(PQD-1) NF-kB activation and enzalutamide therapy in metastatic castration resist

Project: Research project

Project Details


DESCRIPTION (provided by applicant): Prostate cancer is the second leading cause of cancer related deaths for men in the U.S. A common therapy for early stage prostate cancer (after failure of surgery or radiation therapy) is androgen hormone deprivation therapy which blocks the production of androgens that are known to foster the progression of prostate cancer. While initially effective for about 80% of newly diagnosed cases, most prostate cancer patients develop resistance to hormone deprivation therapy within three years and progress to castration resistant prostate cancer (CRPC), and become metastatic. There has been a major focus on the androgen receptor (AR) pathway as the principal therapeutic target for CRPC including recent approved therapies such as abiraterone and enzalutamide. Despite these advances that provide temporary respite, there is still no cure for CRPC. Ultimately, all patients will go on to die from
progressive and resistant prostate cancer. Therefore, there is a pressing need to identify the pathways that perpetuate disease progression during effective AR blockade. NF-KB functions as a master transcription factor that activates inflammatory cytokines/chemokines and underpins the synthesis of genes implicated in cell survival and chemo resistance, angiogenesis and localized invasion. The non-canonical NF-KB pathway involves the processing of p100 to p52. Overproduction of p52 has been observed in several solid tumors including breast and prostate cancers. We have recently demonstrated that p52 protein is anti-apoptotic to CaP cells and promotes survival upon treatment with androgen deprivation or with chemotherapeutic agents. p52 interacts with AR and increases AR activation and androgen regulated PSA and NKX3.1 expression. We propose that activation of p52 signaling will activate resistance pathways in the CRPC microenvironment and thus attenuates therapeutic response to anti-androgen therapy. The goals of the application are two folds: to determine the roles of p52 in AR activation and CRPC progression, and to evaluate p52 activation in promoting a microenvironment-wide mechanism of resistance to the novel AR antagonist, enzalutamide. The specific aims of this proposal are: 1) Determine the functional roles of p52 in CRPC progression. 2) Determine the effects of p52 on modulating treatment response to novel anti-androgen therapeutics in CRPC models. Characterization of these additional resistance-promoting pathways will identify the appropriate complementary approaches that can be used to increase the magnitude and duration of benefit of androgen deprivation therapies such as enzalutamide which will dramatically impact the care of men with CRPC.
Effective start/end date9/12/138/31/16


  • National Institutes of Health: $162,451.00
  • National Institutes of Health: $200,970.00


  • Medicine(all)


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