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2006
Al Yung, M.D.
MD Anderson Cancer Center
Evaluation of Small Molecule Inhibitors of the PI3K/Akt Pathway
Although a significant effort has been focused on the development of conventional and novel therapeutics to treat glioblastoma multiforme (GBM), few current agents prolong survival of patients with high-grade gliomas. A new understanding of the dominant genetic and molecular pathways important in sustaining glioma survival has led to the development of novel, mechanism-based strategies that "target" alterations in cell-signaling pathways as a rational approach to glioma therapy.
The phosphatidylinositol 3-kinase (PI3K) pathway is a key regulator of cancer cell survival, invasion, and angiogenesis mediated by growth factors and other signaling molecules. Combination therapy comprised of small molecules that target various signaling nodes along this pathway is a validated approach to treatment and suggests that small molecule inhibitors targeting the PI3K and Akt signals could have potent and specific anti-tumor effect.
As inhibition of tumor cell proliferation, invasion and angiogenesis is a high priority in treating gliomas, Dr. Yung and his colleagues will test a newly developed inhibitor of PI3K, PX-866 (ProlX), in cultured glioma cells and transplantation xenograft models. They will determine the effect of combining PX-866, with a number of small-molecule inhibitors that targets different effector molecules in the EGFR and PI3K pathways, as well as radiation or temozolomide on tumor cell growth and animal survival.
Novel compounds such as PX-866 are attractive for the treatment of glioma since they can inhibit tumor proliferation and cell migration, and interfere with angiogenesis - another hallmark of tumor progression. The overall goal of this research is to determine the optimal agent or treatment modality to use in combination therapy with PX-866 to maximize antitumor effects.
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