Targeting the PI3K Signaling Axis

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The phosphatidylinositol 3 kinase (P13K) signaling axis is aberrantly activated in the majority of adult highgrade 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 PIKSCA gene that encodes pi 10a, a catalytic subunit of PI3K, or; 4) mutations in the gene PIK3R1 that encodes one ofthe P13K regulatory subunits, p85a. A number of P13K inhibitors are in the early stages of clinical trials. One of these, BKM 120, 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 BKM 120 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 BKM 120 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 ofthe individual P13K isoforms in disease driven by Pten loss.