tbuckley/cabot-search huggingface dataset:
Abstract 4562: Next generation Oncos oncolytic adenovirus with novel anti-cancer double-transgenes shows synergistic anticancer effect in melanoma mouse model
Authors: Lukasz Kuryk, Anne-Sophie Moller
Journal: Cancer Research (2020)

Abstract Oncolytic virotherapy is a promising anti-cancer strategy utilizing genetically engineered viruses to preferentially infect, replicate in and lyse cancer cells. To date, Talimogene laherparepvec is the only FDA approved oncolytic virus (OV), however, many other types of OVs are showing promising results in clinical studies. One example is ONCOS-102, an adenovirus serotype 5/3 chimera expressing GM-CSF as a transgene, which recently reported 33% ORR in advanced anti-PD1 refractory melanoma. Genetically engineered OVs can be armed with different co-stimulatory molecules in order to boost the anti-tumour immune responses. Building on the ONCOS-102 backbone, we have engineered two next generation ONCOS viruses, ONCOS-210 and ONCOS-212, expressing novel double transgenes designed to inhibit tumor growth and metabolism. Here, we describe the characterization and pre-clinical in vitro and in vivo testing of ONCOS-210 and ONCOS-212. The oncolytic properties of ONCOS-210 and ONCOS-212 were confirmed in 4 melanoma cell lines in vitro, demonstrating robust cell lysis and induction of immunogenic cell death. Anti-cancer effects of the viruses were also assessed in i) immunodeficient xenograft and ii) humanized xenograft mouse models to further understand the anti-cancer and immune stimulatory potency of the constructs. Intra-tumoral ONCOS-210 and ONCOS-212 resulted in robust anti-tumor activity in both immune-deficient and immune-competent mice. The double transgenes were shown to act synergistically in vivo, in line with the design hypotheses and proposed mode of action to induce cell lysis and prevent tumor growth. Moreover, the vectors were able to increase tumor infiltration of various immune subsets including CD4+, CD8+, CD8+ expressing PD1+ or CD8+ expressing Granzyme B T cells and reduction of regulatory T-cells and MDSC in the tumour microenvironment, suggesting an ability to prime immune-suppressive tumors to better respond to immunotherapy. These encouraging preclinical findings will be further investigated to elucidate the mode of action and perform toxicological studies to bring ONCOS-210 and ONCOS-212 towards clinical testing. Citation Format: Lukasz Kuryk, Anne-Sophie Moller. Next generation Oncos oncolytic adenovirus with novel anti-cancer double-transgenes shows synergistic anticancer effect in melanoma mouse 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 4562.
Understanding the mechanisms of efficacy of fecal microbiota transplant in treating recurrent <i>Clostridioides difficile</i> infection and beyond: the contribution of gut microbial-derived metabolites
Authors: Laura Martinez-Gili, Julie a K McDonald, Zhigang Liu, Dina Kao, Jessica R Allegretti, Tanya M Monaghan, Grace F Barker, Jesús Miguéns Blanco, Horace R T Williams, Elaine Holmes, Mark R Thursz, Julian R Marchesi, Benjamin H Mullish
Journal: Gut Microbes (2020)

Fecal microbiota transplant (FMT) is a highly-effective therapy for recurrent Clostridioides difficile infection (rCDI), and shows promise for certain non-CDI indications. However, at present, its mechanisms of efficacy have remained poorly understood. Recent studies by our laboratory have noted the particular key importance of restoration of gut microbe-metabolite interactions in the ability of FMT to treat rCDI, including the impact of FMT upon short chain fatty acid (SCFAs) and bile acid metabolism. This includes a significant impact of these metabolites upon the life cycle of C. difficile directly, along with potential postulated additional benefits, including effects upon host immune response. In this Addendum, we first present an overview of these recent advancements in this field, and then describe additional novel data from our laboratory on the impact of FMT for rCDI upon several gut microbial-derived metabolites which had not previously been implicated as being of relevance.
Correction to: Glutamate triggers the expression of functional ionotropic and metabotropic glutamate receptors in mast cells
Authors: Md Abdul Alim, Mirjana Grujic, Paul W. Ackermann, Per Kristiansson, Parmis Blomgran, Pernilla Eliasson, Magnus Peterson, Gunnar Pejler
Journal: Cellular and Molecular Immunology (2020)
Abstract LB-180: A human breast cancer 3D spheroid platform for microscopy based high throughput screening
Authors: Christine Gjerdrum Rines, Kara Gordon, Ranor Basa, Alyson Smith, Robert Oshima, Chen Farhy, Alexey Terskikh, Patrick McDonough, Jeffrey Price
Journal: Cancer Research (2020)

