tbuckley/cabot-search huggingface dataset:
Abstract 5924: A clock gene of TIM promotes colorectal cancer tumorigenesis through binding with myosin-9
Authors: Xiaoqin Yuan, Yi Wang, Lei Wu
Journal: Cancer Research (2020)

Abstract Colorectal cancer (CRC) is a common tumor that is characterized by its high mortality rate. However, the underlying molecular mechanisms that drive CRC tumorigenesis are still not clear. Clock genes have been recognized as playing key roles in tumor development. In our present study, we found the expression of TIM (encoding protein of Timeless), one of the clock genes was up-regulated in CRC tissues comparing to the corresponding normal tissues by the results of IHC and its expression was closely associated with tumor clinical stage and poor overall survival of CRC patients through analysis of clinical CRC patients. Functional studies demonstrated that TIM promoted CRC cell proliferation, migration and invasion in vitro and in vivo. Mechanistic investigations showed that TIM plays a key role in EMT. Immunoprecipitation followed by mass spectrometry revealed that Timeless bound with Myosin-9. Furthermore, we also found TIM regulated the expression level of Myosin-9. And Myosin-9 knockdown retarded the migration and invasion of TIM-overexpressed CRC cells. Furthermore, we found the expression of TIM was regulated by histone acetylation at its promoter area. Our results show that TIM could regulate tumorigenesis of CRC by binding and regulating Myosin-9. Our results also implicate TIM as a potential prognostic biomarker and therapeutic target for CRC. Citation Format: Xiaoqin Yuan, Yi Wang, Lei Wu. A clock gene of TIM promotes colorectal cancer tumorigenesis through binding with myosin-9 [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 5924.
Abstract 340: ABI1 and androgen dependence in prostate cancer
Authors: Leszek Kotula, Baylee A. Porter, Xiang Li, Maria A. Ortiz, Rakesh Khanna, Fan Zhang, Sonia H. Kung, Ladan Fazli, Martin E. Gleave, Gennady Bratslavsky, Jeffrey S. Ross
Journal: Cancer Research (2020)

Abstract Background: Androgen independence is the most challenging problem in the treatment of advanced prostate cancer. Although most patients with early-stage prostate cancer can be cured with surgical and/or radiation treatment, the remainder of patients ultimately recur with metastatic disease upon development of resistance to anti-androgen therapy. Epithelial mesenchymal transition (EMT) and lineage plasticity has been proposed as key mechanisms underlying resistance in treatment-induced prostate cancer with neuroendocrine features (NEPC). There has been a rise in treatment-induced NEPC with increased use of anti-androgen therapies. ABI1 regulates EMT by suppressing FYN-STAT3 activation downstream from noncanonical WNT pathway, but the interaction of ABI1 with androgen pathway is not known. We sought to determine the effect of neoadjuvant hormone treatment (NHT) on ABI1 expression levels in different tumor types. Methods: Here we analyzed ABI1 expression (IHC) in tissue microarray containing 75 tumors with no prior treatment, 198 patients subjected to NHT prior to surgery and 39 castration resistant tumors (total n=307). Androgen-induced ABI1 expression was determined upon R1881 treatment by Western blotting and immunofluorescence in hormone- sensitive LNCaP cells. Results: ABI1 expression was significantly downregulated in tumors from patients undergoing NHT(p&amp;lt;0.05). ABI1 expression was significantly increased in CRPC tumors developed while on hormone therapy compared to ABI1 expression in tumors undergoing NHT (p&amp;lt;0.001), or with NEPC (p&amp;lt;0.001). Consistently with these observations, ABI1 expression was upregulated upon treatment of LNCaP cells with R1881 and downregulated by treatment of cells with enzalutamide. Conclusion: ABI1 is an androgen sensitive gene. ABI1 expression is increased in CRPC, most likely secondary to androgen receptor reactivation. It is subsequently downregulated in NEPC, hence, we hypothesize that this may be a key mechanism driving the NEPC phenotype through promoting EMT. Further understanding of the role ABI1 may play in this transformation will provide a more mechanistic understanding of prostate cancer progression and maylead to improved targeted treatment options. Citation Format: Leszek Kotula, Baylee A. Porter, Xiang Li, Maria A. Ortiz, Rakesh Khanna, Fan Zhang, Sonia H. Kung, Ladan Fazli, Martin E. Gleave, Gennady Bratslavsky, Jeffrey S. Ross. ABI1 and androgen dependence in prostate 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 340.
Abstract 4574: A novel method for inactivating tumor cells for use in a personalized cancer vaccine
Authors: Amanda Michele Guth, Raymond Goodrich, Haemin Park, Matthew Gladstone, Crystal Shanley, Lindsay Hartson, Jon Weston
Journal: Cancer Research (2020)

