One drug may offer a promising new strategy for treating prostate cancer patients

A single drug compound simultaneously attacks difficult-to-treat prostate cancer on several fronts, according to a new study in mice and human cells. It triggers immune cells to attack, helps the immune cells enter the tumor, and reduces the tumor’s ability to burn testosterone for fuel, according to new research from the Washington University School of Medicine in St. Louis. Louis. The drug could offer a promising new strategy for treating patients whose tumors do not respond to conventional therapy.

The study appears online in the journal Nature Communications.

Prostate cancer is notorious for eventually developing resistance to conventional 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 immunotherapy, designed to take the brakes off the immune system’s T cells to get them to fight cancer invaders. Immunotherapies -; most often, immune checkpoint inhibitors -; can be very effective but only in certain cancers, such as melanoma.

“We need to develop better treatments for prostate cancer patients, because most of these tumors develop resistance to the hormone therapies that doctors rely on to treat these cancers,” said senior author Nupam P. Mahajan, PhD, professor of surgery. “Immunotherapy is currently the newest and most promising form of cancer treatment, yet immune checkpoint inhibitors have not been very successful against most solid tumors, including prostate cancer. This study was surprising because we found that this drug activates – cancer T cells in a new way, and it also increases the ability of T cells to enter the tumor. This could lead to more effective strategies for patients with difficult-to-treat cancers.”

The drug, called (R)-9b, is a small molecule that blocks an oncogene, 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 prostate cancer cells. These receptors bind to testosterone and use the hormone to promote tumor growth. The drug’s ability to eliminate the androgen receptor is different 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 that completely lacked this gene to study what happens when it is missing. At first, scientists were puzzled by these mice. Mice missing an entire gene often have obvious problems. But these mice looked nice. And when the researchers looked for tumor growth, they found very little. It was difficult to create cancer in these animals.

“In most of these mice, when we introduced cancer cells as we normally do, there was no sign of tumors,” said Mahajan, also a research member of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “In the few that did develop tumors, the tumors were small compared to wild-type mice. This was the first indication that something important was happening in mice lacking this gene. We found that they were able to mount a strong immune response against the cancer cells.”

When different mice -; mice with this gene -; were implanted in human prostate tumors and given the drug that blocks this gene had the same effect: taking the brakes off the immune system and inducing increased levels of certain types of T cells known to attack cancer. The drug also increases signaling molecules that allow the T cells to enter the tumor and kill cancer cells more effectively. The tumors in these (R)-9b treated mice were much smaller than in control mice.

Given the drug’s success with tumor penetration, researchers investigated whether adding immune checkpoint inhibitors to treatment with the drug would be even more effective, taking the brakes off T cells in more than one way at the same time -; but there was no such improvement.

“Surprisingly, we found that the immune checkpoint inhibitor is being activated.” ACK1exactly the way we’re blocking with this drug compound,” Mahajan said. “It’s possible that immune checkpoint inhibitors don’t work well in these tumors because they’re turning on ACK1, which suppresses the immune response. Similar to prostate cancer, the ACK1 Activation of pathways may also be used by other cancers that do not respond to checkpoints. However, these cancers may respond to (R)-9b, so we also want to study this drug in other solid tumors.”

Mahajan said the drug triggers multiple responses because of the nature of the gene it blocks. Many genes have several roles in the body, and ACK1Its role in the expression of the androgen receptor and in regulating the immune system make it an attractive target for cancer therapy, especially against solid tumors with hormone growth factors, such as prostate and breast cancer.

Mahajan has worked with Washington University’s Office of Technology Management/Technology Transfer to patent the use of this drug in cancer treatment. His team is gathering data to apply for permission from the Food and Drug Administration to test the drug in a clinical trial for prostate cancer patients.

Mahajan and co-author Kiran Mahajan, PhD, assistant professor of surgery, are inventors on two patents related to this work. Both patents are licensed to TechnoGenesys Inc., which they jointly founded. They also own stock and serve as advisors to the company.

Source:

Washington University School of Medicine

Diary reference:

Sridaran, D, et al. Blocking ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade. Nature communication. Nov. 14, 2022.

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