Abstract Breast cancer (BC) tumors originate in epithelial cells and rank second as a cause of cancer-related death in women (in 2020, ~270,000 women will be diagnosed, and 42,000 women will die from this disease in the USA). While important progress has been made on new treatments there is an urgent need to discover new therapeutics. We aim to discover therapeutics that elicits differentiation of BC tumor cells towards a phenotype that ceases proliferation and/or becomes more sensitive to therapeutic drugs. Also, since current high-throughput breast cancer drug discovery screens use conventional 2D cell cultures that do not fully represent the complex microenvironments of tumors in patients and often fail to predict clinical efficacy we are using 3D spheroids to better represent patient tumors. To identify potential therapeutic agents, we will quantify effects of test compounds on epigenetic markers (histone methylation/acetylation) within the nuclei of the tumor cells utilizing the Microscopic Imaging of Epigenetic Landscape (MIEL) assay developed by Alexey Terskikh's laboratory at SBP. The changes in epigenetics occur more rapidly than phenotypic changes resulting from differentiation which enables more rapid screening to identify potential therapeutic agents. Here we show that treating 2D cell cultures of the breast cancer cell line MCF7 with Tamoxifen, DPPE or E2 elicit changes in the epigenetic landscape. These epigenetic changes concur with increase in lipid droplet formation (a feature that is linked to milk-producing breast epithelium), and demonstrates that MIEL can be used as a readout of differentiation status. We are developing protocols to image breast cancer 3D spheroids on Vala Sciences' IC200 Structured Illumination Microscopy (IC200-SIM™ workstation). The SIM™ uses a multi-million array of micro-mirrors to achieve confocal resolution with rapid image acquisition, suitable for high throughput screening of spheroids cultured in the 96- or 384-well format. We envision that when developed, the MIEL-Breast Cancer Differentiation (MIEL-BCD) assay will be used to screen large chemical libraries (e.g., libraries with 100,000 different chemical entities) to identify compounds that promote differentiation of breast cancer cells to non-tumorigenic cells. Citation Format: Christine Gjerdrum Rines, Kara Gordon, Ranor Basa, Alyson Smith, Robert Oshima, Chen Farhy, Alexey Terskikh, Patrick McDonough, Jeffrey Price. A human breast cancer 3D spheroid platform for microscopy based high throughput screening [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 LB-180.
Abstract 6589: Selecting clinical lead of TCRs targeting alpha-fetoprotein-positive liver cancer on balance of risk and benefit
Authors: Xiaobing Luo, Huijuan Cui, Lun Cai, Wei Zhu, Wei-Chih Yang, Michael Patrick, Shigui Zhu, Jiaqi Huang, Xin Yao, Yihong Yao, Yukai He, Yun Ji
Journal: Cancer Research (2020)

