A single drug compound concurrently attacks hard-to-treat prostate cancer on several fronts, in keeping with a recent study in mice and human cells. It triggers immune cells to attack, helps the immune cells penetrate the tumor, and cuts off the tumor’s ability to burn testosterone as fuel, in keeping with recent research from Washington University School of Medicine in St. Louis. The drug may offer a promising recent strategy for treating patients whose tumors don’t respond to plain therapy.
The study appears online within the journal Nature Communications.
Prostate cancer is notorious for eventually developing resistance to plain treatments that block or reduce testosterone, which fuels growth of those tumors. And like many solid tumors, prostate cancer also has proven stubbornly immune to newer immunotherapies, that are intended to take the brakes off the immune system’s T cells to get them fighting cancerous invaders. Immunotherapies -; mostly, immune checkpoint inhibitors -; may be extremely effective but only in certain cancers, comparable to melanoma.
“We’d like to develop higher therapies for prostate cancer patients, because most of those tumors develop resistance to hormone-based therapies doctors depend on to treat these cancers,” said senior writer Nupam P. Mahajan, PhD, a professor of surgery. “Immunotherapy is the latest and most promising kind of therapeutic for cancer straight away, besides, immune checkpoint inhibitors have did not do much against most solid tumors, including prostate cancer. This study was surprising because we found that this drug prompts anti-cancer T cells in a novel way, and it also increases the T cells’ ability to penetrate the tumor. This may lead to a simpler strategy for patients whose cancers are hard to treat.”
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 cut back or eliminate androgen receptors within the prostate cancer cells. These receptors bind to testosterone and use the hormone to fuel tumor growth. The drug’s ability to eliminate the androgen receptor differs from standard drugs that reduce the quantity of testosterone within the body, and other drugs that block the androgen receptor’s function as a transcription regulator.
But since the recent drug was so effective, Mahajan and his colleagues suspected something more was happening. The drug blocks a gene called ACK1. The researchers developed a strain of mice that absolutely lacked this gene in an effort to study what happens when it’s missing. At first, the researchers were baffled by these mice. Mice missing a complete gene often have obvious problems. But these mice seemed high quality. And when the researchers searched for tumor growth, they found little or no. It was difficult to model cancer in these animals.
“In most of those mice, after we introduced cancer cells as we typically do, there was no trace of a tumor,” said Mahajan, also a research member of Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “Within the few that did develop tumors, the tumors were small in comparison with those of wild-type mice. This was the primary clue that something vital was happening in mice missing this gene. We found that they were in a position to mount a sturdy immune response against the cancer cells.”
When different mice -; mice with this gene -; were implanted with human prostate tumors and given the drug that blocks this gene, it had the identical effect: taking the brakes off the immune system and producing increased levels of certain kinds of T cells known to attack cancer. The drug also increased signaling molecules that allow the T cells to penetrate the tumor and kill cancer cells more effectively. The tumors in these (R)-9b treated mice were much smaller than those of mice on top of things groups.
Given the drug’s success in tumor penetration, the researchers investigated whether adding immune checkpoint inhibitors to treatment with the drug could be even simpler, taking the brakes off T cells in a couple of way at the identical time -; but there was no such improvement.
“Surprisingly, we found that the immune checkpoint inhibitor is activating ACK1, the very pathway we’re shutting down with this drug compound,” Mahajan said. “It’s possible immune checkpoint inhibitors don’t work well in these tumors because they’re turning on ACK1, which suppresses the immune response. Much like prostate cancer, the ACK1 pathway activation also may very well be employed by other cancers that don’t reply to checkpoint inhibitors. Nonetheless, these cancers could reply to (R)-9b, so we would really like to analyze this drug in other solid tumors as well.”
Mahajan said the drug spurs multiple responses due to nature of the gene it blocks. Many genes have several roles within the body, and ACK1’s roles in expression of the androgen receptor and in reigning within the immune system make it an appealing goal for cancer therapy, especially against solid tumors with a hormonal growth component, comparable to prostate and breast cancers.
Mahajan has worked with Washington University’s Office of Technology Management/Tech Transfer to file patents on the usage of this drug in cancer treatment. His team is gathering data to use for permission from the Food and Drug Administration to check the drug in a clinical trial for patients with prostate cancer.
Mahajan and co-author Kiran Mahajan, PhD, an assistant professor of surgery, are inventors of two patents related to this work. Each patents are licensed to TechnoGenesys Inc., which they co-founded. In addition they own stock and function consultants for the corporate.
Source:
Washington University School of Medicine
Journal reference:
Sridaran, D, at al. Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance. Nature Communications. Nov. 14, 2022.