tbuckley/cabot-search huggingface dataset:
Abstract 4025: New candidate therapy for BAP1-mutant cancer identified using novel screen
Authors: DAWN A. OWENS, Jeffim N. Kuznetsov, Andy Lopez, Stefan Kurtenbach, Daniel Bilbao, Evan R. Roberts, Claude-Henry Volmar, Claes R. Wahlestedt, Shaun P. Brothers, J. William Harbour
Journal: Cancer Research (2020)

Abstract Inactivation of the oncogene BAP1 is associated with poor prognosis in many cancers, including uveal melanoma (UM). Therapies for mediating the detrimental effects of BAP1 mutations have yet to be developed. Previously, we found that BAP1 depletion in Xenopus causes a striking developmental phenotype and a global dysregulation of differentiation markers across the genetic landscape. This was caused by impaired promoter assembly at commitment genes, marked by decreased H3K27ac levels. Inhibition of HDAC4 protein rescues the affected BAP1-depleted phenotype and genetic regulations, further emphasizing the role of H3K27ac in BAP1 function. Pairing these findings with a lab-devised multitiered screening process, we identified an epigenetic compound that successfully reverses the detrimental effects of the BAP1 deficient phenotype back to phenotypically normal conditions. This multitiered screening process tests prospective compounds for the ability to mediate transcriptional aberrations caused by BAP1 loss in UM cells (phase 1), rescue the BAP1 loss phenotype in Xenopus (phase 2), and provide significant inhibition of UM tumor growth in a mouse model (phase 3). These findings reveal a new application for a promising epigenetic compound as a therapeutic and reversing agent for BAP1 mutant UM. Furthermore, our streamlined process for the testing of promising therapeutic agents can accelerate the testing of such agents and getting them to clinical trials in a timely manner. Citation Format: DAWN A. OWENS, Jeffim N. Kuznetsov, Andy Lopez, Stefan Kurtenbach, Daniel Bilbao, Evan R. Roberts, Claude-Henry Volmar, Claes R. Wahlestedt, Shaun P. Brothers, J. William Harbour. New candidate therapy for BAP1-mutant cancer identified using novel screen [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4025.
Abstract 6363: Small molecule PG3-Oc partially restores the p53 pathway transcriptome and proteome in tumors with mutant p53 through ATF4 transcriptional modulation by ERK1/2 and CDK9
Authors: Xiaobing Tian, Nagib Ahsan, Wafik S. El-Deiry
Journal: Cancer Research (2020)

Abstract The tumor-suppressor p53 prevents cancer development via initiating cell-cycle arrest, cell death, repair, or anti-angiogenesis processes. Over 50% of human cancers harbor cancer-causing mutations in p53. p53 mutations not only abrogate its tumor-suppressor function, but also endow mutant p53 with a gain of function (GOF), creating a proto-oncogene that contributes to tumorigenesis, tumor progression, and chemo- or radiotherapy resistance. Thus, targeting mutant p53 and/or restoring a wild-type p53 signaling pathway provides an attractive strategy for cancer therapy. We previously reported that prodigiosin, a natural product, has potent anti-cancer activity against tumors with mutated p53. The novel synthetic analogue of prodigiosin, PG3-Oc, is potent in reducing both short-term and long-term proliferation in a broad panel of mutant p53 cell lines. PG3-Oc treatment induces genome-wide restoration of p53 target genes, which are mediated by activation of ATF4. We demonstrate that ERK1/2 and CDK9 kinase functions are required for ATF4 transcriptional activity in mutant p53-expressing cancer cells. We have characterized a mechanism of PG3-Oc that engages the apoptosis pathway by upregulation of the pro-apoptotic p53 target gene PUMA in a time-and dose-dependent manner through the ATF4/PUMA axis in colorectal cancer cell lines. We further report the impact of PG3-Oc on the p53 transcriptome and proteome and the role of ATF4. Our results demonstrate feasibility of functional cellular reprogramming to restore p53 pathway signaling and provide novel insights into mechanisms of signaling leading to cell death and tumor suppression with potential clinical relevance in cancer therapy. Citation Format: Xiaobing Tian, Nagib Ahsan, Wafik S. El-Deiry. Small molecule PG3-Oc partially restores the p53 pathway transcriptome and proteome in tumors with mutant p53 through ATF4 transcriptional modulation by ERK1/2 and CDK9 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6363.
Abstract 6123: An indole compound MA-35 attenuates tumorigenesis in an inflammation-induced colon cancer model
Authors: Keigo Kanehara, Shinobu Ohnuma, Takeshi Naitoh, Michiaki Uuno, Takaaki Abe
Journal: Cancer Research (2020)

