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.

Public Health Relevance

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

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
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Special Emphasis Panel (ZCA1-RPRB-7 (M1))
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Massachusetts General Hospital
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Taylor, Jennie W; Dietrich, Jorg; Gerstner, Elizabeth R et al. (2015) Phase 2 study of bosutinib, a Src inhibitor, in adults with recurrent glioblastoma. J Neurooncol 121:557-63
Schmit, Fabienne; Utermark, Tamara; Zhang, Sen et al. (2014) PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context. Proc Natl Acad Sci U S A 111:6395-400
Cheng, Hailing; Liu, Pixu; Zhang, Fan et al. (2014) A genetic mouse model of invasive endometrial cancer driven by concurrent loss of Pten and Lkb1 Is highly responsive to mTOR inhibition. Cancer Res 74:15-23
Francis, Joshua M; Zhang, Cheng-Zhong; Maire, Cecile L et al. (2014) EGFR variant heterogeneity in glioblastoma resolved through single-nucleus sequencing. Cancer Discov 4:956-71
Sullivan, James P; Nahed, Brian V; Madden, Marissa W et al. (2014) Brain tumor cells in circulation are enriched for mesenchymal gene expression. Cancer Discov 4:1299-309
Maire, Cecile L; Ligon, Keith L (2014) Molecular pathologic diagnosis of epidermal growth factor receptor. Neuro Oncol 16 Suppl 8:viii1-6
Wakimoto, Hiroaki; Tanaka, Shota; Curry, William T et al. (2014) Targetable signaling pathway mutations are associated with malignant phenotype in IDH-mutant gliomas. Clin Cancer Res 20:2898-909