Despite relatively rapid advances in our knowledge of gliomagenic lesions and decades of technological advances in neurosurgery, radiation therapy and clinical trials of conventional and novel therapies, little improvement in median survival has been achieved for patients with Grade IV glioblastoma multiforme (GBM). One of the genetic indicator lesions in these tumors is amplification or mutation of the epidermal growth factor receptor (EGFR). This would suggest a rationale for therapeutic targeting of the EGFR and several clinical studies have shown some encouraging responses using EGFR-specific inhibitors. However, many patients whose tumors express amplified WT or mutant EGFR and so would be expected to respond, do not. Moreover, even those patients who do show clear clinical or radiological responses to EGFR inhibitors show progression after some time. These observations indicate that EGFR inhibitor therapies have promise but that a deeper mechanistic understanding of resistance to them is needed. We also hypothesize that EGFR/EGFR* signaling interacts epistatically with other pathways, particularly the PI3-K pathway, that is also a frequent target of genetic alteration in GBM, and that this decreases the effectiveness of EGFR-directed therapeutics. In order to test this and to determine the mechanisms for resistance to these therapies, we propose 2 complementary Aims. Specifically we will: 1) exploit a model of EGFR*-dependent glioma formation, developed during the first funding period of this Program, and current receptor-specific small molecule and antibody-based inhibitory approaches, to define mechanisms by which the requirement for the mutant receptor can be bypassed for tumor survival or which contribute towards eliciting therapeutic resistance;and, 2) define alternative mechanisms that mimic PTEN mutation and hence result in activation of PI3-K pathway signaling.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZCA1)
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Dana-Farber Cancer Institute
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