The phosphatidylinositol 3 kinase (PI3K) signaling axis is aberrantly activated in the majority of adult high-grade gliomas. Activation in glioblastoma (GBM) occurs via one of four mechanisms: 1) Loss of function mutations in the PTEN tumor suppressor;2) Amplification/gain of function mutations in the receptors for EGF or PDGF;3) Activating mutations in the PIK3CA gene that encodes p110?, a catalytic subunit of PI3K, or;4) mutations in the gene PIK3R1 that encodes one ofthe PI3K regulatory subunits, p85a. A number of PI3K inhibitors are in the early stages of clinical trials. One of these, BKM120, is being developed by Novartis and has been shown to pass through the blood brain barrier, making it an excellent candidate for glioblastoma therapy. Project 2 will be centered on a trial of BKM in patients with recurrent glioblastoma. The broad goal of Project 2 is to use the data and clinical materials from patients on our BKM120 trial - in concert with genetically defined mouse models - to address important unresolved questions involving PI3 kinase inhibitors as glioblastoma therapeutics. In addition to the key data on the impact of genetic modifiers on response to BKM120 (if any) coming from the human trial, cell culture and animal studies will address optimization of, and the potential benefits from, combination therapies using BKM120 in concert with standard of care, as well as a number of rationally targeted therapies. Finally, great promise has been seen with inhibitors targeting a single catalytic isoform of PI3K. To prepare clinical testing of this new class of inhibitors, preclinical experiments will be carried out determining the relative importance of the individual PI3K isoforms in disease driven by Pten loss.
Current treatments for glioblastoma are far from satisfactory. The studies proposed here will test the efficacy a blood brain barrier penetrant PI3 kinase inhibitor, a new potential therapeutic that targets a kinase class frequently activated in this disease. In addition preclinical studies are proposed to facilitate treatment with this class of inhibitors. The end goal is to improve the standard of therapy for this disease.
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