In today’s issue of Cancer Discovery a group of international researchers report that an investigational drug had a dramatic response in animal models of neuroendocrine prostate cancer, a lethal form of the disease. The researchers pointed out that fewer than 2% of prostate tumors in men are initially diagnosed as neuroendocrine, but many of the more common adenocarcinoma prostate cancers change their biology during hormone therapy and morph into this lethal subtype.
Today, many men are now treated with new, highly potent androgen suppression therapy, which these researchers believe will significantly increase the risk of future development of neuroendocrine tumors. Current androgen suppression therapies, including the newly developed types, do not work against neuroendocrine cells. These lethal types of cells are often a part of the initial tumor mix and are not suppressed allowing them to continue to grow and spread through a man’s body.
Since most men who die of advanced prostate cancer are treated with androgen suppression therapy, it is impossible to know how many of them developed neuroendocrine tumors because men are not usually biopsied after the initial diagnosis. Recently, studies to define changing biology in prostate cancer are starting, but today we do not have this information.
“Still, there is evidence to suggest that androgen suppression results in a more aggressive cancer in a growing number of men, and now, with this study, we may have a way to treat these patients,” says the study’s lead investigator, Dr. Himisha Beltran, assistant professor of medicine at Weill Cornell Medical College and a medical oncologist at New York-Presbyterian Hospital/Weill Cornell Medical Center.
This study is the largest look at the biology of neuroendocrine prostate cancer tumors. The Weill Cornell researchers undertook the study to see if they could find a way to target these deadly tumors. To accomplish this task they used a next-generation sequence analysis to study the transcriptome — the RNA messages that tumors produce — of neuroendocrine tumors compared to adenocarcinoma prostate cancers.
Prostate cancer samples gathered by researchers from the U.S. and Europe have showed that the majority of neuroendocrine prostate cancers significantly over expressed AURKA and MYCN genes, and 40% of these tumors also had extra copies of these genes. Surprisingly, they also found that a smaller subset of prostate adenocarcinomas also over expressed these genes, and 5% had extra copies. “This may represent a high-risk population that could potentially benefit from screening and early intervention,” says Dr. Beltran.
According to Dr. Rubin, In neuroendocrine prostate cancer, the AURKA and MYCN mutations need to work together to promote cancer development. The kind of lethal interaction has also been found in neuroblastoma, a pediatric brain cancer. But the very good news, he adds, is that aurora kinase inhibitors have been developed and are being tested in a variety of cancers, including some clinical trials.
In this study the researchers were able to demonstrate that the aurora kinase inhibitor PHA-739358 worked against human neuroendocrine prostate cells in the laboratory, and that it had a dramatic response in animal models of neuroendocrine prostate cancer. It shrank large tumors to very small sizes in a short period of time, compared to untreated mice. There was also significantly enhanced sensitivity of neuroendocrine prostate cancer compared to prostate adenocarcinoma, Dr. Rubin says. While PHA-739358 was studied in prostate cancer without success, the researchers suspect that few of the patients who participated had neuroendocrine prostate tumors. Dr. Beltran is preparing a clinical trial to test an aurora kinase inhibitor in prostate cancer patients whose tumors contain neuroendocrine cancer cells or similar molecular alterations involving AURKA and MYCN.
“Not only are we eager to test the drug in patients diagnosed with neuroendocrine prostate cancer, we hope to develop biomarkers that can help us screen patients for these cells before the cancer advances,” says Dr. Beltran.
Joel T Nowak, M.A., M.S.W.