Hope is so important when you have cancer. In prostate cancer, we have seen multiple new therapies being developed and approved. Mostly, these new therapies have been targeted towards later-stage prostate cancer, including 2nd and 3rd line treatments.
The newest ray of hope covers both early to late-stage prostate cancer treatment.
The mainstay for prostate cancer treatment at all stages is hormone therapy (ADT), but ADT eventually fails. A team at Duke Cancer Institute has been working on an alternative treatment approach that would bypass this problem. With support from the Department of Defense (DOD-W81XWH-19-1-0411), the Prostate Cancer Foundation Movember Valor Challenge Award (2018), and the National Institutes of Health (K99- K99CA237618), they have been studying the cellular metabolism of prostate cancer
Their findings, the ray of hope, was published during the week of March 22 in the National Academy of Sciences Proceedings. They described how hormone therapies, both the 1st and 2nd line, target the androgen receptor to starve tumor cells of a crucial fuel source, androgens.
This approach initially works well to halt tumor growth. Still, the cancer cells compensate, switching to a different enzyme to exploit the fuel and increasing as they become resistant to hormone therapies.
They targeted the tumor’s preferred source of fuel – an amino acid called glutamine.
In studies targeting glutamine, they evaluated prostate cancer cell lines, human prostate cancer tissue, and animal models. This novel therapeutic strategy that targeted glutamine successfully inhibited tumor growth. With this success, they are now planning Clinical trials that inhibit glutamine used by tumor cells.
“Instead of inhibiting androgen receptor using hormonal therapy, a better therapeutic strategy is to inhibit glutamine utilization directly,” said senior author Jiaoti Huang, M.D., Ph.D., chair of Duke.
“Since glutamine is not essential for normal tissue, there will be fewer side effects, which is one of the biggest downsides to hormonal therapies,” Huang said. “Direct inhibition of the enzyme that controls glutamine utilization would also make it more difficult for tumor cells to develop resistance.”
The underlying research by Huang and co-authors -- including Daniel George, M.D., professor in the departments of Medicine and Surgery at Duke initiated the study to better understand prostate cancer cell metabolism, which still has many unknowns.
They found that ADT initially inhibits a specific form of a glutamine-converting enzyme called kidney-type glutaminase (KGA). This KGA enzyme depends on the androgen receptor and makes it possible for cancer cells to use glutamine. By suppressing it, hormonal therapies successfully slow cancer growth for a time.
However, the tumor cells find a workaround, switching to a different enzyme -- glutaminase C (GAC) -- which doesn’t rely on the androgen receptor. When tumors make this switch to GAC, they proliferate aggressively, becoming castration-resistant prostate cancer.
“Our work demonstrates this metabolic switch to be one of the key mechanisms in therapeutic resistance and disease progression,” George said.
“Since metabolic activity directly controls cellular proliferation, it may be more difficult for the tumor cells to overcome a metabolic inhibition to develop resistance,” Huang said. “Our study shows that pharmacological inhibition of GAC can significantly suppress castration-resistant prostate cancer.”
It is possible that by targeting glutamine metabolism, the researchers have developed a way to bypass the androgen receptor signaling processes. Instead, by directly suppressing energy production, the building blocks required by prostate cancer cells, we might essentially starve the tumor cells to death.
These findings are another example of a ray of hope in improving our treatment options and reducing the side effects.
