Inhibitors of the Phospho-inositol-3-kinase (PI3K) are currently in clinical development for the treatment of human cancer. Glioblastoma, the most common malignant brain tumor in adults, frequently harbors mutations in the PI3K pathway. We performed a clinical trial with the two PI3K inhibitors SAR245408 and SAR245409 to determine whether these agents inhibit PI3K signaling and tumor cell proliferation in 21 patients with surgically accessible recurrent glioblastoma. We observed reduced phosphorylation of several pathway markers (S6-ribosomal protein, S6 kinase 1, 4E-BP1, PRAS40) in the majority of patients. One patient showed an exceptional treatment response with sustained tumor control for over six months. Further characterization of this tumor revealed focal amplification and mutation of the PDGFRA gene. Subsequent studies with PDGFR amplified cancer cell lines and PDGF-induced transgenic gliomas showed that dual PI3K/mTOR blockade, but not mTOR blockade alone, was sufficient to induce cell death. A PDGFRA mutant that lacks the ability to recruit PI3K was unable to rescue PDGFR-dependent glioma cells from cell death induction following PDGF ligand removal. Our studies identify a critical role of PI3K-mediated signals for tumor maintenance downstream of oncogenic PDGFR and highlight the value of studying extreme responders in small sample size, biomarker rich early phase clinical trials.
|School Location:||United States -- New York|
|Source:||DAI-B 75/10(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Oncology|
|Keywords:||Glioblastoma, Glioma, PDGFR, PDGFRA, PI3K|
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