Elucidating the Functional Role of POU3F2 in Small Cell/Neuroendocrine Prostate Cancer Differentiation
Abstract
Background: Neuroendocrine prostate carcinoma (also known as small cell prostate carcinoma, SCPC hereafter) is an aggressive type of prostate cancer. It is highly metastatic and readily becomes resistant to chemotherapy and radiation therapy. Recent observations from our work and others suggest that the incidence of SCPC is increasing in response to the increased use of next-generation anti-androgens, which are used to treat castration-resistant prostate cancer (CRPC). However, we know very little about how SCPC develops from CRPC. Rationale: We recently discovered that POU3F2, a gene whose function is to control gene expressions during development of the neuronal system, is induced by androgen deprivation, a condition that is similar to hormonal treatment for prostate cancer. We also found evidence that POU3F2 is a marker of SCPC in patient samples and in the TRAMP mouse model of SCPC. POU3F2 affects cell fate, and, if expressed at the wrong time or in the wrong tissues, it can cause serious ill effects. For example, POU3F2 regulates cell survival, tumor growth, and metastasis in melanoma (cancer of pigment cells in skin). Furthermore, POU3F2 can induce cancer stem-like cells with unlimited proliferative potential from mature glioblastoma (brain tumor) cells. The roles that POU3F2 and other pro-neural transcription factors play in prostate cancer progression have not been investigated. Hypothesis/Objectives: We hypothesize that POU3F2 plays a key role in the emergence of SCPC from CRPC. In this study, we propose to evaluate POU3F2 s role in SCPC and to learn the mechanism of treatment resistance in SCPC. We will explore the signaling pathways that regulate POU3F2 expression, as well as the POU3F2 targets, which we can exploit for the prevention and treatment of SCPC. Specific Aim 1: Define the functional role of POU3F2 in SCPC. We will test whether SCPC cells can survive, grow, invade, metastasize, and maintain SCPC characteristics in the absence of POU3F2. We will also evaluate whether SCPC cells without POU3F2 lose the characteristics of stem-like cells and whether they are more sensitive to chemotherapy drugs. We will investigate whether the forced expression of POU3F2 is sufficient to change CRPC cells into SCPC cells. We will further ask what additional genetic changes may work together with POU3F2 to cause phenotypic changes in SCPC. Specific Aim 2: Identify the POU3F2-regulated gene networks to understand SCPC biology. We will systematically find all the DNAs that POU3F2 binds in the entire genome in SCPC cells in order to find the network of genes that are involved in modulating the properties of SCPC. We will also examine the set of genes that POU3F2 binds during the transition from CRPC to SCPC. We will search for potential targets that can be inhibited by drugs for the prevention and treatment of SCPC. Specific Aim 3: Test molecule inhibitors targeting Wnt/beta-catenin signaling for treatment of SCPC. The Wnt/beta-catenin pathway is one of the signaling pathways through which cells communicate with their environment. The Wnt/beta-catenin signaling pathway has been implicated in POU3F2 transcription in other small cell cancers, and also plays an active role in cancer stem cells. We will test the ability of Wnt/beta-catenin inhibitors to inhibit POU3F2 expression and impede the development and growth of SCPC. We will also evaluate whether the Wnt/beta-catenin inhibitors can enhance the effect of chemotherapy drugs by eliminating the cancer stem cells in SCPC. New drugs targeting androgen receptor pathways are improving the treatment of late-stage prostate cancer. However, currently there is no effective treatment for SCPC. Through the proposed research, we expect to discover the mechanisms underlying therapy resistance in SCPC and to find promising modalities for the treatment of SCPC and for preventing the transition from CRPC to SCPC. The knowledge obtained through the pr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610378
Entities
People
- Robert Reiter
Organizations
- United States Army
- University of California, Los Angeles