Mechanisms of Sensitivity to PDGFR Inhibitors in Human Gliomas

As a physician-scientist who studies brain cancer and cares for patients, there is an urgent need to improve our standard of care for this incurable disease. Glioblastomas are the most common primary brain tumors and recent reports have shown that glioblastoma is a heterogeneous group of diseases that can be subclassified by shared genetic aberrations. The implication is that, in part, the underlying genetics may determine the responsiveness to treatments and thus allow us to personalize therapy. Several years ago, we noted a glioblastoma patient with dramatic responsiveness to imatinib mesylate, a platelet derived growth factor receptor (PDGFR) kinase inhibitor. We investigated this case and found a molecular biomarker. We subsequently investigated clinical trial patients on a negative phase I/II trial of imatinib in recurrent malignant gliomas and found this same biomarker in some of the responders. Since then we have been evaluating these cases for mutations and other genetic abnormalities. These results illustrate the potential responsiveness of a molecularly defined subset of glioblastomas and the poor results of prior trials might in fact be due to not enriching for responsive patients. Linking such individual treatment responsiveness to the detailed genetics of tumor will be the crucial next step to truly personalizing cancer therapies. The above data has provided the rationale to initiate a prospective trial of PDGFR inhibitors in biomarker-enriched high-grade glioma patients.