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.
Targeting androgen signaling via androgen deprivation therapy has been the mainstream of clinical interventions in prostate cancer. Recent FDA approved new anti- androgen agents such as enzalutamide only slightly improve median overall survival. There is an urgent need to identify the pathways that perpetuate disease progression during effective AR blockade. Identification of these additional resistance pathways will help to design co-targeting strategies to improve the magnitude and duration of benefit of enzalutamide in men with CRPC.
|Tummala, Ramakumar; Nadiminty, Nagalakshmi; Lou, Wei et al. (2016) Lin28 induces resistance to anti-androgens via promotion of AR splice variant generation. Prostate 76:445-55|
|Liu, Chengfei; Armstrong, Cameron; Zhu, Yezi et al. (2016) Niclosamide enhances abiraterone treatment via inhibition of androgen receptor variants in castration resistant prostate cancer. Oncotarget 7:32210-20|
|Zhu, Yezi; Liu, Chengfei; Armstrong, Cameron et al. (2015) Antiandrogens Inhibit ABCB1 Efflux and ATPase Activity and Reverse Docetaxel Resistance in Advanced Prostate Cancer. Clin Cancer Res 21:4133-42|
|Nadiminty, Nagalakshmi; Tummala, Ramakumar; Liu, Chengfei et al. (2015) NF-ÎºB2/p52:c-Myc:hnRNPA1 Pathway Regulates Expression of Androgen Receptor Splice Variants and Enzalutamide Sensitivity in Prostate Cancer. Mol Cancer Ther 14:1884-95|
|Liu, Chengfei; Lou, Wei; Armstrong, Cameron et al. (2015) Niclosamide suppresses cell migration and invasion in enzalutamide resistant prostate cancer cells via Stat3-AR axis inhibition. Prostate 75:1341-53|
|Liu, Chengfei; Lou, Wei; Zhu, Yezi et al. (2015) Intracrine Androgens and AKR1C3 Activation Confer Resistance to Enzalutamide in Prostate Cancer. Cancer Res 75:1413-22|
|Liu, Chengfei; Lou, Wei; Zhu, Yezi et al. (2014) Niclosamide inhibits androgen receptor variants expression and overcomes enzalutamide resistance in castration-resistant prostate cancer. Clin Cancer Res 20:3198-210|
|Cui, Yuanyuan; Nadiminty, Nagalakshmi; Liu, Chengfei et al. (2014) Upregulation of glucose metabolism by NF-ÎºB2/p52 mediates enzalutamide resistance in castration-resistant prostate cancer cells. Endocr Relat Cancer 21:435-42|
|Zhu, Yezi; Liu, Chengfei; Cui, Yuanyuan et al. (2014) Interleukin-6 induces neuroendocrine differentiation (NED) through suppression of RE-1 silencing transcription factor (REST). Prostate 74:1086-94|