Yuan-Shan Zhu   Associate Professor of Medicine

Prostate cancer - Pathogenesis and treatment

Androgens play a crucial role in the prostate development, growth and pathogenesis of benign prostate hyperplasia (BPH) and prostate cancer. There are two major androgens in humans and mammals, testosterone and dihydrotestosterone (DHT). Although testosterone is the primary secretory androgens from the testes, the active form of androgens in the prostate is DHT. DHT, a more potent androgen than testosterone, is converted from testosterone by 5alpha-reductase isozymes. Two 5alpha-reductase isozymes, type 1 and type 2, are identified in the mammalian system, and the predominant 5alpha-reductase isozyme in the human prostate is 5alpha-reductase-2. Clinical studies have shown that patients with homozygous 5alpha-reductase-2 gene mutations resulting in a decreased plasma DHT, a normal or elevated testosterone level, and an elevated testosterone/DHT ratio have a small, unpalpable and rudimentary prostate, and their plasma prostate specific antigen (PSA) level is undetectable. Treatment with DHT in these patients results in an enlargement of the prostate and an elevation of plasma PSA levels. Furthermore, there is no report of BPH or prostate cancer in these patients. However, DHT does not work alone in the prostate, and its action is modulated by other hormone such as estrogen. Our current studies are focused on the following projects: a. Molecular Basis of Steroid Hormone Interaction in Prostate Diseases: Estrogens have been used for the hormonal therapy of prostate cancer presumably by inhibiting testosterone biosynthesis via a negative feedback of hypothalamus and pituitary. However, due to the severe side effects of estrogens available in the clinic, the implication of estrogens in prostate cancer therapy is limited although these agents may be effective against the cancer. Using in vitro and in vivo models, our studies are designed to test the hypothesis that estrogens via estrogen receptors (ER) produce directly modulation of androgen action in the prostate cells in an ER-isoform and ligand specific manner. By employing molecular and cellular techniques, we are studying how androgens and estrogens interact in the prostate cell; what proteins involve in and how these proteins interact each other; and what are the biological consequences. The elucidation of the effects and mechanisms of androgen-estrogen interaction in the prostate cells will facilitate the development of new estrogen analogs with less side effects for hormonal therapy of prostate cancer, especially androgen-independent prostate cancer. b. The effects and mechanisms of dietary fat in prostate development and pathogenesis: High dietary fat intake is a major risk factor for prostate cancer development. How dietary fat effects the prostate is unclear. One potential mechanism is through the regulation of androgen actions. Our current study is to determine whether dietary fat intake regulates the expression of prostate 5a-reductase isozyme genes, and then potentiate androgen action on prostate growth and pathogenesis; and whether dietary fat intake regulates the IGF signal pathway, which has been shown to affect prostate growth and pathogenesis. Furthermore, we also investigate whether dietary fat intake has an ?imprinting? effect in the prostate as well as in body weight. c. Chinese herbal medicine in the prevention and control of prostate cancer: Prostate cancer is the most diagnosed cancer and the second leading cause of cancer death in American males. Once prostate cancer is metastasized, there is no curable treatment. The current major therapy for metastatic prostate cancer is androgen ablation. However, this therapy is only palliative, and the tumor cells eventually become androgen-independent and proceed to further metastasis and death. Effective alternative therapies are urgently needed. Chinese medicinal herbs are potential sources for developing effective alternative anti-Prostate cancer drugs. We have found a Chinese herbal formula with wide-spectrum anti-tumor activity, inhibiting tumor growth and metastasis. This herbal formula also inhibits cell growth and induces cell apoptosis in multiple prostate cancer cells. Currently, we are determining the effects of this herbal formula in animal models with prostate cancer, elucidating the mechanisms of its action, and ultimately proceeding to clinical trial in patients with advanced prostate cancer if it is successful in animal study.

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  • Yuz2002@med.cornell.edu

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Primary Affiliation

  • Weill Cornell Medical College, Cornell University