tbuckley/cabot-search huggingface dataset:
Abstract 3547: The ISB Cancer Gateway in the Cloud (ISB-CGC): Access, explore and analyze large-scale cancer data through the Google Cloud
Authors: Fabian Seidl, Lauren Hagen, Jacob Wilson, Boris Aguilar, Deena Bleich, Lauren Wolfe, Poojitha Gundluru, Prema Venkatesan, Mi Tian, Suzanne Paquette, Elaine Lee, Danna Huffman, David Pot, William Longabaugh
Journal: Cancer Research (2024)

Abstract Rapid growth of cancer data in recent decades has made data discovery and wrangling difficult for the average cancer research lab. Our mission at the ISB Cancer Gateway in the Cloud (ISB-CGC), part of the NCI’s Cancer Research Data Commons ecosystem, is to democratize access to large cancer datasets. Funded by the NCI, we have performed ETL processes on data from GDC and PDC projects such as TCGA, TARGET, and CPTAC. We generated hundreds of BigQuery tables containing data such as mutations, gene expression, and protein abundance, which enable data analysis in the cloud via SQL. BigQuery analyses are inexpensive and rapid even when scaled to petabyte sized inputs, for example we ran 6.6 billion correlations in 2.5 hours with a total cost of about one dollar. These data can also be accessed affordably from Google Cloud VMs where researchers can develop analysis pipelines in Python, R, and workflow languages such as CWL. We present two recent collaborations: In one BigQuery was used to develop machine learning algorithms that calculated genetic risk scores from TCGA glioblastoma and ovarian cancer copy number variation. In another example researchers combined SQL queries of our BQ tables with data from the ISPY2 Trial initiative and generated an R shiny app that can dynamically create data visualizations for genes of interest in different TCGA cohorts. Citation Format: Fabian Seidl, Lauren Hagen, Jacob Wilson, Boris Aguilar, Deena Bleich, Lauren Wolfe, Poojitha Gundluru, Prema Venkatesan, Mi Tian, Suzanne Paquette, Elaine Lee, Danna Huffman, David Pot, William Longabaugh. The ISB Cancer Gateway in the Cloud (ISB-CGC): Access, explore and analyze large-scale cancer data through the Google Cloud [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 3547.
Abstract 3581: IGFR1 and MEK inhibition synergize to mediate anti-tumor activity in adrenocortical carcinoma
Authors: Suresh Kumar, Nai-Yun Sun, Yasuhiro Arakawa, Diana Varghese, Chuong D. Hoang, Jonathan M. Hernandez, Yves Pommier, Craig Thomas, Jaydira Del Rivero, Nitin Roper
Journal: Cancer Research (2024)

Abstract Adrenocortical carcinoma (ACC) is an aggressive and rare endocrine malignancy with limited treatment options and poor prognosis. IGF2, the ligand for IGFR1, is highly expressed in ACC. However, linsitinib, an IGFR1 inhibitor, failed to improve overall survival over placebo in a randomized, phase 3 clinical trial of metastatic ACC. We hypothesized that combination therapy with IGFR1 inhibition may have greater anti-tumor efficacy in ACC than IGFR1 inhibition alone. To test this hypothesis, we performed high-throughput cell toxicity screening of 2803 clinical-stage compounds with linsitinib in an ACC cell line. MAPK inhibitors were among the top screening hits. MEK inhibitors were chosen for further evaluation given the safety, tolerability, and broad clinical activity of these FDA-approved agents. IGFR1 and MEK inhibitors were strongly synergistic in cytotoxicity across ACC cell lines, ACC organoid short-term cultures derived from surgical tissue resections (PDOs), and PDX-derived organoids (PDXOs). Genetic depletion of IGF2 significantly inhibited growth with cobimetinib and genetic depletion of MEK1 inhibited growth with linsitinib in ACC cell lines. Combination IGFR1 and MEK inhibition downregulated ERK phosphorylation and increased apoptosis compared to either IGFR1 or MEK inhibition alone. Linsitinib combined with cobimetinib significantly reduced tumor growth compared to either linsitinib or cobimetinib alone in an ACC xenograft model. Our study provides preclinical support for testing the combination of IGFR1 and MEK inhibition in patients with ACC. Citation Format: Suresh Kumar, Nai-Yun Sun, Yasuhiro Arakawa, Diana Varghese, Chuong D. Hoang, Jonathan M. Hernandez, Yves Pommier, Craig Thomas, Jaydira Del Rivero, Nitin Roper. IGFR1 and MEK inhibition synergize to mediate anti-tumor activity in adrenocortical carcinoma [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 3581.
Abstract 6933: Decoding the archetypes and eco-hubs of triple-negative breast cancer in responses to chemotherapy
Authors: Yun Yan, Yiyun Lin, Tapsi Kumar, Shanshan Bai, Jianzhuo Li, Tuan Tran, Min Hu, Elizabeth Ravenberg, Maia Rauch, Alyson Clayborn, Alastair Thompson, Bora Lim, Lei Huo, Stacy Moulder, Clinton Yam, Nicholas Navin
Journal: Cancer Research (2024)

