Researchers have identified a gene that could play a key role in the transition to a more aggressive, treatment-resistant type of prostate cancer, according to a recent study published by Duan et al in the Journal of Clinical Investigation. The findings indicated that the gene may be indirectly targeted with an existing class of drugs, representing a potential treatment strategy among patients with aggressive subtypes of prostate cancer.
Background
Previous studies have demonstrated that prostate cancer cells undergo lineage plasticity, a process in which they become resistant to treatment via the androgen receptor, a key disease target. This transition away from dependence on the androgen receptor is a continuum, with cancer cells taking on alternate identities from what is typical in most prostate cancer cases that rely on the androgen receptor.
“Patients whose prostate tumors lose reliance on the androgen receptor do poorly. Our results suggest a therapeutic approach for patients whose tumors have undergone that shift,” emphasized senior study author Joshi J. Alumkal, MD, the Wicha Family Professor of Oncology at the University of Michigan Rogel Cancer Center.
Study Methods and Results
Investigators analyzed factors that may be contributing to lineage plasticity by examining patient tumor biopsies that had undergone the transition. They identified PROX1—a gene responsible for dictating cell identity in both normal cells and cancer cells—as the top upregulated gene. They found that as prostate cancer cells transitioned to an alternate identity, PROX1 became more highly expressed.
After assessing hundreds of patient tumors along the continuum of lineage plasticity, the researchers were able to confirm that PROX1 was an early marker of lineage plasticity. For instance, tumors with low activity on the androgen receptor (double-negative prostate cancer), in addition to tumors that completely lost expression of the androgen receptor (neuroendocrine prostate cancer), turned on PROX1.
Additional analysis showed that PROX1 expression was inversely correlated with androgen-receptor expression in data sets of patients with prostate cancer. Adding PROX1 to prostate cancer cells also turned off the androgen receptor.
“We think PROX1 is regulating the androgen receptor. It may be one explanation for why the androgen receptor gets turned off when tumors undergo lineage plasticity and transition away from the typical glandular prostate cancer identity,” noted Dr. Alumkal.
The researchers then eliminated PROX1 expression with genetic methods in both double-negative prostate cancer and neuroendocrine prostate cancer cells. The cells ceased growing and began to die, suggesting that targeting PROX1 could be an effective strategy to control these tumors. However, the challenge researchers could face is that PROX1 is a transcription factor—meaning that its function to turn on genes and this type of protein may be difficult to target with drugs.
“We examined the proteins that bind to PROX1. Among the top partners were histone deacetylases [HDACs]. We felt like this was guilt by association. We hypothesized that HDACs might cooperate with PROX1 and that targeting HDACs might be like targeting PROX1,” Dr. Alumkal highlighted.
HDACs are already known to play a role in cancer, and several HDAC inhibitors have been approved by the U.S. Food and Drug Administration for other cancer types. PROX1-expressing prostate cancer cells were sensitive to HDAC inhibitors, and treatment with these drugs depleted PROX1 protein. As PROX1 expression decreased, the tumor cells died. The impact was similar to when the researchers genetically removed PROX1 from the cells.
Conclusions
“Our work implicates PROX1 as an important early driver away from androgen-receptor dependence. HDAC inhibitors can block PROX1 and reduce survival of aggressive prostate tumor models that have transitioned away from androgen-receptor reliance,” underscored Dr. Alumkal. “Our results suggest this class of drugs should be prioritized for clinical trials in patients who have aggressive prostate cancer subtypes, for which there are few treatment options,” he concluded.
Disclosure: The research in this study was funded by the National Institutes of Health, U.S. Department of Defense, Joint Institute for Cancer Research, Prostate Cancer Foundation, Canadian Institutes of Health Research, Terry Fox Research Institute, Canadian Cancer Society, BC Cancer Foundation, Smith Family Scholar Award, Sheppard Family Foundation, Benioff Initiative for Prostate Cancer Research, Silver Family Innovation Foundation, National Science Foundation, and Institute for Prostate Cancer Research. For full disclosures of the study authors, visit jci.org.
