Shedding Light on Resistance to Hormone Therapy in Prostate Cancer
Posted: Wednesday, December 5, 2018
Androgen-targeted therapy may initiate epigenetic changes in prostate cancer cells, causing the disease to spread, reported a study in the Journal of Clinical Investigation. Researchers believe that when resistance occurs, adenocarcinoma cells may transform into neuroendocrine cancer cells. However, Rajeev Mishra, PhD, of Cedars Sinai Medical Center, Los Angeles, and colleagues suggest that a simple blood test measuring glutamine levels may help identify when a patient with prostate cancer is not responding to androgen-targeted therapy and possibly predict when treatment resistance will occur.
“This transformation is a problem because neuroendocrine prostate cancer is especially aggressive, metastasizes more readily, and is more resistant to both androgen-targeted therapy and chemotherapy,” senior author Neil A. Bhowmick, PhD, also of Cedars Sinai, stated in an institutional press release.
The investigators found that the Ras inhibitor RASAL3 facilitated oncogenic activity. Androgen-deprivation therapy further promoted the activity RASAL3 and glutamine secretion by prostatic fibroblasts. Via an orthotopic xenograft model, antitumor effects were observed after subsequently inhibiting macropinocytosis and glutamine transport. In the model, antagonizing glutamine uptake seemed to restore sensitivity to the hormone therapy.
Patients with prostate cancer that does not respond to androgen-deprivation therapy had significantly higher blood glutamine levels than did those with therapeutically responsive disease (P = .02), which the investigators believe validates the findings in the model. “While glutamine is known to spur cancer growth, its role in prostate cancer cells to trigger reprogramming of adenocarcinoma cells into neuroendocrine cancer cells is a new and important finding,” commented study coauthor Roberta Gottlieb, MD, in a Cedars-Sinai press release.
