Targeting Glutamine Could Curb Castration-Resistant Prostate Cancer

Targeting glutamine, rather than the androgen receptor (AR), successfully inhibited tumor growth in experiments in prostate cancer cells, tissue and animal models, potentially paving the way to clinical trials, researchers say.

"The current treatment strategy targeting the AR causes serious side effects and the tumors will eventually develop resistance," Dr. Jiaoti Huang of Duke University School of Medicine in Durham, North Carolina, told Reuters Health.

"Directly targeting tumor cell metabolism and avoiding the complex AR signaling network has the potential to avoid the side effects," he said by email, "and it will be more difficult for tumor cells to develop resistance mechanisms."

​

"Patients with the advanced and aggressive forms of prostate cancer, such as small cell neuroendocrine carcinoma, should be better suited for this potential therapy since these tumors are more addicted to glutamine," he noted.

Dr. Huang and colleagues write in Proceedings of the National Academy of Sciences of the United States of America, "Our work has discovered a previously unknown AR function, a metabolic mechanism of hormonal therapy and an important therapeutic target more specific than AR."

In a series of experiments using prostate cancer cell lines, human prostate cancer tissue and animal models, the team discovered that:

- The AR promotes glutaminase 1 (GLS1) expression and glutamine utilization to support prostate cancer cell survival;

- Hormone therapy inhibits the AR, decreasing GLS1 expression and glutamine utilization, thereby achieving a therapeutic effect;

- Eventually, tumor cells compensate by switching GLS1 expression from the AR-dependent kidney-type glutaminase (KGA) isoform to the androgen-independent, enzymatically more potent glutaminase C (GAC) isoform; this switch increases glutamine utilization, hyperproliferation and aggressive tumor cell behavior, which can contribute to the development of castration-resistant disease.

The authors propose a treatment strategy that, unlike hormone therapy, eliminates the need to inhibit the AR. "Targeting GLS1 may achieve similar therapeutic efficacy," they say, "but without the side effects resulting from inhibiting AR's other important physiologic functions."

Dr. Matthew Zibelman of the Department of Hematology/Oncology at Fox Chase Cancer Center in Philadelphia commented by email to Reuters Health, "This is a very exciting finding that could help elucidate a main resistance mechanism prostate cancer cells use to overcome androgen deprivation therapy (ADT)."

"This glutamine pathway may be a metabolic link between classic prostate adenocarcinomas and more aggressive forms of prostate cancer such as neuroendocrine prostate cancer," he said. "These findings could provide a treatment strategy effective across these divergent forms of prostate cancer."

"It is encouraging to know that CB-837, a glutaminase inhibitor already in clinical trials for other cancers, has demonstrated a promising safety profile, so targeting this pathway is known to be possible and tolerable for patients," he said.

Nonetheless, he added, "These findings are purely in vitro, and while promising and exciting, will need validation in further trials to understand if these pathways are as relevant in patients."

—Marilynn Larkin

Source