Abstract With the recent interest in personalized medicine for cancer patients and immune therapy, the field of cancer vaccines has been resurrected. Previous autologous, whole cell tumor vaccine trials have not produced convincing results due, in part, to poor patient selection and inactivation methods that are harsh on the cells. Such methods can inadvertently alter protein structure and antigenic profile in ways that make vaccine candidates ineffective in stimulating immune response to autochthonous tumor cells. We decided to investigate a novel method for inactivating tumor cells that uses UVA/UVB light and the benign chemical riboflavin (Riboflavin and UV Light Inactivation, RF+UV). This process is fast and results in complete inactivation of the tumor cells, but preserves tumor cell integrity and antigenicity due to its rapid, yet gentle inactivation process. Our results demonstrate that the inactivation is complete, that proteins are preserved on the surface of the tumor cells, and that the inactivated tumor cells are immunogenic in that they induce dendritic cell maturation, increased IFNγ production, and the generation of tumor cell-specific IgG immune responses. Moreover, when formulated with an adjuvant (“Innocell vaccine”) and tested in two different murine primary tumor models and one metastatic tumor model, the vaccine led to decreased tumor growth, prolonged survival and decreased metastatic disease. In addition, immune cells obtained from tumor tissue following vaccination showed a decrease in exhausted and regulatory cells, suggesting that activation of intratumoral T cells may be playing a role leading to the reduce tumor growth. Lastly, tumor tissue was obtained from 3 client-owned dogs with spontaneous tumors and used to generate an autologous Innocell vaccines. The vaccine was well-tolerated and induced an inflammatory response in 2 of the 3 dogs. This data suggests that the RF+UV process of inactivating tumor cells for use as antigen-presenting agents in cancer vaccine therapy may provide a more rapid, safer and gentler way to generate autologous whole tumor cell vaccines for use in cancer patients. Citation Format: Amanda Michele Guth, Raymond Goodrich, Haemin Park, Matthew Gladstone, Crystal Shanley, Lindsay Hartson, Jon Weston. A novel method for inactivating tumor cells for use in a personalized cancer vaccine [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 4574.
Abstract 6247: Drug delivery with real time customizable micro-scaled continuous liquid interface printed 3D devices
Authors: C. Tilden Hagan, Cameron J. Bloomquist, Joseph M. DeSimone, Andrew Z. Wang
Journal: Cancer Research (2020)

Abstract Background: Surgery is a key treatment for cancer. However, local recurrence after surgery is common and can lead to significant morbidity and mortality. Current strategies to prevent recurrence include intraoperative radiation or systemic chemotherapy. We hypothesize that local chemotherapy delivery can prevent recurrence while reducing toxicity. To accomplish this, we propose to engineer 3D printed devices that can deliver chemotherapy in a localized and prolonged fashion. Methods: Paclitaxel and a cisplatin prodrug were dissolved into a liquid resin mixture of PEG550-DMA and HEMA. Custom 3D patches were printed on a Carbon 3D continuous liquid interface printer with microneedles protruding from one side of a flat surface substrate. A non-drug loaded flat backing was also printed from the same resin, and adhered to back side of the microneedle patch. Tumor growth recurrence inhibition post surgical resection was assessed in NU/NU mice in both 344SQ/Luc and A431 tumor models. Tumors were inoculated subcutaneously (106 344SQ/Luc, 5 × 105 A431) and allowed to grow until they reached 5-7mm in length. Tumors were then surgically resected and mice were either given an IV drug treatment, or had a 3D printed patch implanted in the surgical pocket. Tumor recurrence was evaluated with both luciferase bioluminescence imaging and physical measurement of tumor size. Toxicity parameters were analyzed with enzyme and CBC tests. Results: All drug loaded patches showed significant tumor growth inhibition compared to their corresponding IV drug treatment groups. While single drug loaded patches were significant in their inhibition of tumor growth compared to IV delivery of the same drug, dual drug loaded patches showed the most significant tumor inhibition compared to either single IV drug treatment or a dual IV drug treatment. There were no significant differences in measured toxicity parameters between groups. Conclusions: Our data demonstrated that local drug delivery through a customizable 3D continuous liquid interface printed drug loaded patch can improve tumor growth recurrence inhibition post surgical resection. Citation Format: C. Tilden Hagan, Cameron J. Bloomquist, Joseph M. DeSimone, Andrew Z. Wang. Drug delivery with real time customizable micro-scaled continuous liquid interface printed 3D devices [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 6247.
Abstract 745: Landscape of FGFRactivating aberrations in Chinese non-small cell lung cancer
Authors: Zhen Zhou, Zichuan Liu, Qiuxiang Ou, Xue Wu, Xiaonan Wang, Yang Shao, Hongyan Liu, Yu Yang
Journal: Cancer Research (2020)

