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Pancreatic Neoplasms: HELP
Articles by Stuart L. Schreiber
Based on 4 articles published since 2009
(Why 4 articles?)
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Between 2009 and 2019, S. L. Schreiber wrote the following 4 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors. 2018

Alvarez, Mariano J / Subramaniam, Prem S / Tang, Laura H / Grunn, Adina / Aburi, Mahalaxmi / Rieckhof, Gabrielle / Komissarova, Elena V / Hagan, Elizabeth A / Bodei, Lisa / Clemons, Paul A / Dela Cruz, Filemon S / Dhall, Deepti / Diolaiti, Daniel / Fraker, Douglas A / Ghavami, Afshin / Kaemmerer, Daniel / Karan, Charles / Kidd, Mark / Kim, Kyoung M / Kim, Hee C / Kunju, Lakshmi P / Langel, Ülo / Li, Zhong / Lee, Jeeyun / Li, Hai / LiVolsi, Virginia / Pfragner, Roswitha / Rainey, Allison R / Realubit, Ronald B / Remotti, Helen / Regberg, Jakob / Roses, Robert / Rustgi, Anil / Sepulveda, Antonia R / Serra, Stefano / Shi, Chanjuan / Yuan, Xiaopu / Barberis, Massimo / Bergamaschi, Roberto / Chinnaiyan, Arul M / Detre, Tony / Ezzat, Shereen / Frilling, Andrea / Hommann, Merten / Jaeger, Dirk / Kim, Michelle K / Knudsen, Beatrice S / Kung, Andrew L / Leahy, Emer / Metz, David C / Milsom, Jeffrey W / Park, Young S / Reidy-Lagunes, Diane / Schreiber, Stuart / Washington, Kay / Wiedenmann, Bertram / Modlin, Irvin / Califano, Andrea. ·Department of Systems Biology, Columbia University, New York, NY, USA. · DarwinHealth Inc, New York, NY, USA. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Institute for Systems Genetics, New York University Langone Medical Center, New York, NY, USA. · Department of Urology, Columbia University, New York, NY, USA. · Division of Pathology, European Institute of Oncology, Milan, Italy. · Broad Institute of Harvard and MIT, Cambridge, MA, USA. · Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Cedars-Sinai Medical Center, Los Angeles, CA, USA. · Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. · PsychoGenics Inc., Tarrytown, NY, USA. · Department of General and Visceral Surgery, Zentralklinik, Bad Berka, Germany. · Sulzberger Columbia Genome Center, Columbia University, New York, NY, USA. · Wren Laboratories, Branford, CT, USA. · Division of Hematology Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. · Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. · Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. · Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA. · Department of Neurochemistry, the Arrhenius Laboratories for Nat. Sci., Stockholm University, Stockholm, Sweden. · Laboratory of Molecular Biotechnology, Institute of Technology, University of Tartu, Tartu, Estonia. · Falconwood Foundation, New York, NY, USA. · Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria. · Department of Pathology, Columbia University, New York, NY, USA. · Department of Pathology, University Health Network, University of Toronto, Toronto, Canada. · Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA. · Division of Colon and Rectal Surgery, State University of New York, Stony Brook, NY, USA. · Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI, USA. · Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA. · Imperial College London, London, UK. · Medical Oncology, National Center for Tumor Diseases Heidelberg, University Medical Center Heidelberg, Heidelberg, Germany. · Mount Sinai School of Medicine, New York, NY, USA. · Department of Surgery, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY, USA. · Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA. · Department of Internal Medicine, Division of Gastroenterology, Charite, Universitätsmedizin Berlin, Berlin, Germany. · Emeritus Professor Gastrointestinal Surgery, School of Medicine, Yale University, New Haven, Connecticut, USA. imodlin@irvinmodlin.com. · Department of Systems Biology, Columbia University, New York, NY, USA. califano@cumc.columbia.edu. · Department of Biomedical Informatics, Columbia University, New York, NY, USA. califano@cumc.columbia.edu. · Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA. califano@cumc.columbia.edu. · J.P. Sulzberger Columbia Genome Center, Columbia University, New York, NY, USA. califano@cumc.columbia.edu. · Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA. califano@cumc.columbia.edu. ·Nat Genet · Pubmed #29915428.

ABSTRACT: We introduce and validate a new precision oncology framework for the systematic prioritization of drugs targeting mechanistic tumor dependencies in individual patients. Compounds are prioritized on the basis of their ability to invert the concerted activity of master regulator proteins that mechanistically regulate tumor cell state, as assessed from systematic drug perturbation assays. We validated the approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare malignancy originating in the pancreas and gastrointestinal tract. The analysis identified several master regulator proteins, including key regulators of neuroendocrine lineage progenitor state and immunoevasion, whose role as critical tumor dependencies was experimentally confirmed. Transcriptome analysis of GEP-NET-derived cells, perturbed with a library of 107 compounds, identified the HDAC class I inhibitor entinostat as a potent inhibitor of master regulator activity for 42% of metastatic GEP-NET patients, abrogating tumor growth in vivo. This approach may thus complement current efforts in precision oncology.

