Pemetrexed and gemcitabine as combination therapy for the treatment of group3 medulloblastoma

Marie Morfouace, Anang Shelat, Megan Jacus, Burgess B. Freeman, David Turner, Sarah Robinson, Frederique Zindy, Yong Dong Wang, David Finkelstein, Olivier Ayrault, Laure Bihannic, Stephanie Puget, Xiao Nan Li, James M. Olson, Giles W. Robinson, R. Kiplin Guy, Clinton F. Stewart, Amar Gajjar, Martine F. Roussel

Research output: Contribution to journalArticlepeer-review

117 Scopus citations

Abstract

We devised a high-throughput, cell-based assay to identify compounds to treat Group3 medulloblastoma (G3 MB). Mouse G3 MBs neurospheres were screened against a library of approximately 7,000 compounds including US Food and Drug Administration-approved drugs. We found that pemetrexed and gemcitabine preferentially inhibited G3 MB proliferation invitro compared to control neurospheres and substantially inhibited G3 MB proliferation invivo. When combined, these two drugs significantly increased survival of mice bearing cortical implants of mouse and human G3 MBs that overexpress MYC compared to each agent alone, while having little effect on mouse MBs of the sonic hedgehog subgroup. Our findings strongly suggest that combination therapy with pemetrexed and gemcitabine is a promising treatment for G3 MBs.

Original languageEnglish
Pages (from-to)516-529
Number of pages14
JournalCancer Cell
Volume25
Issue number4
DOIs
StatePublished - Apr 14 2014

Bibliographical note

Funding Information:
We thank Charles J. Sherr, Richard J. Gilbertson, and all members of the Brain Tumor Program for helpful discussions and insights and members of the Roussel and Sherr laboratories for helpful comments. We are indebted to Dana Farmer, Shelly Wilkerson, Jose Grenet, and Coralie Lefevre for excellent technical expertise; the Small Imaging Core for mouse surgery, MRI, luciferase imaging, and assistance with PK studies; the diagnostic laboratory core for blood analysis; the flow cytometry core for Annexin V and FACS analysis; Marc Valentine for fluorescence in situ hybridization analysis; John Gray for lentiviruses; Brian L. Murphy for IP; Daisuke Kawauchi for neurospheres; Cynthia Wetmore, Michael A. Dyer, and Richard Rahija for establishment of PDXs; and Charles O. Rock for the folate rescue experiment. This work was supported in part by NIH grants CA-096832 (to M.F.R.), CA-155360 and CA-114567 (to J.M.O.), Cancer Center Core grant CA-021765 (to M.F.R. and A.G.), Institut National du Cancer (AVENIR INSERM team, INCa R10067LS to O.A. and L.B.), CNRS (to O.A. and L.B.), Institut Curie (to O.A. and L.B.), a V foundation translational award (to M.F.R. and A.G.), and the American Lebanese-Syrian Associated Charities of St. Jude Children’s Research Hospital.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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