Abstract Backgrounds: In inflammatory bowel disease (IBD), chronic inflammation results in the development of colon cancer known as colitis-associated cancer (CAC), that is associated with tumor necrosis factor-α (TNF-α) signaling. In addition, intestinal fibrosis in IBD patients is a common clinical complication, which is promoted by transforming growth factor β1 (TGF-β1). In our previous study, mitochonic acid (MA-35), derivative of indole-3-acetic acid known as a plant hormone auxin, showed anti-TNF-α effect by inhibiting IκB kinase (IKK) phosphorylation and anti-TGF-β1 effect by inhibiting Smad3 phosphorylation in a renal fibrosis mouse model. Aim: To identify the possible mechanism of anti-tumor effects and anti-fibrotic effects of MA-35 using azoxymethane (AOM)/ dextran sulfate sodium (DSS)-induced CAC mouse model. Methods and Results: MA-35 was orally administered every day for 70 days in an AOM/DSS model with a feeding tube. There was no difference in weight loss between the AOM/DSS group and the AOM/DSS+MA-35 group, however the disease activity index score and the survival rate were improved by MA-35. MA-35 also blocked progression of the anemia and shortening of the colon induced by AOM/DSS. MA-35 surprisingly reduced the formation of tumors in the colon. In the microscopic evaluation, MA-35 reduced inflammation and fibrosis in area with dysplasia. Furthermore, the TNF-α mRNA level in the colon tended to be reduced and the interleukin 6, TGF-β1 and fibronectin 1 mRNA levels in the colon were significant reduced by MA-35. In western blotting, MA-35 inhibited IKK phosphorylation, and both NF-κB p65 phosphorylation and TNF-α as the downstream signals for p-IKK in human colorectal cancer cell line HT-29. Similarly, MA-35 inhibited Smad2/3 phosphorylation, and both fibronectin 1 and TGF-β1 as the downstream signals for p-Smad2/3 in HT-29. Conclusions: MA-35 inhibited the development of CAC by reducing inflammation and fibrosis in an AOM/DSS mouse model by inhibiting both TNF-α signaling and TGF-β1 signaling. MA-35 may be a potent therapeutic agent for inhibiting the development of CAC in IBD patients. Citation Format: Keigo Kanehara, Shinobu Ohnuma, Takeshi Naitoh, Michiaki Uuno, Takaaki Abe. An indole compound MA-35 attenuates tumorigenesis in an inflammation-induced colon cancer model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6123.
Abstract 387: Analysis of FFPE human tumor tissues using CODEX with signal amplification
Authors: Sejal Mistry, Gajalakshmi Dakshinamoorthy, Jessica Yuan, Pieter Noordam, Joseph Kim, Won-Mean Lee, Julia Kennedy-Darling
Journal: Cancer Research (2020)

