Genetic Study Yields Clues to Neuroendocrine Prostate CancerResearchers have identified a signaling pathway that may play an important role in neuroendocrine prostate cancer (NEPC), a very rare but aggressive form of the disease. Based on this discovery, the researchers tested a drug that inhibits the pathway and observed anticancer effects in two model systems. The findings appear in the November issue of Cancer Discovery.
Most cases of NEPC, which accounts for a small percentage of prostate cancers, arise following hormone therapy for prostate adenocarcinoma. To better understand the origins of the disease, Dr. Himisha Beltran of Weill Cornell Cancer Center and her colleagues profiled the gene-expression patterns of 7 NEPC tumors, 30 prostate adenocarcinomas, and 5 benign prostate tissue samples.
When they compared NEPCs and prostate adenocarcinomas, the authors found “dramatic differences” in the expression of certain genes, as well as differences in the number of copies of some genes. Two genes emerged as particularly interesting suspects in the disease—the AURKA gene, which encodes a protein called aurora kinase A and has been implicated in other cancers, and MYCN, another cancer-associated gene.
The researchers confirmed the association of AURKA expression with NEPC by analyzing benign prostate tissue and prostate tumors from a separate, larger cohort of patients. They concluded that the protein products of AURKA and MYCN may work together to induce characteristics of NEPC in prostate cancer cells.
Aurora kinase inhibitors are being evaluated in clinical trials, and the researchers tested one of these drugs against prostate adenocarcinoma and NEPC cells grown in laboratory culture as well as in mice bearing xenograft tumors derived from these cells. In the laboratory experiments, NEPC but not prostate adenocarcinoma cells were sensitive to the inhibitors; in the mice, the inhibitors caused tumor shrinkage of NEPC but not prostate adenocarcinoma xenograft tumors. In addition, drug treatment suppressed the expression of markers of neuroendocrine cells.
“The next step is to initiate a clinical trial,” said Dr. Beltran, who noted that there are no standard therapies for NEPC and that most patients die within a year of diagnosis. A small percentage of patients with prostate adenocarcinomas also show increased expression of the AURKA and MYCN genes, and these patients could be candidates for aurora kinase inhibitors as well, Dr. Beltran explained.
Previous studies have indicated that NEPCs and prostate adenocarcinomas may share the same cell of origin. It is known, for instance, that a genetic rearrangement often found in prostate adenocarcinomas is present at roughly the same rate in NEPCs. The precise number of cases of NEPC is unknown, however, in part because patients with advancing prostate cancer do not always have a biopsy, which is how NEPC is diagnosed.
The study authors cited evidence that long-term androgen deprivation therapy may promote the transformation of prostate cancer cells into NEPC. This suggests that “with the recent introduction of new highly potent androgen deprivation therapies into the clinical arena, the incidence of NEPC may escalate,” they noted.
“The current study is a stepping stone toward identifying neuroendocrine prostate cancer that is usually missed using regular screening modalities,” commented Dr. Sudhir Srivastava, who heads NCI’s Early Detection Research Network. “Understanding the biology of neuroendocrine prostate cancer will lead to better clinical management of this rare form of the disease.”
NCI Cancer Bulletin for November 29, 2011 - National Cancer Institute