Targeting a Novel Androgen Receptor-Repressed Pathway in Prostate Cancer Therapy
Abstract
Rationale and Objectives: Prostate cancer is the most common noncutaneous malignancy and the second leading cause of cancer-related deaths among men in the United States. The mainstay of therapy for advanced disease is medical castration by androgen-deprivation therapy (ADT). Despite initial responses, almost all patients will inevitably develop disease progression to a stage known as metastatic castration-resistant prostate cancer (mCRPC), which associates with a poor prognosis and mean survival time of 16-18 months. ADT has been linked to development of prostate cancer resistance, in part through inducing prosurvival adaptive responses that promote the survival of prostate cancer. Moreover, it is now recognized that androgen receptor (AR) signaling persists during ADT and remains the driver of prostate progression to CRPC. Although novel anti-androgen therapies such as abiraterone acetate and enzalutamide can effectively palliate symptoms and prolong life by a few months, they have not produced a major survival improvement in mCRPC. A better understanding of the resistance mechanisms associated with AR activation/inhibition and identifying novel treatment options will lead to discovery of new targets and development of more rationally targeted and more efficacious therapies for mCRPC. Our primary goal is to investigate the potential role of protein kinase D (PKD) in mediating therapeutic resistance to ADT and to investigate the impact of PKD small molecule inhibitor (SMI)-based combination therapies to curtail ADT-induced therapy resistance. The serine/threonine protein kinase PKD is an emerging therapeutic target for cancer. Dysregulation of PKD has been demonstrated in prostate cancer. Aberrant PKD expression and activity promote tumor survival and progression. Our preliminary data demonstrate a novel link between PKD and AR signaling and identify important downstream targets of PKD that may contribute to the adaptive responses induced by ADT. Our data show that androgen can repress PKD1 expression at both the transcriptional and protein levels. Androgen deprivation or antiandrogen treatment induces PKD1 expression in androgen-sensitive prostate cancer cells, and inhibition of PKD synergizes with the AR antagonist enzalutamide in the killing of prostate cancer cells. Genome-wide expression analysis using PKD SMIs has revealed two novel downstream targets of PKD, Aurora-A kinase (AURKA) and Cenp-E (CENPE), which are mitotic regulators upregulated in response to ADT in prostate cancer patients. It has been shown that AURKA overexpression promotes resistance to ADT. Our data demonstrate that inhibition of PKD by SMIs or knockdown of PKD causes drastic downregulation of AURKA and CENPE in prostate cancer cells. Inhibition of PKD blocks the proliferation of these cells and suppresses the growth of prostate tumor xenografts in mice. These data led us to hypothesize that PKD plays a crucial role in limiting the effectiveness of ADT by increasing prostate cancer survival through upregulating AURKA expression. We further posit that PKD SMIs will enhance the efficacy of AR antagonists in prostate cancer treatment. (1) We proposed studies to determine the mechanisms through which AR represses PKD1 expression in androgen-sensitive prostate cancer cells. Our data have identified fibroblast growth factor receptor substrate 2 (FRS2) as a mediator of AR-induced PKD1 repression. We seek to further delineate its role and downstream signaling pathways that mediate PKD1 repression by androgen. Next, (2) we will determine if androgen deprivation-induced PKD1 expression promotes prostate cancer cell survival and ADT resistance through upregulating AURKA and CENPE. We will define the role of PKD in mitotic cell cycle regulation through AURKA and CENPE and its relevance to the prosurvival function of PKD in the context of ADT. Finally, (3) using mouse PrCa tumor xenograft models, we will determine the functional input
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610173
Entities
People
- Qiming Wang
Organizations
- United States Army
- University of Pittsburgh