Systematic functional interrogation of the GBM genome for curative combination therapy

Systematic functional interrogation of the GBM genome for curative combination therapy

Award: $2,997,067 over 3 years

Principal Investigators: Ronald A. DePinho, MD, Lynda Chin, MD

Background: The challenge of treating cancer is not only its complexity on the genomic and biological levels but also its dynamic nature. Experimentally and genomically, it is clear that cancer is the phenotypic endpoint of multiple mutations that cooperate to confer its malignant properties. Therefore, it stands to reason that a cancer cure will require reversal or inhibition of multiple cooperative genetic aberrations.  To achieve this goal of a cure, we will require (i) a full compendium of functionally validated genetic alterations as targets of therapeutic inhibition, (ii) an understanding of how these genetic alterations are interconnected in a highly redundant and nimble network, and (iii) how the tumor, a system operated by this genetic network, will or can respond to a particular therapeutic agent.

Hypothesis: Systematic functional interrogation of essential and transforming genes in specific clinically-relevant genetic contexts, coupled with integration with network modeling of GBM genome from TCGA data, will define high potential co-extinction targets for validation and therapeutic development.

Primary objective: To pro-actively design optimal combination strategies that can simultaneously target multiple network nodes that are functionally redundant (i.e. capable of providing bypass, compensation or backup) in response to a specific perturbation.

Specific Aims:
1. To identify context-specific transforming and essential genes in GBM
2. To define co-extinction targets in clinically-relevant genetic contexts of GBM
3. To develop co-extinction therapeutic strategies for GBM