ATM KINASE AS A NOVEL TARGET FOR RADIOSENSITIZING AGENTS

Project: Research project

Project Details

Description

The cell cycle checkpoint activation by un-replicated or damaged DNA triggers a transduction cascade that orchestrates a variety of cellular responses including cell-cycle arrest, DNA repair, and apoptotic death. Several members of the phosphatidylinositol 3-kinase related kinase (PIKK) family, including the Ataxia-Telangiectasia (A-T) syndrome is caused by an inherited defect in both alleles of the ATM gene. Based on the extreme radiation hypersensitivity of individuals affected by A-T small-molecule inhibitors of TM catalytic activity may be useful as a novel radiosensitizing agents. In support of this, we have recently shown that the fungal metabolite, wortmannin, inhibits ATM kinase activity at concentrations that induce significant radiosensitization. The long-term goal of the current research project is to advanced the pre-clinical development of ATM kinase inhibitors as sensitizing agents for use in cancer therapy. In preliminary experiments, we found that wortmannin treatment prior to irradiation of S-phase synchronized cells resulted in a significant prolongation of the G2 delay. By comparing the defects in the G2 checkpoint and associated signal transduction pathways in wortmannin treated cells and cells derived from A-T patients, further insight into the mechanism of wortmannin-mediated radiosensitization will be gained. To demonstrate proof-of-principle for the use of ATM inhibitors in the clinical setting, the efficacy of wortmannin as a radiosensitizer in xenograft system will be examined. To accelerate the identification of novel ATM inhibitors, the catalytic activity of a series of ATM truncation and deletion mutants will be assessed in an effort to identify a catalytically active protein fragment. Such a fragment will then be used in the development of high-throughput screen for ATM kinase inhibitors. The identification of potent, specific inhibitors of ATM may lead to the development of noel therapeutic agents in the treatment of cancer.
StatusFinished
Effective start/end date7/1/996/30/04

ASJC

  • Medicine(all)