A compound that kills tumors in mice and human cancer cells in multiple ways!

A new study in mice and human cells shows that a single drug compound simultaneously attacks hard-to-treat prostate cancer on several fronts. It triggers immune cells to attack, helping immune cells penetrate a tumor, and interrupting the tumor’s ability to burn testosterone for fuel, according to new research from 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 treatment.

The study appears online in the journal Nature Communications.

Prostate cancer is notorious for developing resistance to standard treatments that block or reduce testosterone, which fuels the growth of these tumors. Like many solid tumors, prostate cancer has also proven very resistant to newer immunotherapies, which aim to prevent the immune system’s T cells from fighting off cancerous invaders. Immunotherapies – most commonly, immune checkpoint inhibitors – can be very effective but only in some types of cancer, such as melanoma.

Senior researcher Nobaum B. “Immunotherapy is currently the newest and most promising type of treatment for cancer, but even so, immune checkpoint inhibitors fail to do much against most solid tumors, including prostate cancer. This study was surprising because we found that this drug activates anti-apoptotic cells. “It also increases the ability of T cells to penetrate 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 oncogene, the gene that drives cancer. The researchers initially attributed the drug’s success in mouse studies to its ability to reduce or block androgen receptors in prostate cancer cells. These receptors bind to testosterone and use the hormone to fuel tumor growth. The drug’s ability to block 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 regulator of transcription.

But because the new drug was so effective, Mahajan and his colleagues suspected something else was going on. The drug blocks a gene called ACK1. Researchers developed a strain of mice that completely lacked this gene in order to study what happens when it is missing. At first, the researchers were baffled by these mice. Mice that lose an entire gene often have obvious problems. But these mice seemed fine. And when the researchers looked for tumor growth, they found very little. Modeling cancer in these animals has been difficult.

“In most of these mice, when we introduced the cancer cells as we normally would, there was no trace of the tumor,” said Mahajan, who is also a research fellow at the Sitman Cancer Center at Barnes-Jew Hospital and the University of Washington School of Medicine. “In the few that did develop tumors, the tumors were small compared to the tumors of the wild-type mice. This was the first evidence that something significant was going on in the mice that had lost this gene. We found that they were able to mount a strong immune response against the cancer cells.”

When different mice—mice that carry this gene—were implanted with human prostate tumors and given the drug that blocks that gene, it had the same effect: taking the brakes off 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 penetrate the tumor and kill cancer cells more effectively. The tumors in these (R)-9b-treated mice were significantly smaller than those in mice in the control groups.

Given the drug’s success in tumor infiltration, the researchers investigated whether adding immune checkpoint inhibitors to drug treatment would be more effective, removing the brakes from T cells in more ways than one at the same time—but there was no such improvement.

Surprisingly, we found that the immune checkpoint inhibitor is activated ACK1The pathway we’re closing with this drug compound, Mahajan said. “It’s possible that immune checkpoint inhibitors don’t work as well in these tumors because they do ACK1, which suppresses the immune response. Similar to prostate cancer, the ACK1 Activation of the pathway may also be used by other cancers that do not respond to checkpoint inhibitors. However, these cancers can respond to (R)-9b, so we’d like to investigate this drug in other solid tumors as well.”

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 the control of the immune system makes it an attractive target for cancer therapy, especially against solid tumors that have a growth hormone component, such as prostate and breast cancer.

Mahajan worked with the University of Washington’s Office of Technology Management/Technology Transfer to file patents on the drug’s use 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.

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