Understanding the molecular basis of therapeutic resistance in GBM

Brain cancers rank as the fourth leading cause of cancer deaths and extract an incalculable social, economic and medical toll. The most common form of brain cancer is malignant glioma – highly invasive, non-curable and neurologically destructive tumors that, in its most advanced form, Glioblastoma Multiforme, (GBM) carries a median survival of less than one year. In contrast to many other tumor types, countless clinical trials have failed to extend the life of GBM patients. The proposed program rests on the premise that meaningful therapeutic in-roads begin with a more in-depth view of the genetic lesions responsible for the genesis, progression and maintenance of GBM. With such knowledge in hand, it will be possible to conceptualize the rational design of therapies directed specifically to these essential genetic lesions. The remarkable success of the selective tyrosine kinase inhibitor imatinib (Glivec) has validated the concept of molecularly targeted cancer therapy and has galvanized the cancer research community.

Dr. Chin’s research program has focused on the discovery of cancer genes as well as on the development of mouse models of human cancer. Employing high-resolution technologies to scan across the chromosomes of cancer cells, the Chin laboratory has discovered a number of novel genes that are up-regulated in GBM. One such gene appears to be active in greater than 95% of GBM, making it one of the most consistent genetic lesions in this cancer type. Recent functional analysis of the product of this gene has revealed that it lies at the nexus of pathways governing cellular proliferation, cellular survival and cellular disintegration (necrosis). Over-expression of this gene endows normal brain cells (astrocytes) with enhanced growth rates, intense resistance to chemotherapy, and propensity to undergo necrosis. Indeed, hyperproliferation, chemoresistance and necrosis are hallmark features of GBM, raising the possibility that this gene may drive these stereotypical features.

In this proposal, Dr. Chin aims to dissect in great detail the biochemical and physical properties of this novel glioma oncoprotein and to generate mouse models in which to study the impact of overexpression and elimination of function. These biochemical studies will explore this gene’s interactions with the proliferative and survival machinery of the cell. The mouse engineering will exploit existing approaches, used extensively in Dr. Chin’s lab, to introduce engineered genes into the mouse germline. These modified mice will be combined with other genetic lesions that promote glioma formation in order to validate the cancer-promoting actions of this new oncoprotein. In the final phases of this program, this validated target will be the focus of high-throughput drug screens designed to identify small molecule inhibitors of protein that will ultimately be assessed in the gliomaprone mice that over-express the gene.