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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
Summary
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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