Aberrant regulation of growth of the human prostate is responsible for much of the morbidity and mortality associated with BPH and other forms of prostatic neoplasia in the aging adult male population. In part, growth of the prostate is mediated by the paracrine/autocrine interaction between NGF and its cognate high affinity TrkA receptor and the low affinity NGF receptor (LNGFR). Hence, based upon our prior published work in conjunction with additional preliminary studies reported herein, we propose to test the hypothesis that the two types of NGF receptors, TrkA and the LNGFR stimulate and inhibit growth, respectively, in human prostate epithelial cells. Studies to support this hypothesis are proposed as three specific aims. The first specific aim is to characterize expression of the Trk family members, TrkA, TrkB and TrkC in the normal, BPH and neoplastic pathologic prostate by in situ hybridization and immunohistochemistry. Differential expression of these Trk family members will be correlated with the pathology of the prostate and a proliferating cell nuclear antigen (PCNA) proliferation index. In this manner, changes in the expression of the Trks may be related to the rate of growth and pathology of the prostate. The second specific aim will directly test the putative growth stimulatory effects of the TrkA receptor by transfection with a double stable Tet-On inducible expression system in which Doxycycline is used to regulate the level of TrkA overexpression in a prostate epithelial cell line. The induced overexpression of TrkA will be evaluated in relation to the rate of growth of these cells. The third specific aim will directly test the putative growth inhibitory effects of the LNGFR by transfection with a double stable Tet-On inducible expression system in which Doxycycline is used to regulate the level of LNGFR re-expression in a prostate epithelial cell line. The induced re-expression of the LNGFR will be evaluated for changes in the rate of growth of these cells as it pertains to proliferation and induction of programmed cell death. Our studies have already identified NGF receptors as targets for the clinical perturbation of prostate growth. As a result, phase I clinical trials are currently underway with an indolocarbazole Trk antagonist for the treatment of aberrant prostatic growth at Georgetown University Medical Center. A comprehensive investigation of the NGF receptors in the human prostate should be broadly applicable to our understanding of the mechanism of NGF mediated autocrine/paracrine regulation of prostate growth and hasten the translation of these observations to the clinical setting.
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