Abstract Analysis of FFPE human tumor tissues using CODEX with signal amplification Characterizing the complexities of the tumor microenvironment is fundamental to understanding disease mechanisms. The spatial relationships between infiltrating immune cells and the remodeling of the cellular matrix is widely recognized as a key component to defining tumor heterogeneity. Current methodologies for studying cells within the context of tissue architecture, like traditional immunofluorescence (IF) and immunohistochemistry (IHC), are limiting–allowing the assessment of only a few parameters at a time. The CODEX technology has overcome this limitation through a DNA-based labeling strategy, involving adding and removing dye-labeled oligonucleotides (reporters) across multiple cycles to oligonucleotide-labeled antibodies. In this manner, tens of markers can be analyzed on the same tissue. Additionally, CODEX interfaces with existing inverted microscopes and provides a cost-effective, fully automated platform for highly multiplexed imaging. Recently, we expanded our workflow to amplify the fluorescent signal intensities of low expressing biomarkers by combining Tyramide Signal Amplification (TSA) with CODEX. This approach is associated with key markers used to analyze the tumor microenvironment, including PD-L1 and PD-1. We demonstrated signal amplification of more than 50X compared with non-amplified signal. Here, we present the analysis of CODEX data for a panel of over 20 biomarkers on human FFPE tissue including signal amplification of PD-L1, PD-1 and foxp3. Through amplification of key markers as the final cycle of a CODEX experiment, low expression can be measured and used to identify key cell types, including Treg cells and PD-L1 positive tumor and stromal regions. Citation Format: Sejal Mistry, Gajalakshmi Dakshinamoorthy, Jessica Yuan, Pieter Noordam, Joseph Kim, Won-Mean Lee, Julia Kennedy-Darling. Analysis of FFPE human tumor tissues using CODEX with signal amplification [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 387.
Performance and Predictors of Migration of Partially and Fully Covered Esophageal Self-Expanding Metal Stents for Malignant Dysphagia
Authors: Koushik K. Das, Stephen Hasak, Sherif Elhanafi, Kavel H. Visrodia, Gregory G. Ginsberg, Nuzhat A. Ahmad, Thomas Hollander, Gabriel Lang, Vladimir M. Kushnir, Daniel K. Mullady, Barham K. Abu Dayyeh, Navtej S. Buttar, Louis Michel Wong Kee Song, Michael L. Kochman, Vinay Chandrasekhara
Journal: Clinical Gastroenterology and Hepatology (2020)
Abstract 828: gDR suite: an integrative solution for handling cell line drug response data
Authors: Marc Hafner, Arkadiusz Gladki, Jane Li, Eva Lin, Aaron Lun, Scott Martin, Natalia Potocka, Dariusz Scigocki, Steffan Vartanian, Jan Vogel, Allison Vuong
Journal: Cancer Research (2020)

Abstract Assessing the response of cancer cell lines to drugs and treatments that affect their growth is the cornerstone of drug discovery and development. On one hand, large screens are performed across many lines and drugs in a semi-automated manner. On the other hand, small-scale studies, for example focused on factors that contribute to sensitivity and resistance, are generally performed in labs with limited automation. Data from these complementary approaches are rarely handled in the same manner: commercial software are available for the former case, whereas experimentalists in the latter case often handle files manually and process data in spreadsheets. Here we propose a suite of computational tools that enable the processing, archiving, and visualization of drug response data from any experiment, thus ensuring reproducibility and implementation of the FAIR principles. The core of the gDR suite is a database designed to host drug response data from large screens, single-agent treatments, combination experiments, as well as data from complex experimental designs including ligand co-treatments or shRNA. Experimentalists can upload metadata files along with unprocessed output files from plate readers in an interactive web application built with R Shiny. Data normalization and quality control are performed by the software before the data is stored in the database. Data from commercial software or other databases can also be easily pushed into the database through a REST API. To fetch the processed data, we developed an R package as well as another R shiny-based web application. Both tools allow users to efficiently search the database, easily plot the data from the selected experiments, and perform basic analyses. Overall, the gDR suite is a modular software that provides an end-to-end solution for managing drug response data. At the conference, we will describe our implementation and demonstrate how to use the gDR suite. We hope that this tool will facilitate the handling of drug response data and thus contribute to the quality of published data. In addition, we hope that the community will contribute to the gDR suite by adding new functionalities for either importing, plotting, or analyzing the data. Citation Format: Marc Hafner, Arkadiusz Gladki, Jane Li, Eva Lin, Aaron Lun, Scott Martin, Natalia Potocka, Dariusz Scigocki, Steffan Vartanian, Jan Vogel, Allison Vuong. gDR suite: an integrative solution for handling cell line drug response data [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 828.
Abstract 6346: Optimizing precision combination therapies based on single-cell profiling of brain tumor biopsies
Authors: Husam Babikir, Lin Wang, Karin Shamardani, Francisca Catalan, Gary Kohanbash, Manish K. Aghi, Joanna J. Phillips, Aaron A. Diaz
Journal: Cancer Research (2020)

