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DePinho awarded $10.8 million to study malignant gliomas

DF/HCC member Ronald DePinho, MD (DFCI) has successfully renewed funding from the NCI to better understand the pathogenesis of glioblastoma multiforme (GBM). DePinho and colleagues will receive approximately $10.8 million in total costs over five years. The P01, entitled "Genetics and Biology of Malignant Glioma," consists of three projects:

Discovering and modeling genetic events driving glioblastoma pathogenesis
Ronald DePinho, MD (DFCI)
In this project, DePinho and colleagues will refine a unique high-grade glioma model, developed in the first funding period of this program, by incorporating newly discovered glioma-relevant alleles emerging from genetic, functional genomic, and proteomic studies. Specific aims are to:

  • Refine and provide a detailed characterization of high-grade glioma model harboring signature mutations present in human GBM
  • Assess the impact of BcI2L12 over-expression in driving glioma progression in the conditional high-grade glioma model
  • Identify the spectrum of activated RTKs and validate their roles in GBM pathogenesis

Resistance to therapeutics directed at the EGFR/PI3-K pathways in glioblastoma
Webster Cavenee, PhD (Ludwig Institute for Cancer Research)
Frank Furnari, PhD (Ludwig Institute for Cancer Research)
Cavenee, Furnari, and colleagues will exploit biochemical and cell biological analyses that are designed to understand activated EGFR signaling in GBM and how patients respond or progress when treated with EGFR kinase inhibitors. Specific aims are to:

  • Determine mechanisms that lead mutant-EGFR independent tumor maintenance and consequent resistance to receptor and pathway-specific therapies
  • Identify mechanisms that activate the P13-K pathway activating mechanisms and thereby convey EGFR-therapeutic resistance

Identification and characterization of kinase oncogenes in glioblastoma
Lynda Chin, MD (DFCI)
William Hahn, MD, PhD (DFCI)
The final project, headed by Chin and Hahn, is new to the renewal and combines strengths in oncogenomics and high-throughput RNA interference with which they will identify a set of putative oncogenes that are not only amplified in GBM but also necessary for their proliferation and survival. Specific aims are to:

  • Integrate functional genomics for identification of novel oncogene candidates in GBM
  • Validate, both functionally and clinicopathologically, novel oncogene candidates in GBM
  • Investigate the roles in GBM initiation and/or maintenance
  • Develop strategies for therapeutic intervention for GBM