Abstract Background Dysfunction in fibroblast growth factor receptor (FGFR) signaling has been reported in non-small cell lung cancer (NSCLC), particularly in lung squamous cell carcinoma (LUSC). We hereby assessed the frequency of FGFR aberrations in a large Chinese NSCLC population. Methods A total of 10,966 NSCLCs whose tumor specimen and/or circulating cell-free DNA (cfDNA) underwent hybridization capture-based next-generation sequencing (NGS) of 400+ cancer-related genes were retrospectively reviewed. Patients' clinical characteristics and treatment histories were further evaluated. Results FGFR aberrations, including mutations, fusions, and gene amplifications, were detected in approximately 1.9% (210/10,966) of the population. FGFR abnormalities were more frequently observed in LUSCs (6.8%, 65/954) than lung adenocarcinomas (1.3%, 128/9596). Previously reported FGFR oncogenic mutations were identified in 19 patients (~0.17%), of which, 68% were male LUSC patients. Eleven out of the 19 patients (58%) had concurrent altered PI3K signaling, thus, highlighting an intriguing molecular characteristic and potential combination therapeutic strategy of dual-targeting FGFR and PI3K signaling in those patients. Furthermore, FGFR fusions retaining the intact kinase domain were identified in 12 patients (0.11%), including nine FGFR3-TACC3 cases, one FGFR2-INA fusion, one novel FGFR4-RAPGEFL1 rearrangement event, and one novel gene fusion between FGFR1 and the SLC20A2 5'-untranslated region, which may result in FGFR1 overexpression. Concomitant EGFR mutations or EGFR amplifications were observed in six patients, four of whom were previously treated with EGFR tyrosine kinase inhibitors, suggesting that FGFR fusions may act as acquired resistance to anti-EGFR therapies. In addition, FGFR amplification was detected in 24 patients, with FGFR1 amplification being the most common event. Notably, FGFR oncogenic mutations, fusions, and gene amplifications were almost always mutually exclusive events. Conclusion We herein report an incidence of FGFR anomalies in a large Chinese NSCLC population, including mutations, gene amplifications, and previously characterized and novel FGFR fusions involving TACC3, INA, RAPGEFL1, and SLC20A2. Keywords: FGFR, activating mutation, fusion, gene amplification, NSCLC, FGFR inhibitors Citation Format: Zhen Zhou, Zichuan Liu, Qiuxiang Ou, Xue Wu, Xiaonan Wang, Yang Shao, Hongyan Liu, Yu Yang. Landscape of FGFRactivating aberrations in Chinese non-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 745.
Abstract 3911: High-throughput screening of patient-derived HCC organoids for drug discovery
Authors: Alissa Michelle Go Wong, Winnie Cheung, Maggie Wong, Aikha Wong, Helena Lam, Zhe Zhang, Matthew Man, Hui Chen, David Close, Paul Johnston, Anthony Chan, Paul Lai, Joseph Kwong, Nathalie Wong
Journal: Cancer Research (2020)

