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

Salomon Manier1,2,3, Daisy Huynh4, Yu J Shen4

  • 1Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. irene_ghobrial@dfci.harvard.edu salomon_manier@dfci.harvard.edu.

Science Translational Medicine
|May 12, 2017
PubMed

Insights

Researchers identified rocaglates as promising inhibitors of translation initiation for treating multiple myeloma (MM). This novel therapeutic strategy targets the MYC oncogene

Area of Science:

  • Hematological Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Multiple myeloma (MM) is an incurable cancer driven by MYC overactivity.
  • MYC upregulates ribosome biogenesis and translation, crucial for cancer cell growth.

Purpose of the Study:

  • To investigate MYC's oncogenic program in MM.
  • To identify small molecules targeting MYC-driven pathways as potential MM therapeutics.

Main Methods:

  • Screened a diverse small-molecule library for anti-MM activity.
  • Identified rocaglates as potent inhibitors of translation initiation.
  • Performed expression profiling and proteome-wide analysis of MM cells treated with CMLD010509.

Main Results:

  • Rocaglates, particularly CMLD010509, reversed the MYC-driven transcriptional program in MM cells.
  • Treatment selectively depleted short-lived proteins essential for MM survival, including MYC, MDM2, CCND1, MAF, and MCL-1.
  • CMLD010509 demonstrated efficacy in preclinical mouse models of MM.

Conclusions:

  • Targeting MYC-driven translation with rocaglates is a feasible therapeutic strategy for multiple myeloma.
  • CMLD010509 shows significant therapeutic potential for MM treatment.

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