Abstract Triple-negative breast cancer (TNBC) is a highly aggressive type of breast cancer commonly treated with neoadjuvant chemotherapy (NAC). While about 50% of patients achieve a pathological complete response (pCR), the remainder often develop resistance and metastasis, leading poor survivals. Currently, the factors linking pre-treatment cancer cells and the tumor microenvironment (TME) to NAC response are unclear. To investigate this question, we conducted single-cell RNA sequencing on fresh pre-treatment core biopsy samples collected from patients in the ARTEMIS clinical trial. We identified 13 gene expression meta-programs of cancer cells and about 50 cell states of immune and stromal cell types. Based on the cancer cells alone, we identified four TNBC archetypes at patient-level: luminal secretory-associated (LSA), basal-associated (BA), immunoreactive (IR), and luminal androgen receptor (LAR). Notably, the archetype BA and IR were associated with non-pCR and pCR, respectively. Additionally, we found the TNBC ecosystem was composed of eight eco-hubs, reflecting the co-occurrence patterns of cancer and TME cell states. These eco-hubs revealed different cell community across archetypes and NAC outcomes. For example, an eco-hub with a co-occurrence of interferon response-related cancer cells and immune cells was prevalent in the archetype IR and pCR patients. To facilitate a clinical application, we further developed a 13-gene-based machine learning model to predict NAC response. In summary, these results provide new insights into the cellular determinants of TNBC biology and chemotherapeutic response. Citation Format: Yun Yan, Yiyun Lin, Tapsi Kumar, Shanshan Bai, Jianzhuo Li, Tuan Tran, Min Hu, Elizabeth Ravenberg, Maia Rauch, Alyson Clayborn, Alastair Thompson, Bora Lim, Lei Huo, Stacy Moulder, Clinton Yam, Nicholas Navin. Decoding the archetypes and eco-hubs of triple-negative breast cancer in responses to chemotherapy [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 6933.
Abstract 2541: The landscape of circular extrachromosomal amplification in pediatric cancers
Authors: Sunita Sridhar, Owen S. Chapman, Shanqing Wang, Aditi Dutta, Jill P. Mesirov, Lukas Chavez
Journal: Cancer Research (2024)

Abstract Circular extrachromosomal DNA (ecDNA, also known as double minutes, dm) has emerged as a driver of oncogenic copy number amplification, intratumoral heterogeneity, tumor evolution and therapy resistance. We recently screened the whole genomes of 481 medulloblatomas for ecDNA and concluded that medulloblastoma tumors harboring ecDNA are more than twice as likely to progress within 5 years of diagnosis. To evaluate the frequency and clincical impact of ecDNA across the spectrum of childhood cancers, we performed a retrospective analysis of 1671 tumors from 1482 patients across 47 pediatric tumor types from two large cloud pediatric cancer genomics resources, the Children’s Brain Tumor Network and St. Jude Cloud. ecDNA was detected in 15 pediatric tumor types, including ETMR (100%, n=4), osteosarcoma (47%, n=57), rhabdomyosarcoma (40%, n=35), neuroblastoma (30%, n=106), high-grade glioma (20%, n=157), and retinoblastoma (19%, n=32). Patients with tumors containing ecDNA had significantly poorer 5-year overall survival. In sequential samples from the same tumor at diagnosis and relapse, we observe evidence of ecDNA evolution including sequence instability and generation of new high-copy ecDNA amplification not detected at initial diagnosis. These results comprise the most detailed survey to date of the landscape of extrachromosomal amplifications across childhood cancers. Citation Format: Sunita Sridhar, Owen S. Chapman, Shanqing Wang, Aditi Dutta, Jill P. Mesirov, Lukas Chavez. The landscape of circular extrachromosomal amplification in pediatric cancers [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 2541.
Abstract 3984: Full-length TCR and BCR repertoire analysis, integrated with mRNA and surface proteins characterization, in a tumor mouse model
Authors: Ali Rezvan, Xiaoshan Shi, Moen Sen, Stephanie Widmann, Aaron Tyznik
Journal: Cancer Research (2024)

