Molecular mechanisms underlying the development of neuroendocrine prostate cancer.

Prostate cancer is the most common non-cutaneous cancer and the second leading cause of cancer-associated deaths among men in the United States. Androgen deprivation therapy (ADT) is the standard of care for advanced prostate cancer. While patients with advanced prostate cancer initially respond to ADT, the disease frequently progresses to a lethal metastatic form, defined as castration-resistant prostate cancer (CRPC). After multiple rounds of anti-androgen therapies, 20-25% of metastatic CRPCs develop a neuroendocrine (NE) phenotype. These tumors are classified as neuroendocrine prostate cancer (NEPC). De novo NEPC is rare and accounts for less than 2% of all prostate cancers at diagnosis. NEPC is commonly characterized by the expression of NE markers and the absence of androgen receptor (AR) expression. NEPC is usually associated with tumor aggressiveness, hormone therapy resistance, and poor clinical outcome. Here, we review the molecular mechanisms underlying the emergence of NEPC and provide insights into the future perspectives on potential therapeutic strategies for NEPC.

Current and emerging therapies for neuroendocrine prostate cancer.

Neuroendocrine prostate cancer is a histological variant of prostate cancer that is characterized by aggressiveness, poor clinical outcomes, and expression of neuroendocrine markers. Neuroendocrine prostate cancer usually manifests in late-stage prostate cancer patients who have undergone multiple rounds of anti-androgen therapies but can, although rarely, occur in treatment naïve patients de novo. Current therapies to treat neuroendocrine prostate cancer are largely based on their success in treating patients with small cell lung cancer, a lung cancer that shares the neuroendocrine phenotype with neuroendocrine prostate cancer. However, unfortunately these therapies are not durable. In this review, we discuss therapies currently in use to treat neuroendocrine prostate cancer, including platinum-based therapies, taxanes and etoposide. Additionally, we utilize ongoing clinical trials information to identify potential emerging therapies for neuroendocrine prostate cancer. Lastly, we discuss additional potential future opportunities for targeting neuroendocrine prostate cancer.

SU086, an inhibitor of HSP90, impairs glycolysis and represents a treatment strategy for advanced prostate cancer.

Among men, prostate cancer is the second leading cause of cancer-associated mortality, with advanced disease remaining a major clinical challenge. We describe a small molecule, SU086, as a therapeutic strategy for advanced prostate cancer. We demonstrate that SU086 inhibits the growth of prostate cancer cells in vitro, cell-line and patient-derived xenografts in vivo, and ex vivo prostate cancer patient specimens. Furthermore, SU086 in combination with standard of care second-generation anti-androgen therapies displays increased impairment of prostate cancer cell and tumor growth in vitro and in vivo. Cellular thermal shift assay reveals that SU086 binds to heat shock protein 90 (HSP90) and leads to a decrease in HSP90 levels. Proteomic profiling demonstrates that SU086 binds to and decreases HSP90. Metabolomic profiling reveals that SU086 leads to perturbation of glycolysis. Our study identifies SU086 as a treatment for advanced prostate cancer as a single agent or when combined with second-generation anti-androgens.

Gel filtration chromatography as a method for removing bacterial endotoxin from antibody preparations.

The removal of bacterial endotoxins from biological samples is critical to avoid the potentially fatal pyrogenic response possible when introduced to mammalian systems. Endotoxins have a variety of specific characteristics that can be exploited to target their isolation and subsequent removal, but one that has not been extensively characterized is their difference in size from that of monoclonal antibodies. Here, we present a study which utilizes gel filtration chromatography as a method for endotoxin removal from both aggregated and nonaggregated antibody preparations, outlining a mechanistically simple method for removal of this impurity.