TRH Production and Regulation by Human Melanoma

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DESCRIPTION (provided by applicant): The candidate is a medical oncologist who obtained a Ph.D. degree in 1998 while on clinical faculty at the M.D. Anderson Cancer Center. In 1999, she left her clinical faculty position to train as a postdoctoral fellow in the laboratory of Dr. Elizabeth Grimm, Department of Bioimmunotherapy, under a T32 training grant (T32 CA72371, Dr. Gabriel Lopez-Berestein). The long-term career goal of the candidate is to become an independent researcher and head of a laboratory that is focused on translational research in the area of biologic and immunologic therapy for melanoma. The immediate goals of the applicant are to develop a research plan, obtain funding, and carry out that plan to achieve the proposed specific aims; and to develop a longitudinal research plan with funding through the R01 mechanism. The intent is to carry out the proposed research at the M.D. Anderson Cancer Center, with tissue resources available through the Melanoma Tumor Bank. The research proposal is based on the observation of a high prevalence of hypothyroidism among patients with uveal and cutaneous melanoma. It is hypothesized that melanomas produce and secrete thyrotropin-releasing hormone (TRH) as an autocrine growth factor that binds and activates the melanocortin-1 receptor (MC1-R); and that TRH production by melanomas is regulated by TRH control mechanisms functioning normally in the hypothalamus. These mechanisms include stimulation of TRH by low levels of circulating thyroid hormone (hypothyroidism); elevated levels of leptin, signaling through the long isoform of the leptin receptor; and (-melanocyte stimulating hormone signaling through the melanocortin-4 receptor (MC4-R). Preliminary data demonstrate the presence of TRH message and protein in primary melanomas and melanoma cell lines. MC1-R has also been identified in these lines. The first specific aim proposes to verify the role of TRH as an autocrine growth factor for melanoma. Expression of TRH by melanoma cells has been demonstrated in previous experiments. Secretion will be detected and quantified by radioimmunoassay. Co-immunoprecipitation and measurement of cAMP will establish binding and activation of MC1-R by TRH. Effects of TRH on proliferation and migration will also be examined. In Specific Aim #2, cell lines will be used for in vitro studies to determine if one or more of the mechanisms of hypothalamic TRH regulation are relevant to the control of TRH production by melanoma cells.