In the United States, the incidence of brain tumors continues to increase and, presently, brain tumors are the most common solid tumors of childhood and adolescence. Unfortunately, however, these tumors remain highly intractable to therapy and prognosis remains abysmal, with, generally, no long-term survivors among patients with anaplastic astrocytomas or glioblastoma multiforme. Understanding the biology underlying therapeutic failure in brain tumors and the development of more effective therapies for the disease are thus a matter of urgency, as was recently emphasized in the report of the Brain Tumor Review Group appointed by the Directors of the National Cancer Institute and the NINDS. This proposal builds on previous findings from our laboratory, and other laboratories, that the allelo-polymorphic glutathione S-transferase P1 (GSTP 1) gene is frequently over-expressed in human malignant gliomas and is a major determinant of failure of chemotherapy and is associated with poor patient survival. Decreased GSTP1 expression or inhibiting its activity has also been shown to enhance the efficacy of chemotherapy. The GSTP1 protein is a major enzyme of Phase II metabolism and thus is involved in metabolic inactivation of anticancer agents leading to drug resistance. It is also a potent inhibitor of jun N-terminal kinase, and consequently plays a significant role in multiple cell signaling cascades and apoptosis. Our hypothesis is that rationally designed small molecules that bind to the GSTP1 active site and inhibit the GSTP1 protein with high affinity and specificity will have significant antitumor activity against gliomas and will overcome GSTP 1-based drug resistance and thereby, enhance the efficacy of chemotherapy in gliomas. In preliminary studies, we identified a novel class of GSTP1 inhibitors, using a rational strategy of structure-based ligand design, computer modeling, high throughput screening, and in vitro efficacy studies to target the 3-dimensional active site of the GSTP1 protein with high affinity and specificity. In this project, we will further optimize this lead and develop candidates with high in vitro and in vivo antiglioma activity for human clinical trials. The studies are likely to lead to a novel class of therapeutic agents for the treatment of malignant gliomas and other human malignancies that are characterized by high GSTP1 expression. The mechanistic studies will provide important insights into the role of GSTP1 in metabolism and signaling in glioma cells. The absence of GSTP1 expression in the normal tissues from which these tumors arise suggests a potential high therapeutic index of these agents. Our final goal in this project is to conduct a clinical trial of the lead GSTP1 inhibitor from this study, as well as, one that targets the GSTP1 G-site and is already in Phase I/II clinical trial.
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