2. Academic Validation
  3. 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. [email protected] [email protected].
  • 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.
PMID: 28490664 DOI: 10.1126/scitranslmed.aal2668
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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