Prostate cancer uses the metabolic switch to thrive after hormone therapy

Microscopic image of prostate cancer adenocarcinoma (the most common form of prostate cancer) Photo credit: Wikipedia

A team of researchers from Duke Health looked at the cell metabolism of prostate cancer and identified a major cause of hormone therapy failure. At the same time, a way was shown to circumvent the problem with the help of a completely new therapeutic approach.

The findings, published in the Proceedings of the National Academy of Sciences the week of March 22nd, describe how hormone therapies target the androgen receptor to essentially starve tumor cells, a crucial fuel source. This works fine at first to stop tumor growth, but then the cancer cells compensate, switch to a different enzyme to use the fuel, and multiply when they become resistant to hormone therapies.

The research team at the Duke Cancer Institute used this finding to propose a treatment strategy that does not require the androgen receptor to be completely inhibited. Your goal is to directly target the tumor’s preferred source of fuel – an amino acid called glutamine.

In studies with prostate cancer cell lines, human prostate cancer tissue and animal models, the novel therapeutic strategy was able to successfully inhibit tumor growth. Clinical studies are currently planned with a currently available drug that inhibits the consumption of glutamine by tumor cells.

“Rather than inhibiting the androgen receptor with hormone therapy, a better therapeutic strategy is to directly inhibit glutamine utilization,” said lead author Dr. med. Jiaoti Huang, chairman of the Duke’s Pathology Department.

“Because glutamine is not essential for normal tissue, there are fewer side effects, which is one of the biggest drawbacks of hormone therapy,” said Huang. “Direct inhibition of the enzyme that controls glutamine utilization would also make it more difficult for tumor cells to develop resistance.”

Huang and co-authors – including Dr. Daniel George, professor in Duke’s medicine and surgery departments who led the design of the clinical trial – initiated the study to better understand prostate cancer cell metabolism, which still has many unknowns.

They found that hormone therapy first inhibited a certain form of the glutamine-converting enzyme called kidney-type glutaminase (KGA). This KGA enzyme depends on the androgen receptor and enables cancer cells to use glutamine. By suppressing them, hormone therapies have been successful in slowing cancer growth for a period of time.

But the tumor cells eventually find a workaround and switch to another enzyme – glutaminase C (GAC) – that doesn’t rely on the androgen receptor. When tumors switch to GAC, they multiply aggressively and become castration-resistant prostate cancer.

“Our work shows that this metabolic switch is one of the key mechanisms behind therapeutic resistance and disease progression,” said George.

By specifically combating glutamine metabolism, the researchers succeeded in bypassing the complex androgen receptor signaling processes and instead suppressing the energy and building block production of prostate cancer cells directly, which essentially causes tumor cells to starve.

“Because metabolic activity directly controls cell proliferation, it can be more difficult for tumor cells to overcome metabolic inhibition in order to develop resistance,” said Huang. “Our study shows that pharmacological inhibition of GAC can significantly suppress castration-resistant prostate cancer.”

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More information:
Lingfan Xu el al., “A Glutaminase Isoform Switch Drives Therapeutic Resistance and Disease Progression in Prostate Cancer”, PNAS (2021). Provided by Duke University Medical Center

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