Androgen ablation remains the only effective form of systemic therapy for patients with advanced prostate cancer due to the ineffectiveness of standard forms of cancer therapy. Unfortunately, progression to androgen-independent cancer occurs within a few years of androgen withdrawal and this is associated with extremely poor therapeutic options and with negative prognosis. The transcription factor NFkappaB has emerged as a key regulator of oncogenesis based on its ability to suppress apoptosis and to promote cell proliferation. Importantly, NFkappaB activation has been shown to strongly suppress chemotherapy efficacy. Preliminary data provided in this application support the role of NFkappaB in the growth/survival of a prostate cancer model (human CWR22). Inhibition of NFkappaB through the use of a novel IkappaB kinase (IKK) inhibitor (PS-1145, Millenium Pharmaceuticals) caused reduction in growth of the androgen-dependent CWR22 tumor and, importantly, completely suppressed the recurrence of this tumor following androgen ablation. Activation of NFkB, as measured by phosphorylation of the p65 subunit of NFkappaB, falls following androgen ablation in the CWR22 model and strongly recurs in the androgen-independent tumor. Interestingly, androgens were able to enhance the phosphorylation of the p65 subunit of NFkappaB in a rapid manner presumably independent of the ability of androgen receptor (AR) to regulate transcription. Phosphorylation of the p65 subunit is highly elevated in prostate tumors derived from a PTEN model and in human androgen-independent tumors. Additionally, we provide evidence that NFkappaB is a positive regulator of PSA gene expression, suggesting a potential cooperation between androgen receptor (AR) and NF-kappaB . The underlying hypothesis of this proposal is that constitutive activity of NFkappaB in androgen-dependent prostate cancer provides either a growth or survival function and that enhanced activation of NFkappaB potentially through phosphorylation of the p65/RelA subunit promotes recurrence of the androgen-independent phenotype. We also hypothesize that androgens signal directly to NFkappaB to promote growth and/or cell survival. Additionally, it is proposed that NFkB activation provides a strong level of prostate cancer chemoresistance. Our objectives are to test animal models to determine a role for NFkB in prostate cancer and to test NFkB inhibitors as potential novel therapies for this disease.
The aims of this proposal have significant translational potential since PS-1145 is being studied as a novel and reasonably safe inhibitor of NFkappaB. Our results may validate the use of NFkappaB inhibitors in prostate cancer therapy and should provide an understanding of the mechanisms associated with prostate cancer development and recurrence.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Experimental Therapeutics Subcommittee 1 (ET)
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Arya, Suresh
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University of North Carolina Chapel Hill
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