Multi-acting compound a new solution to drug-resistant prostate cancer

The growth of tumours in prostate cancer are fuelled by testosterone, contributing to a vicious cycle that eventually becomes resistant to standard treatments. Researchers from Washington University School of Medicine in St. Louis, or WUSTL, have found a drug compound that triggers immune cells to attack hard-to-treat prostate cancer and also cuts off the tumour’s ability to use testosterone.

Prostate cancer is known to be resistant to newer immunotherapies, which are intended to take the brakes off the immune system’s T cells to get them fighting cancerous invaders.

“Immunotherapy is the newest and most promising type of therapeutic for cancer right now, but even so, [immunotherapies such as] immune checkpoint inhibitors have failed to do much against most solid tumours, including prostate cancer,” said Dr. Nupam P. Mahajan, Professor of Surgery and research member of Siteman Cancer Center at Barnes-Jewish Hospital and WUSTL.

“This study was surprising because we found that this drug activates anti-cancer T cells in a novel way, and it also increases the T cells’ ability to penetrate the tumour. This could lead to a more effective strategy for patients whose cancers are hard to treat.”

The drug is called (R)-9b, a small molecule that blocks an oncogene i.e., a gene that drives cancer. The researchers initially attributed the drug’s success in mouse studies to its ability to reduce or eliminate androgen receptors in the prostate cancer cells. These receptors bind to testosterone and use the hormone to fuel tumour growth – the drug’s ability to eliminate the androgen receptor differs from standard drugs that reduce the amount of testosterone in the body, and other drugs that block the androgen receptor’s function as a transcription regulator.

But because the new drug was so effective, Mahajan and his colleagues suspected something more was going on. Then they noticed the drug also blocks a gene called ACK1.

The researchers developed a strain of mice that totally lacked this gene in order to study what happens when it’s missing. At first, the researchers were baffled by these mice. Mice missing an entire gene often have obvious problems. But these mice seemed fine. And when the researchers looked for tumour growth, they found very little. It was difficult to model cancer in these animals.

“In most of these mice, when we introduced cancer cells as we typically do, there was no trace of a tumour,” said Mahajan. “In the few that did develop tumours, the tumours were small compared to those of wild-type mice. This was the first clue that something important was happening in mice missing this gene. We found that they were able to mount a robust immune response against the cancer cells.”

When another set of mice with the ACK1 gene were implanted with human prostate tumours and given the drug that blocks this gene, it had the same effect: stimulating the immune system and producing increased levels of certain types of T cells known to attack cancer.

The drug also increased signaling molecules that allow the T cells to penetrate the tumour and kill cancer cells more effectively. The tumours in these (R)-9b treated mice were much smaller than those of mice in control groups.

Mahajan said the drug spurs multiple responses because of the nature of the gene it blocks. In short, ACK1’s roles in expression of the androgen receptor and in reigning in the immune system make it an appealing target for cancer therapy, especially against solid tumours with a hormonal growth component, such as prostate and breast cancers.

Mahajan and his colleagues are gathering data to apply for permission from the US Food and Drug Administration to test the drug in a clinical trial for patients with prostate cancer.

Category: Pharmaceuticals