The inability of radiotherapy to control tumor growth is still a daunting clinical problem leading to failure of the overall treatment regimens. The fundamental question is; could tumor cells be specifically sensitized to ionizing radiations (IR) by heat or agents that produce effects similar to heat by targeting essential molecules or structures exclusively expressed (present) in tumor cells. One such factor, expressed in most tumors and silent in somatic cells, is telomerase, the enzyme required for cell immortality. Because of this, telomerase is an attractive target for inhibition in anticancer therapy. Telomeres are maintained by telomerase and the catalytic unit of telomerase (TERT) interacts with HSP70. Telomere stability is influenced by ATM (ataxia telangiectasia mutated), a major regulator of cellular responses to IR. ATM, a protein kinase, is activated by IR and phosphorylates a number of different substrates following activation. TERT activity is negatively regulated by downstream effectors of ATM. Based on the fact that hTERT interacts with HSP70 and such interactions may be dependent on ATM signaling, thereby potentially altering the tumor cells' response to IR. To test our hypothesis that heat treatment modulates the IR induced ATM and TERT signaling pathway, experiments will be performed to determine whether heat treatment influences radiation induced ATM kinase activity, telomerase activity, telomere structure and TERT interactions with telomeres in cells with and without expression of HSP70 and/or HSC70. In addition, experiments are proposed that will elucidate whether inactivation of ATM and TERT function will enhance the heat induced sensitization to IR induced cell kill. Determining the influence of heat and/or IR on ATM function and telomere metabolism in presence and absence of HSP70 and/or HSC70 will not only add to our understanding of the mechanisms of heat induced radiosensitization but may also aid the development of new tumor treatment strategies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Subcommittee G - Education (NCI)
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Washington University
Saint Louis
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