A single drug compound simultaneously attacks difficult-to-treat prostate cancer on multiple fronts, according to a new study in mice and human cells. It triggers immune cells to attack, helps immune cells enter the tumor and cuts off the tumor’s ability to burn testosterone for fuel, according to new research from the Washington University School of Medicine in St. Louis. The drug may offer a promising new strategy for treating patients whose tumors do not respond to standard therapy.
The study appears online in the journal Communication Nature.
Prostate cancer is known to eventually develop resistance to standard treatments that block or reduce testosterone, which fuels the growth of these tumors. And like many solid tumors, prostate cancer has also proven stubbornly resistant to new immunotherapies, which aim to rein in the immune system’s T cells to get them to fight off cancerous invaders. Immunotherapies — most commonly, immune checkpoint inhibitors — can be extremely effective, but only in certain cancers, such as melanoma.
“We need to develop better therapies for prostate cancer patients because most of these tumors develop resistance to the hormone therapies doctors rely on to treat these cancers,” said lead author Nupam P. Mahajan, PhD, professor of surgery. “Immunotherapy is the newest and most promising type of treatment for cancer today, but even so, immune checkpoint inhibitors have failed to do much against most cancers. solid tumors, including prostate cancer. This study was surprising because we found that this drug activates anti-cancer T cells in a new way, and it also increases the ability of T cells to enter the tumor. This could lead to a more effective strategy for patients whose cancers are difficult to treat.
The drug, called (R)-9b, is a small molecule that blocks an oncogene, a cancer-causing gene. The researchers initially attributed the drug’s success in mouse studies to its ability to reduce or eliminate androgen receptors in prostate cancer cells. These receptors bind to testosterone and use the hormone to fuel tumor growth. The ability of the drug to eliminate the androgen receptor differs from standard drugs that reduce the amount of testosterone in the body and other drugs that block the function of the androgen receptor as a transcription regulator.
But because the new drug was so effective, Mahajan and his colleagues suspected something more was going on. The drug blocks a gene called ACK1. The researchers developed a strain of mice completely lacking this gene in order to study what happens when it is absent. At first, researchers were baffled by these mice. Mice lacking an entire gene often have obvious problems. But these mice seemed fine. And when researchers looked for tumor growth, they found very little. It was difficult to model cancer in these animals.
“In most of these mice, when we introduced cancer cells like we usually do, there was no trace of a tumor,” said Mahajan, also a researcher at the Siteman Cancer Center at Barnes-Jewish Hospital and the Washington University School of Medicine. “In the few mice that developed tumors, the tumors were small compared to those in wild-type mice. It was the first clue that something important was going on in the mice that lacked this gene. We found that they were able to mount a robust immune response. against cancer cells.
When different mice – mice carrying this gene – were implanted with human prostate tumors and given the drug that blocks this gene, it had the same effect: removing the brakes on 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 T cells to enter the tumor and kill cancer cells more effectively. The tumors of these mice treated with (R)-9b were much smaller than those of the mice in the control groups.
Given the drug’s success in tumor penetration, researchers investigated whether adding immune checkpoint inhibitors to treatment with the drug would be even more effective, suppressing T cells in more than one way. at once – but there was no such improvement. .
“Surprisingly, we found that the immune checkpoint inhibitor activates ACK1the very pathway that we are closing with this drug compound,” Mahajan said. “It’s possible that immune checkpoint inhibitors don’t work well in these tumors because they activate ACK1, which suppresses the immune response. Similar to prostate cancer, ACK1 activation of the pathway could also be used by other cancers that do not respond to checkpoint inhibitors. However, these cancers might respond to (R)-9b, so we would like to study this drug in other solid tumors as well.”
Mahajan said the drug elicits multiple responses due to the nature of the gene it blocks. Many genes have multiple roles in the body, and ACK1The roles of in androgen receptor expression and in regulation of the immune system make it an attractive target for cancer treatment, particularly against solid tumors with a hormonal growth component, such as prostate cancers and breast.
Mahajan worked with the University of Washington’s Office of Technology Management/Tech Transfer to file patents for the use of this drug in the treatment of cancer. His team is collecting data to seek permission from the Food and Drug Administration to test the drug in a clinical trial for patients with prostate cancer.