A new study in mice and human cells shows that a single medication component simultaneously fights difficult-to-treat prostate cancer on numerous fronts. According to new research from the Washington University School of Medicine in St. Louis, it causes immune cells to launch an attack, aids the immune cells in penetrating the tumor, and prevents the tumor from using testosterone as fuel. The medication might present an exciting new approach to treating patients whose cancers don’t respond to conventional therapy.
The growth of these tumors is fueled by testosterone, which is why prostate cancer is infamous for eventually developing resistance to traditional treatments that block or diminish this hormone. Prostate cancer has also shown tenacious resistance to newer immunotherapies, which are meant to unblock the immune system’s T cells and have them combat malignant invaders, just like many solid tumors. Only select malignancies, including melanoma, respond well to immunotherapies, most frequently immune checkpoint inhibitors.
The majority of these tumors become resistant to the hormone-based therapy that doctors use to treat these diseases, thus we need to discover better therapies for prostate cancer patients, according to senior author and professor of surgery Nupam P. Mahajan, PhD. “Despite the fact that immune checkpoint inhibitors have not been very effective against the majority of solid tumors, including prostate cancer, immunotherapy is now the most innovative and promising type of cancer treatment.” This study was unexpected because we discovered that this medicine uniquely activates anti-cancer T cells and enhances their capacity to infiltrate tumors. “For patients with tumors that are difficult to treat, this could result in a more successful strategy.”
The medication, R-9b, is a tiny chemical that inhibits an oncogene, or cancer-causing gene. The drug’s efficacy in animal tests was first attributed by the researchers to its capacity to decrease or eradicate androgen receptors in prostate cancer cells. When testosterone binds to these receptors, the hormone stimulates the development of tumors. The drug’s capacity to block the androgen receptor’s ability to regulate transcription differs from conventional medications that lower the body’s level of testosterone and other medications that block the androgen receptor’s ability to do so.
But because the new medication was so successful, Mahajan and his associates thought there might be more going on. The medication inhibits the ACK1 gene. For the purpose of examining what occurs when this gene is absent, the researchers created a line of mice that are completely deficient in this gene. The researchers were initially perplexed by these animals. Mice with a complete gene missing frequently display glaring issues. But these mice appeared healthy. Additionally, the researchers found very little tumor growth when searching for it. It proved challenging to simulate cancer in these animals.
In the majority of these mice, Mahajan said, “there was no indication of a tumor when we introduced cancer cells as we routinely do.” Mahajan is also a research associate at the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “The few tumors that did form were mild in comparison to those in mice of the wild type.” This was the first indication that mice lacking this gene were experiencing significant events. “They were able to develop a powerful immune response against the cancer cells, as we discovered.”
The medicine that disables this gene had the same impact when it was given to different mice—mmice with this gene—tthat had been implanted with human prostate cancers. It released the immune system’s brakes and elevated numbers of certain T cells that are known to target cancer. The medicine also enhanced the signaling chemicals that let T lymphocytes enter the tumor and more efficiently attack cancer cells. When compared to mice in control groups, the tumors in these R-9b-treated mice were significantly smaller.
Given the drug’s success in penetrating tumors, the researchers looked into whether adding immune checkpoint inhibitors to the drug’s treatment would make it even more successful by deactivating T cells in many ways at once. However, there was no such improvement.
Interestingly, we discovered that the immune checkpoint inhibitor activates ACK1, which is the very route that this pharmacological molecule is intended to block, according to Mahajan. “Immune checkpoint inhibitors may not be effective against these malignancies because they activate ACK1, which inhibits the immune response.” Similar to prostate cancer, other malignancies that do not respond to checkpoint medications may also activate the ACK1 pathway. “We would like to research R-9b in other solid tumors as well because these diseases may respond to it.”
According to Mahajan, the medicine causes a variety of reactions due to the way it affects the gene it suppresses. Many genes play many functions in the body, and ACK1’s functions in controlling immune response and androgen receptor expression make it an intriguing target for cancer treatment, particularly in solid tumors with a hormonal component to growth, such as breast and prostate malignancies.
In order to submit patents on the use of this medication in the treatment of cancer, Mahajan collaborated with the Office of Technology Management and Tech Transfer at Washington University. His team is gathering information in order to submit an application to the Food and Drug Administration to test the medication on individuals with prostate cancer.
