The importance of hypoxia as a critical determinant in tumor progression and response to therapy has been well-documented. It is hypothesized that the effects of hypoxia on malignant progression are based on transcriptional changes in gene expression. The development of tumor cell cytotoxins based on the critical regulators of hypoxia-induced transcription represents a new therapeutic approach. One major regulator of transcription under hypoxic conditions is the hypoxia-inducible transcription factor 1 (HIF-1). Thus, the central focus of this project will be to identify compounds that are selectively cytotoxic to tumor cells that possess elevated levels of HIF-1. The HIF-1 transcription factor is a tumor specific target and is induced by hypoxia as well as oncogenes and dysregulated growth factors. In recent years, we have developed a great deal of knowledge about the pathways and genetic determinants that influence the stabilization and activity of the oxygen-sensitive HIF-1alpha subunit of HIF-1. Recent studies indicate that mutations of proline 402 or 564 will prevent HIF-1alpha binding to VHL, an E3 ubiquitin ligase, and therefore stabilized under aerobic conditions. While pharmacologic and genetic inhibitors of HIF-1alpha stabilization and activity have been identified, no in-depth screen has been performed to identify drugs that selectively kill tumor cells that possess elevated HIF-1 levels. Thus, the major goal of this grant is to identify compounds that result in cellular growth inhibition or cytotoxicity in a HIF-1/VHL-dependent manner by performing both in silico and functional screens of the NCI drug screening libraries, as well as commercial libraries that possess wide chemical diversity. We possess the equipment and methodology to perform such screens to identify new HIF-1/VHL-dependent cytotoxins. Ultimately during this grant period, we will identify one compound that has the desired selectivity and potent anti-tumor activity in transplanted tumors to take into the clinic. This project will also investigate mechanisms of drug cytoxicity that are HIF-1 dependent. We envision that such studies will provide new insights into how to exploit HIF-1 for future drug development by identifying specific pathways that lead to cytoxicity directly through HIF-1 or in combination with HIF-1.
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