Glioblastomas (GBMs) are among the deadliest and least responsive of human tumors to therapy. The mechanisms driving GBM drug resistance are, however, still not well understood, thus making it difficult to design more effective strategies and/or to develop novel therapeutics to overcome this resistance. Glutathione S-transferase P1, GSTP1, a multifunctional protein involved in phase II metabolism and in the regulation of cell signaling is frequently highly expressed in GBM and a large number of preclinical and clinical studies have shown it to be a major determinant of tumor drug resistance, treatment failure and poor patient survival. p53 encodes a transcription factor activated by a variety of cellular stresses, including, those inflicted by anti-cancer agents. Once activated, p53 acts in a complex cellular network triggering a cascade of downstream pathways to protect genomic integrity of the cell. Mutations in the p53 gene, both inactivating and gain-of-function, are among the most common genetic defects in human cancer, including, GBM. Consequently, p53 mutational status has been intensively investigated, both preclinically and in clinical studies, for its role in tumor response to therapy. These studies, however, have yielded mixed results, with some showing a strong correlation between the presence of p53 mutations and drug resistance while others have shown that wild-type p53, rather than the mutated form, is associated with drug resistance. This apparent conflicting role of p53 in tumor drug resistance reflects the complexity of the p53 network, the functional heterogeneity of p53 mutations and the fact that the full spectrum of downstream p53 targets has not been fully characterized. Recently, we made the provocative finding that the human GSTP1 gene contains a functional canonical p53 binding motif and is transcriptionally activated by p53 in tumor cells. The crosstalk between p53 and GSTP1 could thus be a major component of the cellular function of these two genes and their encoded proteins, particularly, in the protection of the cellular genome against genotoxic compounds, many of which are GSTP1 substrates. A better understanding and characterization of the p53-GSTP1 interaction will provide important insights into the biology of the resistance phenotype and a basis for developing novel strategies to improve the outcome of chemotherapy. The findings might also shed light on the underlying basis of the apparent conflicting relationship between p53 status and outcome of cancer chemotherapy and the increasing recognition of a critical role for p53 in cellular metabolism. The hypothesis to be tested is that transcriptional activation of the GSTP1 gene by wild-type 53 and gain-of-function p53 mutants will increase GSTP1 gene expression, resulting in enhanced GSTP1-mediated drug metabolism and downstream inhibition of MAP kinase signaling leading to more aggressive growth and a drug resistant phenotype in glioblastomas.
The Specific Aims to test this novel hypothesis of tumor drug resistance are:
Aim 1. Determine the relationship between p53 gene status and transcriptional activity of the GSTP1 gene in GBM;
Aim 2. Investigate the functional and mechanistic basis for the p53-dependent transcriptional regulation of the GSTP1 gene in GBM cells and Aim 3. Investigate the impact of the p53-GSTP1 crosstalk on drug resistance in GBM and examine whether this can be targeted to improve therapeutic efficacy in glioblastoma.
GBMs are characterized by a high rate of p53 mutations and high GSTP1 expression, both of which impact on treatment outcome. The results of this research will provide a basis for novel GBM treatment strategies. This is significant and timely, given the current lack of effective GBM therapies and that both p53 and GSTP1 inhibitors are being actively being developed and are in various stages of preclinical and clinical evaluation.
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