Immune-inflammatory signaling and hormone-refractory prostate cancer evolution.

Scripps Research Institute, The, La Jolla CA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is a heterogeneous disease that progresses from prostatic intraepithelial neoplasia to locally invasive adenocarcinoma and then to hormone-refractory carcinoma. In tumors confined to the prostate, radical prostatectomy and radiotherapy are effective. However, no effective treatments are available for hormone-refractory PCa. Androgen deprivation therapy (ADT) is initial systemic therapy for advanced PCa and is used as an adjuvant to local therapy for high-risk disease, but, tragically, responses in advanced disease are only transient. Thus, research on the mechanisms of hormone refractory PCa formation, especially studies that are likely to result in novel therapeutic approaches, is of great importance. In our Preliminary Studies, selectively blocking NF-?B, the principle inflammatory transcription factor, in immune cells, dramatically impairs the development of castration resistant prostate cancer (CR-PCa) in both transgenic and xenograft PCa mouse models. We also found that one of the critical participants in this inflammatory response is tumor infiltrating B cells, which produce LTa:¿ heterotrimers that stimulate LT¿R on PCa cells to induce IKKa nuclear translocation and activation, thereby enhancing androgen-independent growth. Accordingly, we propose to define how LTs and LTs-induced IKKa nuclear translocation and activation mediate the formation of CR-PCa, and the relevance of LTs expression, IKKa nuclear localization and activation to human prostate cancer. We believe our studies will provide new insights into how B cells-derived LTs control CR-PCa, and will lay the foundation for developing novel therapeutic strategies for the treatment and/or prevention of hormone refractory PCa.