial data revealed that inhibition of this pathway is either not effective or often results in development of resistance and relapse of the disease. Thus, identification of additional targets and therapeutic combinations are urgently needed. We previously reported that TBK1-mediated TRAF2 Ser-11 phosphorylation enhances NF-κB activation to promote cancer cell survival under conditions of cellular stresses. Recently, we discovered that GSK3β directly phosphorylates TRAF2 at Thr-7 upon Ser-11 phosphorylation by TBK1, and that phosphorylation of both Thr-7 and Ser-11 is essential for sustained NF-κB activation and BC cell resistance to PI3K-AKT inhibition. TBK1 and its close homologue IKKε are overexpressed in ~70% of BC and play critical roles in BC cell survival. GSK3β is a constitutively active kinase activity in unstimulated normal cells, but its activity is suppressed in most cancer cell types by AKT-mediated phosphorylation. These published reports and our new findings suggest that inhibition of AKT in BC cells leads to increased phosphorylation of TRAF2 by TBK1 and GSK3β, which confers resistance to PI3K-ATK inhibition. Bioinformatic analyses revealed that TRAF2 and GSK3β are also overexpressed in invasive BC, and significantly correlate with poor prognosis. As expected, inhibition of both AKT and TBK1 or GSK3b synergistically induced apoptosis in BC cell lines in vitro and significantly suppressed xenograft BC tumor growth in vivo. Thus, our data suggest that further investigation of the efficacies of combined PI3K/AKT and TBK1/GSK3β inhibition in PDX models of BC has the potential to develop new strategies for BC treatment. Citation Format: Hasem Habelhah, Laiqun Zhang. TBK1 and GSK3 mediated TRAF2 phosphorylation confers resistance to PI3K-AKT inhibition in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4616.
Abstract 7362: Integrated analysis of scRNAseq and spatial omics in brain metastatic lung cancer tumor tissue
Authors: Haruka Hirose, Takahiro Tsuji, Yasuhiro Kojima, Akihiko Yoshizawa, Yoshiki Arakawa, Hiroaki Ozasa, Hiroaki Wake, Teppei Shimamura
Journal: Cancer Research (2024)

Abstract Spatial omics technologies have made significant advances in recent years, improving our understanding of the spatial localization of cells and intercellular interactions. Intercellular interactions are essential for maintaining proper tissue function and homeostasis, and dysregulation of these interactions can contribute to various diseases, including cancer and autoimmune disorders. Ligand proteins, one of the signaling molecules responsible for cell-cell interactions, bind to cell surface receptors and trigger intracellular signaling pathways. The effective range of ligand signaling, i.e. the extent to which a cell spatially and directly transmits information via the ligand, has not been systematically studied, although it may determine the occurrence of cell-cell interactions. The authors have previously developed methodologies combining spatial transcriptomics and single-cell RNA sequencing to analyze intercellular interactions at the single-cell level in spatial dimensions. Additionally, we have devised a technique to model the spatial diffusion of ligands from spatial transcriptomics and estimate the spatial range of ligand action. In this study, we used these developed methods to elucidate events in the tumor microenvironment of brain metastatic lung cancer tissue. Specifically, an integrated analysis of metastatic brain tumor samples was performed using visium and single-cell data from the same patient. The results suggest the presence of a heterogeneous microglial subpopulation, including clusters enriched in cytokines and chemokines for angiogenesis and wound healing, clusters associated with immune tolerance via IL-10 signaling, clusters enriched in gene sets related to phagocytosis, antigen processing, and antigen presentation, and clusters related to clearance of pathogens and residues. The presence of homogeneous microglial subpopulations was suggested. Furthermore, these subpopulations exhibited different spatial distributions, suggesting that they interact with surrounding cancer cells through different mechanisms. Citation Format: Haruka Hirose, Takahiro Tsuji, Yasuhiro Kojima, Akihiko Yoshizawa, Yoshiki Arakawa, Hiroaki Ozasa, Hiroaki Wake, Teppei Shimamura. Integrated analysis of scRNAseq and spatial omics in brain metastatic lung cancer tumor tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7362.
Abstract 6480: In-hospital mortality risk factors for uveal melanoma patients in the emergency department
Authors: Alice A. Beneke, Kamil Taneja, Lauren Ladehoff, Kevin Root, Eric Toloza
Journal: Cancer Research (2024)

Abstract Purpose: A considerable amount of uveal melanoma patients present to the emergency department (ED) for a complication related to their primary tumor. However, there is not much research into the primary reasons for these patients to present to the ED and their outcomes. Methods: The Nationwide Emergency Department Sample was queried from the last quarter of 2015 to 2019 to identify patients with a diagnosis of uveal melanoma. Multivariable logistic regression, with patient- and hospital-level characteristics as covariates, was used to identify factors associated with increased risk of in-hospital death. Results: From the last quarter of 2015 to 2019, there were 7,561 ED encounters with a secondary diagnosis of uveal melanoma. Most patients were at least 65 years of age (43.5%), male (52.5%), and a Medicare beneficiary (44.2%), or belong to a family in the 3rd income quartile (25.6%). The median age of these patients was 61 years (IQR: 32-74). Most patients presented to hospitals in the South (40.8%), with a Trauma Level I designation (47.2%), and to a metropolitan teaching hospital (72.6%). The most common diagnosis for presentation to the ED were the following general clinical categories: blood disorders (7.1%), genitourinary tract disorders (5.1%), infections (6.0%), respiratory diseases (9.0%), nervous system disorders (4.8%), endocrine/nutrition disorders (4.3%), and vascular disorders (8.3%). The rate of metastatic uveal melanoma was 5.8%. The rate of in-hospital mortality was 3.6%. In a multivariable logistic regression identified the following clinical categories as factors associated with a higher risk of in-hospital death: infections (odds ratio [OR]=10.22; p&amp;lt;0.001), metastases (OR=10.22; p&amp;lt;0.001), genitourinary tract disorders (OR=7.05; p&amp;lt;0.001), respiratory diseases (OR=3.31; p=0.031), and vascular disorders (OR=3.14; p=0.044). Nervous system, blood, and endocrine/nutrition disorders were not associated with a higher rate of in-hospital mortality. The only demographic variable associated with a higher risk of in-hospital death was being part of the top income quartile (OR=3.10; p=0.14). Conclusion: Physicians have to be mindful of different complications associated with uveal melanoma that can lead to presentation to the ED and possible in-hospital death. Specifically, physicians need to be mindful of infections, metastases, genitourinary tract disorders, respiratory diseases, and vascular disorders in these patients. Citation Format: Alice A. Beneke, Kamil Taneja, Lauren Ladehoff, Kevin Root, Eric Toloza. In-hospital mortality risk factors for uveal melanoma patients in the emergency department [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6480.