Abstract Background: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with a poor prognosis and limited therapeutic options. Alpha-fetoprotein (AFP), an established clinical biomarker of HCC, has been employed as an attractive target for T cell-based immunotherapy against this disease given its high expression in the tumor and restricted expression in normal tissues. We have identified a number of T cell receptors (TCRs) recognizing the HLA-A*02:01 restricted AFP158-166 peptide FMNKFIYEI, providing a TCR candidate pool for identifying TCRs with optimal clinical benefit. Methods: To select the ideal AFP TCR for clinical use, we evaluated the efficacy and safety profile of 7 TCRs on balance of their potency and specificity by testing their reactivity to normal and transformed cells covering a variety of primary cell types and HLA serotypes, and potential protein candidate in human genome by an extensive alanine scan (X-scan). Results: We first selected three TCR candidates based on the in vitro anti-tumor activity. Next we eliminated two potential cross-reactive TCRs based on their reactivity against normal and transformed cells covering a variety of primary cell types and HLA serotypes, respectively. We then excluded the potential cross-reactivity of the selected TCR with protein candidate in human genome identified by X-scan. Conclusion: Up to date we have selected a AFP TCR with the optimal affinity, function, and safety profile, bearing properties that are expected to allow AFP TCR redirected T cells to specifically differentiate between AFP levels on tumor and normal tissues. An early phase clinical trial using T cells transduced with this TCR to treat HCC patients (NCT03971747) has been initiated. Citation Format: Xiaobing Luo, Huijuan Cui, Lun Cai, Wei Zhu, Wei-Chih Yang, Michael Patrick, Shigui Zhu, Jiaqi Huang, Xin Yao, Yihong Yao, Yukai He, Yun Ji. Selecting clinical lead of TCRs targeting alpha-fetoprotein-positive liver cancer on balance of risk and benefit [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 6589.
Abstract 5308: Genetic characterization of sarcomatoid carcinomas reveals multiple novel actionable mutations and identifies <i>KRAS</i> mutation as a biomarker of poor prognosis
Authors: Ying Ding, Yang W. Shao, Chenglong Na, Jiani C. Yin, Hongjin Hua, Ran Tao, Yue Jiang, Ran Hu, Xiao He, Chen Miao, Dongqin Zhu, Zhihong Zhang
Journal: Cancer Research (2020)

Abstract Background: Sarcomatoid component occurs in various epithelial malignancies and is associated with an aggressive disease course and poor clinical outcome. As it is largely rare, the molecular events underlying sarcomatoid carcinomas (SCs) remain poorly characterized. Here, we performed targeted next-generation sequencing (NGS) on patients with surgically resected SCs comprising distinct tissues of origin. Methods: A total of 71 patients with pathological diagnosis of sarcomatoid carcinoma and underwent surgery were retrospectively enrolled in this study. Overall survival was defined as the time from surgery to death from any cause. Patients alive or lost to follow-up were censored. Genomic DNA from formalin-fixed paraffin-embedded samples was extracted for NGS and tumor mutation burden (TMB) analysis. Results: In general, SCs occurred more commonly in males, except those of the gallbladder. SCs of the lung and the larynx were associated with a higher proportion of smokers (p=0.0015). Alterations in TP53, RB1, TERT and KRAS were highly frequent, with KRAS mutations being a biomarker of poor prognosis (median OS = 8 vs 16 months, p=0.03). Multiple novel alterations in potentially actionable genes, including ROS1 and NTRK1 fusions and ERBB2 amplification, were detected in the extra-pulmonary cohort. A relatively high proportion (30%) of extra-pulmonary SC patients had high TMB, with a median of 5.39 mutations per Mb. Lastly, copy number variations were common in SCs, and were non-overlapping between the primary and metastatic tumors. Conclusions: Taken together, our results suggest that comprehensive genetic testing may be necessary to inform treatment options and identify prognostic biomarkers. Citation Format: Ying Ding, Yang W. Shao, Chenglong Na, Jiani C. Yin, Hongjin Hua, Ran Tao, Yue Jiang, Ran Hu, Xiao He, Chen Miao, Dongqin Zhu, Zhihong Zhang. Genetic characterization of sarcomatoid carcinomas reveals multiple novel actionable mutations and identifies KRAS mutation as a biomarker of poor prognosis [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 5308.
Abstract 4626: <i>TBX1</i> functions as a potential oncogene in breast cancer
Authors: Shuya Huang, Xiang Shu, Jie Wu, Jifeng Wang, Xingyi Guo, Jie Ping, Joshua A. Bauer, Jirong Long, Xiao-Ou Shu, Wei Zheng, Qiuyin Cai
Journal: Cancer Research (2020)

