Raje N, Hideshima T, Mukherjee S, Raab M, Vallet S, Chhetri S, Cirstea D, Pozzi S, Mitsiades C, Rooney M, Kiziltepe T, Podar K, Okawa Y, Ikeda H, Carrasco R, Richardson PG, Chauhan D, Munshi NC, Sharma S, Parikh H, Chabner B, Scadden D, Anderson KC. 2009. Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma. Leukemia. 23(5):961-70. Pubmed: 19151776 DOI:10.1038/leu.2008.378


Cyclin D dysregulation and overexpression is noted in the majority of multiple myeloma (MM) patients, suggesting its critical role in MM pathogenesis. Here, we sought to identify the effects of targeting cyclin D in MM. We first confirmed cyclin D mRNA overexpression in 42 of 64 (65%) patient plasma cells. Silencing cyclin D1 resulted in >50% apoptotic cell death suggesting its validity as a potential therapeutic target. We next evaluated P276-00, a clinical-grade small-molecule cyclin-dependent kinase inhibitor as a way to target the cyclins. P276-00 resulted in dose-dependent cytotoxicity in MM cells. Cell-cycle analysis confirmed either growth arrest or caspase-dependent apoptosis; this was preceded by inhibition of Rb-1 phosphorylation with associated downregulation of a range of cyclins suggesting a regulatory role of P276-00 in cell-cycle progression through broad activity. Proliferative stimuli such as interleukin-6, insulin-like growth factor-1 and bone-marrow stromal cell adherence induced cyclins; P276-00 overcame these growth, survival and drug resistance signals. Because the cyclins are substrates of proteasome degradation, combination studies with bortezomib resulted in synergism. Finally, in vivo efficacy of P276-00 was confirmed in an MM xenograft model. These studies form the basis of an ongoing phase I study in the treatment of relapsed/refractory MM.

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David Scadden’s laboratory is dedicated to discovering the principles governing blood cell production, with the ultimate goal of guiding the development of therapies for blood disorders and cancer.

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