Funding Agency:

The Pittsburgh Foundation

Total Project Period:

10/01/07 - 09/30/08

Total Project Award:

$20,000

Principal Investigator:

Ian Pollack, MD

Co-Investigator:

None

Project Summary:

Malignant astrocytomas are the most common and deadly primary brain tumors. Their limited response to conventional therapy reflects resistance to undergoing apoptosis in response to DNA damage or mitogen depletion, resulting from tumor suppressor gene mutations and aberrant activation of growth factor signaling.

However, our preliminary studies indicated that despite the limitation in apoptotic triggering, effector pathways of apoptosis may remain intact and can be activated by inhibiting growth factor-mediated signaling. These studies also demonstrated that although a subset of gliomas were highly responsive to modulation of individual signaling pathways, many showed incomplete growth inhibition, reflecting activation of parallel pathways. This led us to examine the efficacy of combinatorial strategies for signaling inhibition, using agents targeting distinct pathways.

Our initial studies suggested the potential for intriguing, synergistic interactions between signaling modulatory approaches, such as inhibition of PKC and Raf or JAK/STAT. Based on our findings, we hypothesized that therapeutic approaches that block rationally selected combinations or growth signaling pathways will provide a novel strategy for inducing glioma cytotoxicity.

To test this hypothesis, we will examine the effects on glioma growth and viability of inhibiting combinations of parallel pathways, such as PKC, Ras/Raf, and STAT, which transmit proliferative signals from aberrantly activated upstream receptors. These studies will incorporate a panel of cell lines with defined genetic alterations to assess whether genotypic features influence efficacy, an establish biological surrogates or response. These studies will incorporate analyses of cell proliferation, clonogenicity, apoptotic labeling, and Western blotting to assess inhibition of the p0athways modulated by the signaling-based therapies.

In vitro observations will then be confirmed in rodent glioma models. Taken together, these studies will provide a foundation for translating signal transduction inhibition as a therapeutic approach for gliomas, and indicate ways in which these strategies can be used to enhance efficacy of other therapies.