Abstract Glioblastomas (GBM) display dramatic levels of intra-tumoral heterogeneity. This heterogeneity contributes significantly to resistance to standard and emerging treatments. As a result, GBM remains the deadliest primary tumor of the adult brain. Moreover, most preclinical studies of GBM use models of primary GBM, most studies of clinical specimens use tissue derived from primary GBMs, despite the fact that most clinical trials enroll patients at recurrence. There is a paucity of information about recurrent GBM. To address these critical barriers, we devised a strategy to optimize precision drug combinations based on an understanding of a patient's intratumor heterogeneity, ascertained via single-cell profiling. We conducted single-nucleus RNA sequencing (snRNA-seq) and/or single-nucleus assay for transposon-accessible chromatin (snATAC-seq) sequencing for 16 recurrent GBMs. For 6 of these cases we also derived cell lines from patient biopsies. We identified lineage hierarchies of proliferating cells and their more differentiated progeny. Based on this, we performed an in vitro drug-combination screen using FDA-approved chemotherapies, targeting pathways learned from these single-cell signatures. We found that targeting distinct cellular states in the inferred lineage hierarchy of a patient's tumor provides a more complete treatment than targeting one state alone. Additionally, we will present the results of our ongoing in vivo validation activities and profiling efforts. This work presents a novel paradigm for identifying precision combinations of chemotherapies targeted to phenotypes learned from single-cell profiling of a patient's tumor biopsy. Citation Format: Husam Babikir, Lin Wang, Karin Shamardani, Francisca Catalan, Gary Kohanbash, Manish K. Aghi, Joanna J. Phillips, Aaron A. Diaz. Optimizing precision combination therapies based on single-cell profiling of brain tumor biopsies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6346.
Abstract 4396: A bioinformatics approach for cancer immunotherapeutic target identification by evaluating surfaceome gene and protein expression (CITIESGAPE) in tumor and pan-normal tissues
Authors: Xiangjun Tian, Jing Wang, Yifei Wang, Zhongting Zhang, Michael Roth, Jonathan B. Gill, Richard Gorlick
Journal: Cancer Research (2020)

Abstract Targeted therapeutic strategies and some immunotherapies for cancer including but not limited to therapeutic antibodies, antibody-drug conjugates (ADCs) and CAR-T cells therapy demand precisely targeting cell-surface proteins that are distinctively expressed by cancer cells. We developed a robust analytical tool for cancer immunotherapeutic target identification by evaluating surfaceome gene and protein expression (CITIESGAPE) that are uniquely overrepresented by the tumor in contrast to pan-normal tissues. The first step was to run differential expression testing on RNA-seq transcriptome of cancer (for example, data from TARGET and TCGA) against each normal tissue (31 tissues from GTEx_v8), from which candidate genes were defined as those are higher expressed in tumor than all normal tissues (minimum LogFC &amp;gt; 1 and maximum q &amp;lt; 0.05). We then validated the protein expression level of candidate genes through the Human Protein Atlas (HPA) and ProteomicsDB (The latter includes mass spectrometry-based label-free proteomic data of some tumor cells and 39 normal tissues). The final and crucial step was to run surfaceome protein predicting using the COMPARTMENTS database, the HPA database and the Membranome database (v2.0), depending on an optimized confidence score. We have applied this analytical pipeline to search surfaceome proteins that are unique to Osteosarcoma, a common primary malignant bone tumor in children and young adults, and obtained 57 candidates that are potential immunotherapeutic targets. To date, eight of the top confident candidates have been further validated in clinical samples, patient-derived cell lines and xenograft models. We believe this robust analytical tool could be adaptable to other types/subtypes of cancer in searching of candidate surfaceome proteins for targeted therapy and immunotherapy, as well as precision medicine and personalized therapy. Citation Format: Xiangjun Tian, Jing Wang, Yifei Wang, Zhongting Zhang, Michael Roth, Jonathan B. Gill, Richard Gorlick. A bioinformatics approach for cancer immunotherapeutic target identification by evaluating surfaceome gene and protein expression (CITIESGAPE) in tumor and pan-normal tissues [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4396.
Targeting Complement C5a Receptor 1 for the Treatment of Immunosuppression in Sepsis
Authors: Oliver Sommerfeld, Anna Medyukhina, Sophie Neugebauer, Mohamed Ghait, Svenja Ulferts, Amelie Lupp, Rainer König, Reinhard Wetzker, Stefan Schulz, Marc Thilo Figge, Michael Bauer, Adrian T. Press
Journal: Molecular Therapy (2020)