Abstract Current in vitro models of primary liver cancer insufficiently recapitulates the tumor heterogeneity and pathophysiology of the original patient's tumor. This significantly hinders translational studies and often leads to the high rate of clinical trial attrition and poor patient response. Recent technological advances in organoid culture methods have been reported to overcome these limitations. Our group has successfully established 3 patient-derived HCC tumor organoids that closely recapitulate the patient's pathophysiology. Conventional short-term monolayer culture of the same 3 tumors as well as 3 non-tumoral adjacent liver and 3 normal liver organoids were established and compared with 5 HCC cell lines from ATCC for their drug response profiles. Subsequent drug screening was performed using a panel of 100 drugs, of which 70 are FDA-approved for either HCC or other cancers, as well as 30 pipeline compounds targeting frequently mutated pathways in HCC. We found that our screening pipeline could achieve robust z' scores and reproducible data points with technical and biological replicates. Principal component analysis of Total Area under curve (AUC) values show distinct and progressive changes between Normal Liver, Non-tumoral adjacent liver, and Tumor organoids. Upon comparison with HCC cell lines Hep3B, HepG2, Huh7, SNU398 and PLC5, we found HCC patient-derived short term cultures, particularly organoids have more diverse drug sensitivity profiles and may be a better indicator of patient heterogeneity. Interestingly, FDA-approved drugs for HCC such as Regorafenib show high sensitivity and tumor specificity to ATCC cell lines (ATCC vs Normal liver P=0.00017***), but this specificity was reduced and lost in patient-derived 2D cultures (P=0.045*) and organoids (P=0.895), respectively. This may explain the observed hepatotoxicity observed in HCC patients and warrant further investigation of more targeted ways of treating HCC. Citation Format: Alissa Michelle Go Wong, Winnie Cheung, Maggie Wong, Aikha Wong, Helena Lam, Zhe Zhang, Matthew Man, Hui Chen, David Close, Paul Johnston, Anthony Chan, Paul Lai, Joseph Kwong, Nathalie Wong. High-throughput screening of patient-derived HCC organoids for drug discovery [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 3911.
Abstract 4411: A gene set enrichment analysis approach in single-cells along pseudotime trajectories reveals the dynamic activity of oncogenic pathways
Authors: Alexander T. Wenzel, Devora Champa, Stephen B. Howell, Jill P. Mesirov, Olivier Harismendy
Journal: Cancer Research (2020)

Abstract Single cell RNA-sequencing (scRNA-seq) has advanced studies of heterogeneous tissues and cell populations in both healthy and disease states. Dimensionality reduction methods leverage this highly granular data to identify cellular states not captured by “bulk” gene expression or to organize cells along ‘pseudotime' trajectories related to biological processes such as cell cycle or cellular differentiation. Cellular states and trajectories are often annotated using individual marker genes and not gene sets or pathways, despite their more reliable and interpretable association to biological processes. Gene Set Enrichment Analysis (GSEA) was designed to test the enrichment of gene sets in bulk transcriptomic data, but due to the sparsity of the expression data, has not been adapted to single cell analysis. We propose a method to compute gene set enrichment for scRNA-seq data, which calculates an enrichment score for each cell in the dataset. We apply this method to a set of matched ovarian cancer cell lines with acquired resistance to carboplatin. After aligning the cells to a cell-cycle derived pseudotime trajectory, the activity of pathways which were dysregulated in bulk expression profiles appeared to change with the cell cycle progression. The analysis further identified interferon alpha signaling induction in resistant cells, independent of differences in cell cycle progression. Hence, by quantifying and analyzing pathway-level transcriptional activity in the context of a single-cell pseudotime trajectory, the proposed method provides more interpretable annotation of biological processes altered in cancer progression and treatment. Citation Format: Alexander T. Wenzel, Devora Champa, Stephen B. Howell, Jill P. Mesirov, Olivier Harismendy. A gene set enrichment analysis approach in single-cells along pseudotime trajectories reveals the dynamic activity of oncogenic pathways [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 4411.
Abstract 5712: Nutrient scarcity confers breast cancer brain metastasis sensitivity to serine synthesis pathway inhibition
Authors: Bryan Ngo, Eugenie Kim, Sophia Doll, Sophia Bustraan, Alba Luengo, Shawn M. Davidson, Ahmed Ali, Gino Ferraro, Diane Kang, Jing Ni, Roger Liang, Ariana Plasger, Edward R. Kastenhuber, Roozbeh Eskandari, Sarah Bacha, Roshan Sriram, Benjamin D. Stein, Samuel F. Bakhoum, Edouard Mullarky, Matija Snuderl, Nello Mainolfi, Vipin Suri, Adam Friedman, Mark Manfredi, David M. Sabatini, Drew Jones, Min Yu, Jean J. Zhao, Rakesh K. Jain, Matthew G. Vander Heiden, Matthias Mann, Lewis C. Cantley, Michael E. Pacold
Journal: Cancer Research (2020)