Abstract Full-length TCR and BCR analysis with single-cell multiomic assays provides an understanding of immune responses, offering insights into the complete receptor structure and functionality that is crucial for accurately assessing the diversity and specificity of immune repertoires. Studying mouse immune cell heterogeneity can be achieved by simultaneous mRNA and surface protein profiling. However, when coupled with full-length TCR and BCR analysis, this integrated approach provides a more comprehensive understanding of immune responses and cellular function in healthy and diseased conditions. In this study, we used the MC38 colon carcinoma model to study T and B cell heterogeneity and clonotype diversity. We stained single-cell suspensions prepared from bone marrow, thymus, spleen and tumor tissues with 20 AbSeq (CITE-Seq) antibody oligos and sample-multiplexing tags. We then loaded 50,000 isolated T and B cells into two lanes of an 8-lane microwell cartridge for single-cell capture by a single-cell analysis system. To aid in the simultaneous analysis of clonality and gene expression, we carried out library preparation using a full-length TCR/BCR multiomic assay and a mouse immune response panel. The combination of mRNA and protein expression confirmed the elevated expression of exhaustion and activation markers in tumor-infiltrating lymphocytes (TILs). We identified high-frequency clonotypes within TILs and tracked their frequency across other tissues. Tumor-burdened mice splenic T cells showed shared TCR combinations with TILs, which were absent in healthy tissue. The results show the ability to successfully profile T and B cell receptors using a full-length TCR/BCR multiomic assay in a mouse tumor model and the use of transcriptome, protein and TCR/BCR clonal information to investigate immune cell characteristics across multiple samples. For Research Use Only. Not for use in diagnostic or therapeutic procedures. BD, the BD Logo and BD Rhapsody are trademarks of Becton, Dickinson and Company or its affiliates. © 2023 BD. All rights reserved. NPM-2536 (v1.0) 1023 Citation Format: Ali Rezvan, Xiaoshan Shi, Moen Sen, Stephanie Widmann, Aaron Tyznik. Full-length TCR and BCR repertoire analysis, integrated with mRNA and surface proteins characterization, in a tumor mouse model [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 3984.
Abstract 1708: Transposable element derived enhancers in ovarian cancer
Authors: Lily L. Nguyen, Atma Ivancevic, Benjamin G. Bitler, Edward B. Chuong
Journal: Cancer Research (2024)

Abstract There is global epigenetic dysregulation during transformation from normal to cancerous cells. One of the many consequences of this global epigenetic dysregulation is the reactivation of transposable elements (TEs). TEs compose roughly half of the human genome and are normally repressed through epigenetic mechanisms such as DNA methylation and histone modifications. Endogenous retroviruses (ERVs) are a class of TEs that contain long terminal repeats (LTRs) with putative gene regulatory motifs. LTRs can be co-opted to be pro-tumorigenic by becoming non-canonical promotors for oncogenic genes. While several examples of TE-derived promotors have been reported in cancer, the potential significance of TE-derived enhancers remains largely unexplored. Here, we utilized publicly available multi-omics datasets (bulk and single-cell ATAC-seq, bulk and single-cell RNA-seq, and chromatin profiling) in the context of ovarian cancer to determine if there are tumor specific, TE-derived-enhancers that have gene regulatory function. We used CRISPRi technology to functionally validate a putative TE-derived enhancer and gene regulatory axis. We discovered that on the bulk tissue level, several TE families are enriched at open chromatin sites and sites marked by H3K27Ac (enhancer mark) of ovarian tumors, suggesting the presence of tumor specific, TE-derived enhancers. On the single-cell level, we discovered that ovarian cells have the highest expression of these TE transcripts compared to stromal and immune cells in the tumor microenvironment, suggesting that the increased TE-derived enhancer activity observed on the bulk level are specific to ovarian cells. Lastly, when we silenced a specific LTR18 locus upstream of a gene, TIPARP, TIPARP gene expression was also repressed, suggesting that these putative TE-derived enhancers have gene regulatory function. Determining the regulatory role of these TE-derived enhancers will provide novel insights into cancer-related transcriptomes. Citation Format: Lily L. Nguyen, Atma Ivancevic, Benjamin G. Bitler, Edward B. Chuong. Transposable element derived enhancers in ovarian cancer [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 1708.
Abstract 3556: A pan-cancer <i>ex vivo</i> drug screen database for next-generation pharmacogenomics and functional precision oncology
Authors: Anneliese Markus, Karl Pichotta, Jeffrey Quinn, Jessica White, Christopher Tosh, Jinrui Liu, Erin Coyne, Wesley Tansey
Journal: Cancer Research (2024)