Complement factor C5a was originally identified as a powerful promoter of inflammation through activation of the C5a receptor 1 (C5ar1). Recent evidence suggests involvement of C5a not only in pro- but also in anti-inflammatory signaling. The present study aims to unveil the role of C5ar1 as potential therapeutic target in a murine sepsis model. Our study discloses a significantly increased survival in models of mild to moderate but not severe sepsis of C5ar1-deficient mice. The decreased mortality of C5ar1-deficient mice is accompanied by improved pathogen clearance and largely preserved liver function. C5ar1-deficient mice exhibited a significantly increased production of the pro-inflammatory mediator interferon-γ (IFN-γ) and a decreased production of the anti-inflammatory cytokine interleukin-10 (IL-10). Together, these data uncover C5a signaling as a mediator of immunosuppressive processes during sepsis and describe the C5ar1 and related changes of the IFN-γ to IL-10 ratio as markers for the immunological (dys)function accompanying sepsis. Complement factor C5a was originally identified as a powerful promoter of inflammation through activation of the C5a receptor 1 (C5ar1). Recent evidence suggests involvement of C5a not only in pro- but also in anti-inflammatory signaling. The present study aims to unveil the role of C5ar1 as potential therapeutic target in a murine sepsis model. Our study discloses a significantly increased survival in models of mild to moderate but not severe sepsis of C5ar1-deficient mice. The decreased mortality of C5ar1-deficient mice is accompanied by improved pathogen clearance and largely preserved liver function. C5ar1-deficient mice exhibited a significantly increased production of the pro-inflammatory mediator interferon-γ (IFN-γ) and a decreased production of the anti-inflammatory cytokine interleukin-10 (IL-10). Together, these data uncover C5a signaling as a mediator of immunosuppressive processes during sepsis and describe the C5ar1 and related changes of the IFN-γ to IL-10 ratio as markers for the immunological (dys)function accompanying sepsis.
Abstract 5034: Effect of estrogen on heteronemin-induced anti-proliferation in breast cancer cells
Authors: Zi-Lin Li, Yi-shin Pan, Tung-Yung Huang, Ya-Jung Shih, Yi-Ru Chen, Heng-Yuan Tang, Jacqueline Whang-Peng, Hung-Yun Lin, Paul J. Davis, Kuan Wang
Journal: Cancer Research (2020)

Abstract Estrogen, 17β-estradiol (E2) has multiple functions in breast cancers including stimulating cancer growth and interfering with chemotherapeutic efficacy. Heteronemin, a marine sesterterpenoid-type natural product, processes anti-proliferative effect in cancer cells. In the current study, we investigate the antitumor mechanism of heteronemin in breast cancer cells and further explore its molecular targets. Heteronemin exhibited potent cytotoxic effects against breast cancer cells. On the other hand, E2 stimulated cancer cell growth. Heteronemin and E2 showed different effects on gene expression of proliferation, angiogenesis or growth factor receptors in breast cancer cells. NanoString® analysis was further used to detect mRNAs, heteronemin repressed gene expression of transforming growth factor (TGF)-β, mothers against decapentaplegic homolog (SMAD) and PCNA, whose protein products play important roles in regulating cell growth, angiogenesis, and metastasis. The results indicate that heteronemin was able to modulate cell adhesion, expression of extracellular matrix (ECM) receptors, TGF-β pathway, cell motility, membrane integration, metastasis response, matrix metalloproteinase (MMP) remodeling, regulation of metabolism, sprouting angiogenesis, transcription factors, and vasculogenesis in breast cancer cells. However, those effects were partially reversed by E2. Furthermore, Heteronemin and E2 altered several signaling transduction pathways. In summary, this study provides insight into the complex pathways by which anti-proliferation is induced by heteronemin in E2-depleted and -repleted environments. Citation Format: Zi-Lin Li, Yi-shin Pan, Tung-Yung Huang, Ya-Jung Shih, Yi-Ru Chen, Heng-Yuan Tang, Jacqueline Whang-Peng, Hung-Yun Lin, Paul J. Davis, Kuan Wang. Effect of estrogen on heteronemin-induced anti-proliferation in breast cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5034.