We have utilized our in vitro and in vivo models of the multiple myeloma (MM) cell in the BM milieu to demonstrate the molecular mechanisms whereby novel agents target tumor cells, host interactions, and the BM microenvironment to overcome conventional drug resistance. We have then rapidly translated these laboratory findings to the clinic leading to FDA approvals of six novel treatments in the past five years;importantly, the median survival of MM patients has been extended from 3 to 7 years as a direct result of these advances. Our preclinical in vitro and in vivo efforts combining bortezomib with lenalidomide demonstrated synergistic MM cytotoxicity, and our derived clinical trials in newly diagnosed patients showed remarkable response;together, these data provided the rationale for the proposed clinical study in Project 1. We hypothesize that genetic changes identified using extensive oncogenomic profiling in Projects 2 and 4 represent novel therapeutic targets in MM. In this Project, we will use our robust human MM model systems to stringently validate the role of these novel targets in MM cell growth, survival, and drug resistance;and assess the therapeutic potential of these targets, both alone and in combination with established and emerging MM therapeutics. We will use a high-throughput shRNA-based assay directed at these targets to identify those regulating MM cell growth and survival in vitro (Specific Aim 1);validate the functional role of selected molecular targets regulating MM cell growth, survival, and drug resistance using our in vitro and in vivo models of human MM in the bone marrow milieu (Specific Aim 2);and evaluate the impact of potential therapeutic agents directed against these validated novel molecular targets, alone and in combination in MM (Specific Aim 3). This proposal will therefore identify the next generation of targeted therapies in MM.
This project will validate biologically relevant and clinically applicable targets in myeloma and develop therapeutic agents directed at these targets in vitro and in vivo for potential clinical consideration.
|GullÃ , Annamaria; Di Martino, Maria Teresa; Gallo Cantafio, Maria Eugenia et al. (2016) A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan-Refractory Multiple Myeloma Cells. Clin Cancer Res 22:1222-33|
|Prabhala, R H; Fulciniti, M; Pelluru, D et al. (2016) Targeting IL-17A in multiple myeloma: a potential novel therapeutic approach in myeloma. Leukemia 30:379-89|
|Magrangeas, Florence; Kuiper, Rowan; Avet-Loiseau, HervÃ© et al. (2016) A Genome-Wide Association Study Identifies a Novel Locus for Bortezomib-Induced Peripheral Neuropathy in European Patients with Multiple Myeloma. Clin Cancer Res 22:4350-5|
|Ohguchi, Hiroto; Hideshima, Teru; Bhasin, Manoj K et al. (2016) The KDM3A-KLF2-IRF4 axis maintains myeloma cell survival. Nat Commun 7:10258|
|Dimopoulos, Meletios A; Orlowski, Robert Z; Facon, Thierry et al. (2015) Retrospective matched-pairs analysis of bortezomib plus dexamethasone versus bortezomib monotherapy in relapsed multiple myeloma. Haematologica 100:100-6|
|Bianchi, Giada; Munshi, Nikhil C (2015) Pathogenesis beyond the cancer clone(s) in multiple myeloma. Blood 125:3049-58|
|Jagannathan, S; Vad, N; Vallabhapurapu, S et al. (2015) MiR-29b replacement inhibits proteasomes and disrupts aggresome+autophagosome formation to enhance the antimyeloma benefit of bortezomib. Leukemia 29:727-38|
|Hu, Y; Song, W; Cirstea, D et al. (2015) CSNK1Î±1 mediates malignant plasma cell survival. Leukemia 29:474-82|
|Hebraud, Benjamin; Magrangeas, Florence; Cleynen, Alice et al. (2015) Role of additional chromosomal changes in the prognostic value of t(4;14) and del(17p) in multiple myeloma: the IFM experience. Blood 125:2095-100|
|Mitsiades, Constantine S (2015) Therapeutic landscape of carfilzomib and other modulators of the ubiquitin-proteasome pathway. J Clin Oncol 33:782-5|
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