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.

Public Health Relevance

The goals of the proposed research are to define the roles of lymphotoxin (LT)-directed signaling in controlling the development of androgen-independent (AI) prostate cancer (PCa), which is essentially an incurable malignancy. Using state-of-the-art genetic and molecular approaches, the proposed studies will provide new insights into how LT-directed signaling regulates AI PCa formation, and we firmly believe that these studies will lay the foundation for developing novel therapeutic strategies for the treatment and/or prevention of hormone refractory prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA140956-02
Application #
8235834
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Mohla, Suresh
Project Start
2011-04-01
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
2
Fiscal Year
2012
Total Cost
$405,676
Indirect Cost
$186,992
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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