Abstract We have previously identified a genetic variant, rs34331122 in the 22q11.21 locus, to be associated with breast cancer risk in genome-wide association studies. This SNP is located in the intronic region of the T-box transcription factor 1 (TBX1) gene. TBX1 is a member of the T-box transcription factor gene family, which plays important roles in embryogenesis and organogenesis. Previous studies have indicated that TBX1 exerted potential tumor suppressor functions in mouse skin tumors and human thyroid cancer. However, the biological functions and molecular mechanisms of TBX1 in breast cancer remain largely unknown. In this study, we investigated whether the association of the 22q11.21 locus with breast cancer risk was mediated by the TBX1 gene. Using The Cancer Genome Atlas (TCGA) data, we found that TBX1 expression was significantly upregulated in breast cancer tissues compared to adjacent normal breast tissues. To investigate the biological functions of the TBX1 gene in breast cancer, we knock-downed TBX1 gene expression using siRNAs in MDA-MB-231, MCF-7 and T47D breast cancer cell lines. Our results showed that knocking down TBX1 expression significantly inhibited breast cancer cell proliferation, migration and invasion. We further performed RNA sequencing in both TBX1 knocked-down and control MDA-MB-231 cells. Our differential gene expression and gene set enrichment analyses showed that knocked-down TBX1 expression significantly downregulated cell cycle-related genes, including CDC6, CDK6, DHFR, CIT, ORAI1 and TOP2A (P &amp;lt; 10−30). These six downregulated genes in TBX1 knocked-downed MDA-MB-231 cells were further confirmed by quantitative real-time PCR (qPCR). Furthermore, using the JASPAR database to predict TBX1 binding motif, we found that TBX1 may bind to the promoter regions of these six genes. In summary, our results suggest that TBX1 acts as a potential oncogene in breast cancer through regulating the expression of cell cycle-related genes, and the associations between genetic variants in the 22q11.21 locus and breast cancer risk may be mediated through altered expression of the TBX1 gene. Citation Format: Shuya Huang, Xiang Shu, Jie Wu, Jifeng Wang, Xingyi Guo, Jie Ping, Joshua A. Bauer, Jirong Long, Xiao-Ou Shu, Wei Zheng, Qiuyin Cai. TBX1 functions as a potential oncogene in breast cancer [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 4626.
Abstract 5840: IRE1a is required for ROS homeostasis and PERK protein stability in response to UVB irradiation
Authors: Jeongin Son, Stephen Worrel, Adam Glick
Journal: Cancer Research (2020)

Abstract IRE1α is required for ROS homeostasis and PERK protein stability in response to UVB irradiation UV induced stress is one of the primary driving factors of human skin cancer. UV irradiation can activate Endoplasmic Reticulum (ER) stress and the Unfolded Protein Response (UPR). Inositol-requiring enzyme 1a (IRE1α) is one of the key players in the UPR. Previous studies have shown that UVB irradiation can activate IRE1α in human and mouse skin cells, but the function of IRE1α in the UV response has not yet been characterized. Here we show that IRE1α expression is transiently downregulated after UVB irradiation and that in the absence of IRE1α the stability and activation of PKR-like endoplasmic reticulum kinase (PERK) is compromised. Basal levels of PERK are reduced in the absecence of IRE1α. Following UV irradiation, loss of IRE1α not only causes rapid degradation of PERK protein but also suppresses phosphorylation of the PERK target, Nuclear factor erythroid-2-related factor 2 (NRF2), and NRF2 dependent antioxidant gene expression. Similarly, PERK protein is rapidly degraded following thapsigargin treatment in the absence of IRE1α, suggesting a general regulation of PERK stability by IRE1α. Additionally, keratinocytes with either knockout or knockdown of IRE1α have increased intracellular ROS and cytosolic calcium. Overexpression of both wildtype and RNase defective human IRE1α can rescue the increased ROS levels. Additionally, the increased ROS is also suppressed by treatment with an inhibitor of the ER localized Inositol triphosphate receptor (InsP3R) which regulates calcium efflux from the ER. Because PERK regulates cytosolic calcium through inhibiting InsP3R, our result suggests that IRE1α is critical for suppressing intracellular ROS through stabilization of PERK. We conclude that crosstalk between IRE1α and PERK is essential for the basal and UVB- induced oxidative stress response, and this may have important implications for UV related damage and skin cancer development. Citation Format: Jeongin Son, Stephen Worrel, Adam Glick. IRE1a is required for ROS homeostasis and PERK protein stability in response to UVB irradiation [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 5840.
Myeloid/Lymphoid Neoplasms with Eosinophilia and TK Fusion Genes, Version 3.2021, NCCN Clinical Practice Guidelines in Oncology
Authors: Aaron T. Gerds, Jason Gotlib, Prithviraj Bose, Michael W. Deininger, Andrew Dunbar, Amro Elshoury, Tracy I. George, Ivana Gojo, Krishna Gundabolu, Elizabeth Hexner, Gabriela Hobbs, Tania Jain, Catriona Jamieson, Andrew T. Kuykendall, Brandon McMahon, Sanjay R. Mohan, Vivian Oehler, Stephen Oh, Animesh Pardanani, Nikolai Podoltsev, Erik Ranheim, Lindsay Rein, Rachel Salit, David S. Snyder, Brady L. Stein, Moshe Talpaz, Swapna Thota, Pankit Vachhani, Martha Wadleigh, Katherine Walsh, Dawn C. Ward, Mary Anne Bergman, Hema Sundar
Journal: Journal of the National Comprehensive Cancer Network (2020)

