MOLECULAR RESPONSE TO HYPERTHERMIA IN PROSTATE CARCINOMA--HEAT SHOCK RESPONSE

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We aim to study the role of hyperthermia in the treatment of adenocarcinoma of the prostate and will explore the cellular and molecular factors that govern the response of prostate carcinoma to hyperthermia and radiation, with the aim of optimizing therapy. It has become clear that the effectiveness of tumor treatment by hyperthermia is governed by the heat shock response, a complex cellular responses which involves the coordinated expression of a cohort of genes encoding heat shock proteins (HSPs) that protect cellular proteins during heat shock, the activation of stress kinases and the release of pro-inflammatory lipid modulators that may mediate resistance to treatment. We aim to apply this knowledge to prostate carcinoma as a basis for the rational design of treatment, through two major routes. Firstly, we aim to develop the use of drugs not used for the primary treatment of cancer as relatively non-toxic hyperthermia sensitizes. We will examine three cases of drugs including; (i) nitroimidazole hypoxic cell sensitizes and bioreductive drugs (ii) non steroidal anti-inflammatory drugs (NSAIDs) and (iii) protein kinase inhibitors. The drugs ar targeted against responses to hyperthermia within the cell (heat shock response; iii) and tissue reactions to heat (microcirculatory and inflammatory changes; i, ii). The second major approach to optimizing hyperthermia is to monitor the degree of induction of the heat shock response in patient biopsies before and after treatment with hyperthermia as an assay for tumor sensitivity. We will measure the tumor concentration of HSP70, the HSP whose expression most closely correlates with the resistance of cells to hyperthermia. This will permit us to determine the relationship between the responses of prostate carcinomata to adjuvant hyperthermia and the activation of the heat shock response. The ultimate aim of the project is to enhance tumor treatment by hyperthermia by developing an assay for tumors resistant to hyperthermia that can be treated with the hyperthermia sensitizes developed during the project.