Adipose Stem Cell-Based Therapeutic Targeting of Residual Androgens in African Americans With Bone-Metastatic Prostate Cancer.

摘要

The disproportionate incidence and mortality of prostate cancer (CaP) among African Americans (AA) in comparison to Caucasian American (CA) are not well understood. It is believed that high circulating androgens reported in AA men may account for such racial disparities. It has been shown that metastatic tumors maintain functional androgen receptor signaling, suggesting that local (intracrine) androgens may contribute to the outgrowth of castration-adapted tumors under androgen deprivation therapy (ADT). Evidence exists for direct correlation between increased obesity and body-mass-index (BMI), which is significantly higher in AA-men, and the risk for aggressive CaP. Active steroidogenic pathways are active in adipocytes and adipose-derived mesenchymal stem cells (ASCs) are often recruited to tumor-stroma. Our goal will be to exploit the tumor-tropism of normal ASCs to deliver androgen inactivating genes to tumor microenvironments and enable an effective treatment strategy against CRPC. This will be achieved by: (a) investigate if intracrine production of testosterone by osteotropic ASCAA modulates growth and metastatic potential of CaP cells under ADT in vitro and in vivo; (b) determine if -HSD-expressing osteotropic ASCCont will nullify the ADMSCAA-mediated CaP cell growth and metastasis in vitro; and (c) examine the efficacy of therapeutically engineered ASCCont to target and inhibit CaP tumor growth under CRPC in vivo. The proposed work will be innovative, because it capitalizes on an adjuvant approach for ADT by tumor-site specific inactivation of androgens. Considering the aggressive nature CaP, the outcome of our study is expected to have a positive impact on establishing preventive and/or therapeutic intervention strategies to reduce or circumvent PC, especially among AA-men.