1. Academic Validation
  2. Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma

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

  • Sci Transl Med. 2017 May 10;9(389):eaal2668. doi: 10.1126/scitranslmed.aal2668.
Salomon Manier 1 2 3 Daisy Huynh 4 Yu J Shen 4 Jia Zhou 4 Timur Yusufzai 4 Karma Z Salem 4 Richard Y Ebright 4 Jiantao Shi 4 Jihye Park 4 Siobhan V Glavey 4 William G Devine 5 Chia-Jen Liu 4 Xavier Leleu 6 Bruno Quesnel 3 Catherine Roche-Lestienne 3 John K Snyder 5 Lauren E Brown 5 Nathanael Gray 4 James Bradner 4 Luke Whitesell 7 John A Porco Jr 5 Irene M Ghobrial 1
Affiliations

Affiliations

  • 1 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. irene_ghobrial@dfci.harvard.edu salomon_manier@dfci.harvard.edu.
  • 2 Department of Hematology, Lille Hospital, 59000 Lille, France.
  • 3 INSERM UMR-S 1172, University of Lille 2, 59000 Lille, France.
  • 4 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • 5 Boston University Center for Molecular Discovery, Boston, MA 02215, USA.
  • 6 Department of Hematology, University Hospital of Poitiers, 86021 Poitiers, France.
  • 7 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
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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