2 Article A small-molecule inducer of PDX1 expression identified by high-throughput screening. 2013

Yuan, Yuan / Hartland, Kate / Boskovic, Zarko / Wang, Yikai / Walpita, Deepika / Lysy, Philippe A / Zhong, Cheng / Young, Damian W / Kim, Young-Kwon / Tolliday, Nicola J / Sokal, Etienne M / Schreiber, Stuart L / Wagner, Bridget K. ·Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA. · Chemical Biology Platform, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. · Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Howard Hughes Medical Institute, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. · Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. · Laboratory of Pediatric Hepatology and Cell Therapy, Catholic University of Leuven, Brussels 1200, Belgium. · Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: bwagner@broadinstitute.org. ·Chem Biol · Pubmed #24290880.

ABSTRACT: Pancreatic and duodenal homeobox 1 (PDX1), a member of the homeodomain-containing transcription factor family, is a key transcription factor important for both pancreas development and mature β cell function. The ectopic overexpression of Pdx1, Neurog3, and MafA in mice reprograms acinar cells to insulin-producing cells. We developed a quantitative PCR-based gene expression assay to screen more than 60,000 compounds for expression of each of these genes in the human PANC-1 ductal carcinoma cell line. We identified BRD7552, which upregulated PDX1 expression in both primary human islets and ductal cells, and induced epigenetic changes in the PDX1 promoter consistent with transcriptional activation. Prolonged compound treatment induced both insulin mRNA and protein and also enhanced insulin expression induced by the three-gene combination. These results provide a proof of principle for identifying small molecules that induce expression of transcription factors to control cellular reprogramming.

3 Article Gossypol and an HMT G9a inhibitor act in synergy to induce cell death in pancreatic cancer cells. 2013

Yuan, Y / Tang, A J / Castoreno, A B / Kuo, S-Y / Wang, Q / Kuballa, P / Xavier, R / Shamji, A F / Schreiber, S L / Wagner, B K. ·Chemical Biology Program, Broad Institute, Cambridge, MA 02142, USA. ·Cell Death Dis · Pubmed #23807219.

ABSTRACT: The histone methyltransferase G9a is overexpressed in a variety of cancer types, including pancreatic adenocarcinoma, and promotes tumor invasiveness and metastasis. We recently reported the discovery of BRD4770, a small-molecule inhibitor of G9a that induces senescence in PANC-1 cells. We observed that the cytotoxic effects of BRD4770 were dependent on genetic background, with cell lines lacking functional p53 being relatively resistant to compound treatment. To understand the mechanism of genetic selectivity, we used two complementary screening approaches to identify enhancers of BRD4770. The natural product and putative BH3 mimetic gossypol enhanced the cytotoxicity of BRD4770 in a synergistic manner in p53-mutant PANC-1 cells but not in immortalized non-tumorigenic pancreatic cells. The combination of gossypol and BRD4770 increased LC3-II levels and the autophagosome number in PANC-1 cells, and the compound combination appears to act in a BNIP3 (B-cell lymphoma 2 19-kDa interacting protein)-dependent manner, suggesting that these compounds act together to induce autophagy-related cell death in pancreatic cancer cells.

4 Article A small-molecule probe of the histone methyltransferase G9a induces cellular senescence in pancreatic adenocarcinoma. 2012

Yuan, Yuan / Wang, Qiu / Paulk, Joshiawa / Kubicek, Stefan / Kemp, Melissa M / Adams, Drew J / Shamji, Alykhan F / Wagner, Bridget K / Schreiber, Stuart L. ·Chemical Biology Program, Broad Institute, Cambridge, Massachusetts 02142, United States. ·ACS Chem Biol · Pubmed #22536950.

ABSTRACT: Post-translational modifications of histones alter chromatin structure and play key roles in gene expression and specification of cell states. Small molecules that target chromatin-modifying enzymes selectively are useful as probes and have promise as therapeutics, although very few are currently available. G9a (also named euchromatin histone methyltransferase 2 (EHMT2)) catalyzes methylation of lysine 9 on histone H3 (H3K9), a modification linked to aberrant silencing of tumor-suppressor genes, among others. Here, we report the discovery of a novel histone methyltransferase inhibitor, BRD4770. This compound reduced cellular levels of di- and trimethylated H3K9 without inducing apoptosis, induced senescence, and inhibited both anchorage-dependent and -independent proliferation in the pancreatic cancer cell line PANC-1. ATM-pathway activation, caused by either genetic or small-molecule inhibition of G9a, may mediate BRD4770-induced cell senescence. BRD4770 may be a useful tool to study G9a and its role in senescence and cancer cell biology.