Abstract The metabolic milieu of the brain is severely deprived of nutrients, including the amino acids serine and its catabolite glycine. The metabolic rewiring required for tumor cells to survive in the nutrient-limited environment of the brain and the metabolic vulnerabilities this confers are poorly understood. Here we demonstrate that cell-intrinsic de novo serine synthesis is a major determinant of triple-negative breast cancer (TNBC) brain metastasis. Whole proteome comparison of TNBC cells that differ in their capacity to colonize the brain reveals that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is the most significantly upregulated protein in cells that efficiently metastasize to the brain. Expression of catalytically active PHGDH in a non-brain trophic cell line promoted brain metastasis. Furthermore, genetic silencing or pharmacological inhibition of PHGDH attenuated brain metastasis burden in mice. These findings indicate that nutrient availability determines serine synthesis pathway dependence in brain metastasis, and suggest that PHGDH inhibitors may be useful in the treatment of patients with cancers that have spread to the brain. Citation Format: Bryan Ngo, Eugenie Kim, Sophia Doll, Sophia Bustraan, Alba Luengo, Shawn M. Davidson, Ahmed Ali, Gino Ferraro, Diane Kang, Jing Ni, Roger Liang, Ariana Plasger, Edward R. Kastenhuber, Roozbeh Eskandari, Sarah Bacha, Roshan Sriram, Benjamin D. Stein, Samuel F. Bakhoum, Edouard Mullarky, Matija Snuderl, Nello Mainolfi, Vipin Suri, Adam Friedman, Mark Manfredi, David M. Sabatini, Drew Jones, Min Yu, Jean J. Zhao, Rakesh K. Jain, Matthew G. Vander Heiden, Matthias Mann, Lewis C. Cantley, Michael E. Pacold. Nutrient scarcity confers breast cancer brain metastasis sensitivity to serine synthesis pathway inhibition [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 5712.
Abstract 4082: Hsp90B protects MAST1 from CHIP-mediated ubiquitination and degradation providing cisplatin resistance
Authors: Chaoyun Pan, Jie Li, Austin Boese, Sumin Kang
Journal: Cancer Research (2020)

Abstract Microtubule-associated serine/threonine kinase 1 (MAST1) plays a key role in cisplatin resistance of human cancers. However, the mechanism underlying MAST1 regulation remains elusive. We identified the hsp90B as a direct MAST1 binding partner essential for its stabilization via a proteomics screen. Targeting hsp90B in cancer cells sensitizes cisplatin treatment mainly through MAST1 destabilization. Mechanistically, hsp90B protects MAST1 from ubiquitination at lysine 317 and 545 by the E3 ubiquitin ligase CHIP and prevents proteasomal degradation. The role of the hsp90B-MAST1-CHIP signaling axis in cisplatin resistance was clinically validated in cancer patients. Furthermore, a combination of hsp90 inhibitor and MAST1 inhibitor lestaurtinib further inhibited MAST1 activity and consequently potentiated the cisplatin effect in a patient-derived xenograft model. Our study not only reveals the mechanism of MAST1 regulation in tumors but also demonstrates a promising combinatorial therapy to overcome cisplatin resistance in human cancers. Citation Format: Chaoyun Pan, Jie Li, Austin Boese, Sumin Kang. Hsp90B protects MAST1 from CHIP-mediated ubiquitination and degradation providing cisplatin resistance [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 4082.