A recent report in Cancer Discovery, a journal of the American Association for Cancer Research, suggests that a new treatment may be on the horizon for neuroendocrine prostate cancers (NEPC), the most lethal subtype of this disease which most commonly evolves from preexisting prostate adenocarcinoma (PCA).
Malignant neuroendocrine (NE) cells are devoid of androgen receptors. As a result, the expression of neuroendocrine cells is not suppressed by androgen ablation, clonal propagation of androgen receptor-negative neuroendocrine cells. This means that NE cells may have an important role in the development of androgen-independent prostatic carcinoma. This has significant implications for the treatment of prostate cancer, because several of the hormones that are secreted by neuroendocrine differentiated, malignant prostatic cells are potential candidates for use in drug treatment.
Mark Rubin, M.D., professor of pathology and laboratory medicine at Weill Cornell Medical College, said although fewer than 2% of men with prostate cancer present with neuroendocrine prostate cancer, the more common prostate adenocarcinoma can also evolve into a neuroendocrine prostate cancer, and the prognosis is grim. ?This is a highly lethal form of prostate cancer,? said Rubin. ?It is also rare enough that it?s hard to get samples. This study is the largest of its kind, and it shows that we may be able to treat this highly aggressive disease.?
Rubin and colleagues used next-generation RNA sequencing to profile samples of seven neuroendocrine prostate cancers, 30 prostate adenocarcinomas and five benign samples of prostate tissue. They found that the genes AURKA and MYCN were overexpressed and amplified in 40% of neuroendocrine prostate cancers and in 5% of prostate adenocarcinomas. Moreover, the researchers found that treatment with the investigational aurora kinase (AURKA) inhibitor PHA-739358, a small-molecule 3-aminopyrazole derivative, inhibited the growth of these neuroendocrine tumors.
The researchers found that the drug candidate inhibits all Aurora kinase family members, essential for cell proliferation by controlling chromatid segregation, and showed a dominant Aurora B kinase inhibition?related cellular phenotype and mechanism of action in cells in vitro and in vivo. They also noted cross-reactivities with some receptor tyrosine kinases relevant for cancer.
Not a homogenous disease
Rubin said that PHA-739358 has been studied in prostate cancers before without success, but this may be due to the fact that previously studied prostate cancers were not neuroendocrine cancers. ?Prostate cancer is not a homogenous disease. We need to continue to sort out the aggressive disease from the indolent and treat accordingly,? said Rubin.
The study was funded by the Prostate Cancer Foundation, the Ann and William Bresnan Foundation, the Early Detection Research Network and the Department of Defense.
Beltran H, Rickman DS, Park K, Chae SS, Sboner A, MacDonald TY, et al. Molecular Characterization of Neuroendocrine Prostate Cancer and Identification of New Drug Targets. Cancer DiscoveryNovember 2011 1; 487