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Evaluation of AZD9291 in Glioblastoma patients with activated EGFR

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? DESCRIPTION (provided by applicant): Glioblastoma (GBM) is among the most aggressive and common primary brain tumors in adults. GBM patients have an extremely poor prognosis, and current treatments (including surgery, radiation therapy, and chemotherapy) have failed to extend median survival beyond 15 months. Therefore, the need for an effective GBM therapy is urgent. To achieve this goal, we need to understand the molecular machinery that drives GBM. Recent studies indicate that GBMs are heterogeneous, and four major subtypes have been identified by The Cancer Genome Atlas (TCGA) program. To further understand the molecular heterogeneity of GBM, we recently characterized a panel of 20 patient-derived glioblastoma xenografts (PDGX) at the proteomic level and compared each with the proteome of its corresponding parent tumor. An examination of the proteomic profiling of 20 PDGX revealed that 7 of them have activated epidermal growth factor receptor (EGFR) arising from both wild-type EGFR amplification and EGFRvIII. Such data is consistent with the observation that EGFR dysfunction is seen in a large proportion of GBMs. Furthermore, we found these specific PDGX with activated EGFR have elevated phosphorylation of several other proteins, including HER2, which only underscores the importance of testing an EGFR tyrosine kinase inhibitor (EGFR-TKI), such as AZD9291, since it has been proven to inhibit both EGFR and HER2. Another key characteristic of AZD9291 is its good brain penetration. Previous studies of EGFR-TKI in GBM patients have failed because of two fatal flaws: 1) the trial included all GBM patients, instead of just those with activated EGFR originating from a specific EGFR genotype, and 2) the EGFR-TKI had poor brain penetration. Both flaws have been removed from this proposed study. In fact, the proposed study will subdivide GBM patients with activated EGFR into two groups: 1) patients whose activated EGFR is wild-type; and 2) patients whose activated EGFR is EGFRvIII. This segregation is warranted because our data show that activated EGFR from wild-type and EGFRvIII utilize different signaling pathways. The focus of the UH2 part (stage 1) of this application is to test AZD9291 in preclinical models of GBM with activated EGFR originating from either wild-type EGFR with gene amplification or EGFRvIII (Aim 1). A positive response in the proposed preclinical studies will lead to the second goal of the UH2 part, which will involve phase 1b studies (Aim 2) to determine whether AZD9291, at safe doses, reaches the tumor, engages the target, and inhibits downstream signaling. A positive response from phase 1b studies will lead to UH3 part (stage 2), which will assess the efficacy of AZD9291 in phase 2a trials (Aim 3) consisting of control (standard of care) and treated arm (AZD9291 plus standard of care). Because of AZD9291's unique properties, our molecularly-defined preclinical models, and our inclusion of only those GBM patients expressing the target, the proposed studies will be the first to properly evaluate whether or not an EGFR-TKI can control GBM growth in patients whose tumor is driven by specific abnormalities in EGFR. To successfully complete the proposed study, we have assembled a well-rounded team consisting of Drs. Kwatra (PI), Lesser (PI), and Gilbert (director of the Brain Tumor Trials Collaborative).
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