Abstract Large-scale drug screens across thousands of drugs and biological models enable pan-cancer analyses that can reveal novel insights into therapeutic response and resistance. Existing databases, such as the Cancer Dependency Map only screen established 2D cell lines, which are known to poorly translate to patients. Ex vivo models such as patient-derived cells, spheroids, and organoids, have consistently demonstrated superior translatability from drug screening responses as they better replicate the original tumor. However, the cost, complexity, and difficulty of developing and screening ex vivo models has thus far prevented the establishment of any large-scale database comparable to existing cell line databases. We present the pan-preclinical (PPC) project, a large pan-cancer database of ex vivo drug responses comprising 2.1M raw dose-response measurements with curve-level summary statistics and metadata. The PPC database is assembled from over 30 previously published ex vivo studies and contains 2,880 ex vivo models spanning 106 cancer subtypes tested against subsets of 3,023 drugs. Compounds are harmonized across studies and paired with detailed chemoinformatics derived from PubChem. Each ex vivo sample is matched to an underlying patient and paired, where available, with genomics, transcriptomics, and clinical information such as sex, treatment history, and overall survival. Two thirds of the underlying studies did not originally make the underlying drug screening data available at publication time, making the PPC database a novel resource beyond data integration. Results: To investigate the power of the PPC database, we developed a preliminary computational modeling and statistical analysis pipeline. A hierarchical Bayesian factor model was developed to estimate dose-response curves, remove batch effects across studies, and impute missing drugs. Low-dimensional projections of ex vivo drug responses show biologically meaningful clustering. Statistical analyses of both observed and imputed drug responses recapitulate standard of care drugs as significantly effective across several cancer types. Overall, we envision the PPC project laying the foundation for the next generation of large-scale pharmacogenomic analyses and aiding in the coming era of functional precision oncology. Citation Format: Anneliese Markus, Karl Pichotta, Jeffrey Quinn, Jessica White, Christopher Tosh, Jinrui Liu, Erin Coyne, Wesley Tansey. A pan-cancer ex vivo drug screen database for next-generation pharmacogenomics and functional precision oncology [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 3556.
Abstract 1863: α-ABN501, a novel antibody targeting claudin-3, demonstrates the potential to be a new therapeutic option for small cell lung cancer
Authors: Jae Choi, Sunghyun Hong, Ha Yeon Park, Jaemun Kim, Sangin Lee, Myeung-Ryun Seo, Sang-Beom Bang, Hyo-Jin Shin, Kwang-il Jeong, Hobin Yang, Sungyoul Hong, Jun Young Choi, Na Young Kim, Young Kee Shin, Saehyung Lee
Journal: Cancer Research (2024)

