Liz Meszaros, MDLinx | May 08, 2017
In patients with advanced prostate cancer resistant to anti-androgen therapy, molecular reprogramming of tumor cells may be the underlying cause of treatment resistance and the development of castration-resistant prostate cancer (CRPC), and researchers may have identified the mechanisms and genes that are the culprits. They published their results in a recent issue of the journal Cancer Discovery.
Traditionally, treatment for prostate cancer patients with recurrent or advanced disease consists of anti-androgen medications. Unfortunately, most of these patients seem to fail treatment, and go on to develop an aggressive form of prostate cancer, CRPC.
“It’s been a mystery why some patients do not respond to anti-androgens, and why a subset of these patients actually get worse after treatment,” said study co-leader Cory Abate-Shen, PhD, the Michael and Stella Chernow Professor of Urological Oncology and professor of urology, medicine, systems biology, and pathology & cell biology, Columbia University Medical Center (CUMC), New York, NY. “Our findings show that in many of these patients, the tumor cells are reprogrammed so that they are no longer dependent on androgens.”
Dr. Abate-Shen and fellow researchers developed a strain of mice lacking Trp53 and Pten, two tumor-suppressor genes that are mutated in roughly 25% of patients with advanced prostate cancer. After treatment with abiraterone, an anti-androgen agent, mice failed to respond and demonstrated accelerated tumor growth.
“We found a number of genes that were overexpressed in mice with CRPC and also conserved in patients with the disease. Among the most interesting of these was SOX11, which regulates the development of the nervous system,” said study co-leader Michael M. Shen, PhD, professor of medical sciences.
Aggressive prostate cancers often contain neuroendocrine-like cells lacking androgen receptors. This is in contrast to most localized, slow-growing prostate cancers, which are mainly comprised of epithelial cells rich in androgen receptors. The response to anti-androgen therapy of each of these types of cancers is thus explained, with aggressive cancers being less responsive, and localized cancers more responsive.
“This raised the question, where are the neuroendocrine-like cells in prostate tumors coming from?” said Dr. Abate-Shen. “While previous research hinted that epithelial tumor cells may be reprogrammed to become neuroendocrine-like cells, our study provides the first direct evidence that this reprogramming is actually occurring and that it is mediated, at least in part, by SOX11.”
Drs. Abate-Shen and Shen also showed that SOX11 acts similarly in human prostate cancer cells, and they identified regulator genes that control SOX11 and other genes involved in prostate cancer reprogramming.
“By giving anti-androgens to patients with CRPC, we are eliminating the cancer cells that need androgen to survive and enriching the tumor with the remaining neuroendocrine-like cells. The net effect is to create an even more aggressive tumor,” said Dr. Shen. “Based on our findings, genetic testing to identify SOX11 and the master regulators may be considered before embarking on anti-androgen therapy for patients with advanced prostate cancer,” he concluded.
The study was supported by grants from the National Institutes of Health (P30 CA013696, UL1 TR00040, P01 CA173481, CA154293, DK076602, CA196662, U54 CA209997, R35 CA197745, UL1 TR001873), the Pacific Northwest Prostate Cancer SPORE (P50 CA097186), the DOD Prostate Cancer Research Program (PC150051, PC131821), the Prostate Cancer Foundation, the TJ Martell Foundation for Leukemia, Cancer and AIDS Research, the National Health and Medical Research Council of Australia, the Swiss National Science Foundation, and the FM Kirby Foundation.