Influence of Androgen Deprivation and Tumor Microenvironment on Epigenetic Silencing of Tumor Metastasis Suppressor KISS1 during Prostate Cancer Progression



 DESCRIPTION (provided by applicant): In the United States, prostate cancer (PCa) is the most commonly diagnosed cancer in males and it results in approximately 30,000 deaths per year. Although early detection and hormone-based therapies generally result in rapid responses and reduce mortality from PCa, current therapies for advanced PCa or recurrent PCa are still not curative. Even patients who have undergone apparently successful surgical resection may experience recurrence locally or at distant sites months or years later. Moreover, subsequent to depriving the tumor of male hormones, the PCa becomes androgen-independent (AI), or castration-resistant PCa (CRPC). Unfortunately for many cases, the size or the histology of the primary tumor does not provide reliable prognosis since few tumor cells may have already disseminated by the time most cancers are clinically diagnosed. Thus, a large percentage of patients often go through chemotherapies and treatments to eliminate residual or disseminated cells before macro-metastases develop just as a precaution. KISS1, a metastasis suppressor, its expression levels have prognostic relevance and are negatively correlated to invasiveness in several human cancers, including PCa. More strikingly, KISS1 expression maintains disseminated tumor cells in a dormant state and strongly inhibits colonization and macro-metastases development. These characteristics make KISS1 a very unique candidate in controlling the metastatic spread of prostate cancer in a therapeutic context. Patients diagnosed with prostate cancer by biopsy can be separated into those who should be treated from those who might just be followed carefully (watchful waiting) according to KISS1 expression level or KISS1 promoter methylation status. Our study will provide a reproducible and low cost-to-detect diagnostic marker or prognostic marker through establishing the correlation among KISS1 epigenetic silencing, KISS1 expression and cancer progression. It is our expectation to identify KISS1 expression status as a new biomarker that distinguishes indolence and aggressive cancers to avoid unnecessary chemotherapy associated severe side effects. The other objective of this study is to reveal the mechanisms that modulate the reversible expression of KISS1. Our studies will demonstrate how KISS1 gene silencing develops and what are possible mechanisms regulating its expression during cancer progression. The comprehensive investigation of the regulatory mechanism of KISS1 expression in PCa progression can lead to the development of effective treatment strategies for low KISS1 expressing PCa patients. The approach to prevent KISS1 silencing or re-express KISS1 according to the mechanisms could apply to males who are not eligible for therapy other than by removal of male hormones, and who have recurrent prostate cancers after therapies. With the modulation of KISS1 expression in prostate cancers, the response of prostate cancer to male hormone deprivation could be greatly improved and the metastatic spread of prostate cancer can be reduced. The dual roles of KISS1 in keeping tumor cells in dormancy along with preventing CRPC recurrence at the same time provide a new way for prostate cancer patients to approach more manageable organ-confined diseases for long term PCa management, which will improve overall patient's survival.