Research ArticleCancer

Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma

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Science Translational Medicine  10 May 2017:
Vol. 9, Issue 389, eaal2668
DOI: 10.1126/scitranslmed.aal2668

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Rocaglates rocking multiple myeloma

Multiple myeloma is a difficult-to-treat hematologic malignancy, where the MYC oncoprotein often plays a key role by stimulating ribosome production and up-regulating protein translation to satisfy the needs of rapidly proliferating cancer cells. By performing a high-throughput screen, Manier et al. determined that small-molecule rocaglate derivatives are active in multiple myeloma. The authors focused on one lead rocaglate derivative and showed that it reversed the effects of MYC, blocked excessive translation, induced tumor cell apoptosis, and decreased tumor cell proliferation. The treatment was safe and effective in multiple mouse models, suggesting rocaglates as potential therapeutic candidates for multiple myeloma.

Abstract

Multiple myeloma (MM) is a frequently incurable hematological cancer in which overactivity of MYC plays a central role, notably through up-regulation of ribosome biogenesis and translation. To better understand the oncogenic program driven by MYC and investigate its potential as a therapeutic target, we screened a chemically diverse small-molecule library for anti-MM activity. The most potent hits identified were rocaglate scaffold inhibitors of translation initiation. Expression profiling of MM cells revealed reversion of the oncogenic MYC-driven transcriptional program by CMLD010509, the most promising rocaglate. Proteome-wide reversion correlated with selective depletion of short-lived proteins that are key to MM growth and survival, most notably MYC, MDM2, CCND1, MAF, and MCL-1. The efficacy of CMLD010509 in mouse models of MM confirmed the therapeutic relevance of these findings in vivo and supports the feasibility of targeting the oncogenic MYC-driven translation program in MM with rocaglates.

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