Molecular Target Variation Across Environments and at Margins of Glioblastoma

Glioblastoma (GBM; WHO grade IV) is the most frequent primary brain tumor and has a dismal prognosis. A common goal in neuro-oncology is to develop therapies targeted at molecular mechanisms of tumor progression. One potential detractor to such approaches is the tremendous heterogeneity within a given patient’s GBM, such that molecular targets could vary depending on the micro-environment from which they are sampled. Following neurosurgical resection of these highly infiltrative tumors, it will be critical to direct therapies at drugable targets present at the residual invasive tumor near the resection margin, rather than at those of the bulk resected tumor, since these could differ substantially. Our preliminary data and the literature suggest that transcriptional programs and EGFR/PPDGFRA amplification events vary across regions within GBM. Downstream signaling networks and drugable targets likely show similar variation. We initiated a Phase II clinical trial of 5-Aminolevulinic Acid (5-ALA), a fluorescent compound that accumulates in glioma cells, thereby enhancing visualization and neurosurgical resection and allowing definition of macro-environments that include 1) perinecrotic glioma, 2) bulk glioma, and 3) glioma margin. Using this novel neurosurgical platform, we propose to define spatial and temporal molecular variations of human GBMs including transcriptional and phospho-protein profiles, EGFR/PDGFRA amplification and downstream network activation by multiplex quantum dots. We also investigate molecular alterations that evolve within recurrent GBM in patient samples as compared to those present at the tumor margin of the primary tumor. A GBM xenograft model in which hypoxia and necrosis are induced using photo-activated compounds that cause vaso-occlusion will be used to precisely monitor spatial and temporal evolution of molecular variation. We hypothesize that the transcriptional profiles, genomic amplification, and drugable tyrosine kinases vary spatially and temporally, and will differ at the residual tumor margin as compared to the bulk tumor.