Bypassing androgen pathway dependence in advanced prostate cancer.
Bluemn, Eric Gregory
MetadataShow full item record
Continued reliance of castration-resistant prostate cancer (CRPC) on androgen receptor (AR) signaling has spurred the development of novel, potent antiandrogen therapeutics. The clinical use of successively more potent antiandrogens will likely generate CRPC that is independent of AR-driven pathways for survival. This is corroborated by an increase in AR-null neuroendocrine-like prostate cancers (NEPCa) following extended androgen deprivation therapy (ADT). However, there are currently no models of epithelial-like Androgen Pathway-Independent Prostate Cancer (APIPC) that have been generated from previously AR-positive models. We took a two-step approach to study APIPC in more detail: Aim 1) Utilize high-throughput functional genomics to screen for genes/pathways regulating ligand-independent CRPC growth and Aim 2) Develop a cell-line model of APIPC from an AR-positive cell line through Total Androgen Pathway Suppression, and identify the emergent growth pathway sufficient for androgen pathway-independent growth. In Aim 1 we identified a protein phosphatase 2A (PP2A) regulatory subunit (PPP2R2C) as a suppressor of CRPC growth. Using in vitro molecular biology we demonstrated that loss of PPP2R2C promotes non-AR-mediated castration-resistant growth in previously androgen-dependent cell lines. We also found that PPP2R2C expression is downregulated in primary and metastatic prostate tumors compared to benign prostate epithelia. Furthermore, investigation of retrospective outcomes from patients surgically treated for primary prostate cancer indicated that low PPP2R2C expression is associated with a poor prognosis. Aim 2 successfully led to the development of an APIPC model cell line that does not express AR or androgen-regulated genes, and relies on an autocrine growth pathway for androgen-free survival. Furthermore, it does not express markers of neuroendocrine prostate cancer, a well-defined AR-null prostate cancer variant. By analyzing a panel of human metastases, we were able to identify a subset of tumors that also do not express AR, androgen-regulated genes, or markers of neuroendocrine prostate cancer. These data suggest that metastatic prostate tumors can compensate for total loss of androgen receptor signaling by deregulating alternative growth and survival pathways in vitro and in vivo. Our results identify signaling pathways that may be targeted to inhibit the development of AR-null disease.