Eosinophilic disorders and related syndromes represent a heterogeneous group of neoplastic and nonneoplastic conditions, characterized by more eosinophils in the peripheral blood, and may involve eosinophil-induced organ damage. In the WHO classification of myeloid and lymphoid neoplasms, eosinophilic disorders characterized by dysregulated tyrosine kinase (TK) fusion genes are recognized as a new category termed, myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA , PDGFRB or FGFR1 or with PCM1-JAK2 . In addition to these aforementioned TK fusion genes, rearrangements involving FLT3 and ABL1 genes have also been described. These new NCCN Guidelines include recommendations for the diagnosis, staging, and treatment of any one of the myeloid/lymphoid neoplasms with eosinophilia (MLN-Eo) and a TK fusion gene included in the 2017 WHO Classification, as well as MLN-Eo and a FLT3 or ABL1 rearrangement.
Abstract 5328: mTOR inhibitor enhances anti-tumor effect of BET bromodomain inhibitor in small cell lung cancer
Authors: ANJU KUMARI, Lisa Gesumaria, Patricia Fetsch, Markku Miettinen, Keith Hughitt, Beverly Mock, Craig Thomas, David S. Schrump, Haobin Chen
Journal: Cancer Research (2020)

Abstract Introduction: Small cell lung cancer (SCLC) is one of the two recalcitrant cancers designated by NCI, and its 2-year survival rate has not improved over the past two decades. Novel therapy is urgently needed. BET bromodomain inhibitor (BETi), which targets transcriptional coactivator BET bromodomain proteins, has been reported to be effective in SCLC. However, given that SCLC is notorious for rapid development of drug resistance, it is necessary to identify drugs that can synergize with BETi to form a combinatorial drug regimen. Methods: A high-throughput drug combination matrix screen was performed to identify potential agents that can synergize with BETi. Synergy between the identified candidate drugs and BETi was further validated in various SCLC cell lines by using the CellTiter-Glo assay as well as in several SCLC PDX models by examining tumor growth suppression and survival of tumor-bearing mice. Cleavage of caspase 3 and poly (ADP-ribose) polymerase (PARP) was analyzed by IHC and western blot in SCLC PDX tumors and in vitro cell lines to assess apoptosis after drug treatment, respectively. Results: The high-throughput screen identified multiple inhibitors of the PI-3K/AKT/mTOR pathway to synergize with BETi by causing a significantly higher rate of apoptosis and cell growth inhibition. A comparison among the inhibitors that specifically target PI-3K, AKT or mTOR revealed that the combination of BETi and mTOR inhibitor (mTORi) have the highest level of synergy. The BETi/mTORi combo also showed synergy in several SCLC cell lines that are initially resistant to single agent BETi. The antitumor effect of the BETi/mTORi combinatorial treatment was further confirmed in several SCLC PDX mouse models. When compared to either single agent or vehicle, the BETi/mTORi combo treatment led to a greater degree of tumor growth suppression and a more prolonged survival of the tumor-bearing mice. This enhanced antitumor effect is connected with a significantly more apoptosis (cleaved caspase 3 or PARP) found in SCLC tumor tissues and cell lines treated with the BETi/mTORi combo. Conclusion: mTORi can enhance the antitumor effect of BETi in SCLC by causing more apoptosis. Citation Format: ANJU KUMARI, Lisa Gesumaria, Patricia Fetsch, Markku Miettinen, Keith Hughitt, Beverly Mock, Craig Thomas, David S. Schrump, Haobin Chen. mTOR inhibitor enhances anti-tumor effect of BET bromodomain inhibitor in small cell lung cancer [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 5328.