“In identifying this protein pathway, which determines the formation of neuroendocrine tumors, we’ve identified new markers that can be used to distinguish the dangerous cells and find new targets for therapy,” said Dr. Ronai, associate director of Sanford-Burnham’s National Cancer Institute-designated Cancer Center.
This study uncovers a protein named Siah2, which initiates a cascade of molecular events that turns a non-malignant tumor into a metastatic neuroendocrine tumor. In collaboration with four other medical centers across the United States, Dr. Ronai and his colleagues analyzed human prostate cancer samples and found that Siah2 and the other proteins it triggers is detected more often in the aggressive neuroendocrine forms of prostate tumors than in other types. By acting as markers for particularly aggressive prostate cancers, Siah2 and its partners could provide doctors with an early warning sign for tumors that are likely to metastasize.
To further validate these findings, the Siah2 gene was inactivated in mice already prone to developing aggressive prostate tumors. Although benign growths still appeared, they failed to develop into neuroendocrine tumors.
“When we inhibit the Siah2 pathway in mice, we eliminate the neuroendocrine-type cells from the prostate tumors,” explained Jianfei Qi, Ph.D., postdoctoral researcher in Dr. Ronai’s laboratory and first author of the study. “Since prostate cancers containing neuroendocrine-type cells are resistant to current therapies, we are pleased to find that targeting Siah2 might provide an alternate approach to treating this disease.”
Members of the Sanford-Burnham research team are now looking for chemical compounds that inhibit the activity of Siah2 or other proteins along the chain. They hope to find a new drug that will block the series of molecular events leading to the formation of neuroendocrine-type cancer cells, thus keeping prostate tumors in check.
This study was supported by a grant from the National Cancer Institute, a division of the National Institutes of Health (NIH).
Qi J, Nakayama K, Cardiff RD, Borowsky AD, Kaul K, Williams R, Krajewski S, Mercola D, Carpenter PM, Bowtell D, Ronai ZA. Siah2-dependent concerted activity of HIF & FoxA2 regulates formation of neuroendocrine phenotype & neuroendocrine prostate tumors. Cancer Cell. Published July 13, 2010