The theme of this proposal is to both enhance target discovery/confirmation in the projects and to translate such findings regarding potential targets including BH3 proteins/apoptosis machinery, ubiquitin ligases, and key transcription factors. Some or all of these targets will be tested as potentially useful therapeutic strategies by means of early phase clinical trials. Clinical Research Support Core resources are required to carry out these clinical trials and assays on human leukemia cells obtained both at diagnosis/relapse and during the course of therapeutic studies. The personnel in this core will closely interact with the biostatisticians in Core C for trial design, data quality assurance and analysis of results. This Core will be responsible for obtaining required diagnostic and post-treatment samples which will be stored in the tissue bank facility described in Biospecimen Core B after obtaining appropriate consent. Thus the overall Specific Aims of the clinical research support core are to: 1. Collect cells at diagnosis and relapse from patients with AML and higher-risk MDS for storage and annotation in Biospecimen Core B who will perform key biology-defining assays and provide cells to the projects for target development and validation 2. To conduct clinical trials (including obtaining material for ancillary studies) with agents derived from preclinical science in the projects To accomplish these aims we will: * Recruit and enroll eligible patients (including appropriate numbers of individuals across age, gender, ethnicity and racial groups) f o r t h e clinical trials in myeloid leukemias * Coordinate the operation of the clinical trials described in this application. Ensure that study parameters are followed;confirm eligibility for patient registration, treatment program adherence, HIPPA compliance, appropriate dose modification, collection of ancillary data and specimens, adverse event reporting, and toxicity/response assessment * Collect research specimens and distribute ancillary samples via the Biospecimen Core C sample acquisition, storage and distribution mechanism to investigators at the relevant laboratories in the Projects (in some cases straightforward assays may be carried out by Core D shortly after blast isolation if required) * Act as liaison with pharmaceutical companies, outside physicians and hospitals to coordinate the collection of research specimens and follow-up data * Provide central data management for collection and documentation of individual patient information

Public Health Relevance

The research carried out in this project will enable the development of less toxic and more specific therapies for patients with AML and high risk MDS. We plan to rapidly translate laboratory discoveries into useful therapies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-C (J1))
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Brigham and Women's Hospital
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Townsend, Elizabeth C; Murakami, Mark A; Christodoulou, Alexandra et al. (2016) The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice. Cancer Cell 29:574-86
Arreba-Tutusaus, P; Mack, T S; Bullinger, L et al. (2016) Impact of FLT3-ITD location on sensitivity to TKI-therapy in vitro and in vivo. Leukemia 30:1220-5
Tanaka, Minoru; Roberts, Justin M; Seo, Hyuk-Soo et al. (2016) Design and characterization of bivalent BET inhibitors. Nat Chem Biol 12:1089-1096
Wu, H; Hu, C; Wang, A et al. (2016) Discovery of a BTK/MNK dual inhibitor for lymphoma and leukemia. Leukemia 30:173-81
Wu, H; Hu, C; Wang, A et al. (2016) Ibrutinib selectively targets FLT3-ITD in mutant FLT3-positive AML. Leukemia 30:754-7
Puram, Rishi V; Kowalczyk, Monika S; de Boer, Carl G et al. (2016) Core Circadian Clock Genes Regulate Leukemia Stem Cells in AML. Cell 165:303-16
Brien, Gerard L; Valerio, Daria G; Armstrong, Scott A (2016) Exploiting the Epigenome to Control Cancer-Promoting Gene-Expression Programs. Cancer Cell 29:464-76
Zhu, Nan; Chen, Mo; Eng, Rowena et al. (2016) MLL-AF9- and HOXA9-mediated acute myeloid leukemia stem cell self-renewal requires JMJD1C. J Clin Invest 126:997-1011
Schneider, Rebekka K; Schenone, Monica; Ferreira, Monica Ventura et al. (2016) Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9. Nat Med 22:288-97
Hatcher, John M; Weisberg, Ellen; Sim, Taebo et al. (2016) Discovery of a Highly Potent and Selective Indenoindolone Type 1 Pan-FLT3 Inhibitor. ACS Med Chem Lett 7:476-81

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