Abstract Small Cell Lung Cancer (SCLC) is the most aggressive and lethal type of lung cancer, characterized by a poor prognosis, with a 5-year survival rate of only 7% for overall SCLC patients. Limited treatment options such as chemotherapy and immune-checkpoint inhibitor therapy are available for SCLC patients, very often followed by rapid recurrence and metastasis. Thus, new effective treatment options for SCLC remain high unmet medical needs. Overexpression of claudin-3 (CLDN3), one of the tight junction proteins, is observed in various types of cancers. The abnormal conformation of tumor cell growth leads to the external exposure of CLDN3, in contrast, the normal cells that maintain high polarity do not expose CLDN3 externally. Therefore, CLDN3 could be a potential therapeutic target and biomarker. Based on the analysis of the expression pattern of CLDN3 using a single-cell RNA sequencing dataset derived from SCLC patients, we found that CLDN3 could be a superior and unique target of SCLC compared to others (e.g., DLL3 and B7H3). Hence, we developed a fully human monoclonal antibody, afucosylated ABN501 (α-ABN501), which has high specificity and strong affinity to CLDN3-expressing cells. The α-ABN501 antibody showed CLDN3-dependent killing effects against the SCLC cells, expressing different levels of CLDN3, as assessed via the antibody-dependent cellular cytotoxicity (ADCC) assay wherein using NK cells expressing CD16a (NK-92MI-CD16a), peripheral blood mononuclear cells (PBMC), and primary NK cells. Further, the efficacy study in the CLDN3-expressing SCLC cell derived xenograft mouse model revealed that α-ABN501 was highly efficacious in inhibition of tumor growth. Collectively, we elucidated that the ADCC activity of α-ABN501 was dependent on the expression level of CLDN3 and especially specific to the SCLC cells, which underlines significant suppression of tumor growth. Present study data sets suggest that the α-ABN501 can be a potential new therapeutic option for SCLC. In addition, the α-ABN501 antibody is currently under way of development into new drug platforms for further applications. Citation Format: Jae Choi, Sunghyun Hong, Ha Yeon Park, Jaemun Kim, Sangin Lee, Myeung-Ryun Seo, Sang-Beom Bang, Hyo-Jin Shin, Kwang-il Jeong, Hobin Yang, Sungyoul Hong, Jun Young Choi, Na Young Kim, Young Kee Shin, Saehyung Lee. α-ABN501, a novel antibody targeting claudin-3, demonstrates the potential to be a new therapeutic option for small cell lung cancer [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 1863.
Abstract 2127: Enhancing radiosensitivity in biliary tract cancer: The dual role of surufatinib in tumor suppression and macrophage reprogramming
Authors: Ningyu Wang, Hong Ma, Xiangping Mei, Ai Huang, Yong Xiao, Jing Yao
Journal: Cancer Research (2024)

Abstract Background: Biliary tract cancer (BTC) is notorious for its unfavorable clinical outcomes. Radiotherapy (RT) is a crucial component in BTC treatment. This study explores the radiosensitizing potential and mechanisms of Surufatinib (SF), an oral tyrosine kinase inhibitor, distinguished by its anti-angiogenic and immunomodulatory effects. Methods: In a NOZ mouse xenograft model, tumor growth and expressions of Ki-67, CD31 were analyzed. NOZ and TFK1 BTC cells treated with SF and/or RT underwent assessments for viability, cycle, and apoptosis using CCK8, colony formation, and flow cytometry. Macrophage polarization in SF/RT-treated tumor cell-macrophage co-cultures was studied using Elisa, qRT-PCR, and flow cytometry. Results: In vivo, SF impeded angiogenesis and bolsters the anti-tumor effect of radiotherapy. SF combined with RT significantly reduced subcutaneous tumor growth in nude mice, and diminished Ki-67 and CD31 expressions. In vitro, SF heightened cholangiocarcinoma cells' radio-sensitivity, causing DNA double-strand breaks and apoptosis. SF and radiotherapy combined notably increased γ-H2A expression and apoptosis levels (P&amp;lt;0.05). SF induced inflammatory response changes, favoring M2 to M1 macrophage polarization. In a tumor cell-macrophage co-culture, the SF-radiotherapy group showed increased IL-6 and decreased TGF-β (P&amp;lt;0.05), with upregulated M1 markers (IL-6, CXCL10) and downregulated M2 markers (TGF-β, CCL22, Arg-1) in macrophages (P&amp;lt;0.05). Both in vivo and in vitro, SF significantly reduced CD206+ M2-type macrophages (P&amp;lt;0.05). Conclusion: Surufatinib alters the immune microenvironment in cholangiocarcinoma, reversing the immunosuppressive macrophage polarization induced by radiotherapy and reprogramming M2-type macrophages into M1-type, thereby enhancing the radiosensitivity of cholangiocarcinoma. Citation Format: Ningyu Wang, Hong Ma, Xiangping Mei, Ai Huang, Yong Xiao, Jing Yao. Enhancing radiosensitivity in biliary tract cancer: The dual role of surufatinib in tumor suppression and macrophage reprogramming [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 2127.