An orally administered CDK12/CDK13 degrader was found to slow down the destruction of cancerous cells, improving patient outcomes.
Researchers from the University of Michigan Rogel Cancer Center have found new, important insights into how changes in the CDK12 gene drive the progression of prostate cancer. Their findings, published in Cell Reports Medicine, reveal mechanisms behind these genetic changes but also potential therapeutic strategies that may offer hope for patients in the advanced stages of the disease.
Prostate cancer is one of the most common cancers among men, and while many cases are treatable, there is a subset that is particularly aggressive. Researchers identified that about 7% of patients with metastatic prostate cancer exhibited a loss of the CDK12 gene. This genetic alteration has been associated with the more aggressive form of the disease, and its role extend has also played a part in the development of some ovarian cancers.
The study aimed to understand how the loss of CDK12 contributes to cancer progression at a molecular level. To achieve this, researchers came up with a rodent model that replicated the genetic changes seen in human prostate cancer. When team triggered the loss of CDK12 in the prostate of the rodents, they observed the formation of preliminary lesions, indicating early stages of cancer development. However, when the researchers also purposely caused the loss of the p53 oncogene (a tumor suppressor), the mice developed full-blown invasive prostate cancer. This dual loss provided the researchers with a model that closely parallels the progression of prostate cancer in humans.
At the cellular level, the loss of CDK12 leads to considerable DNA damage. The research team discovered that the absence of this gene activates other cancer-driving genes, causing them to be overexpressed and leading to rapid DNA replication. The combination of these two processes results in the buildup of DNA damage, driving cancer progression.
One of the most notable outcomes of this research was the identification of a potential therapeutic strategy. The team discovered that CDK13, a partner gene to CDK12, plays a vital role in the cancer development process. They came up with a protein degrader that specifically targets both CDK12 and CDK13 simultaneously, effectively stopping the growth of cancer cells in their tracks. The degrader can be administered orally, making it easy to deploy on humans as well. Many protein degraders have historically been too large to be absorbed through the gastrointestinal tract, requiring intravenous delivery.
The team also specifically uncovered that knocking down CDK12 and CDK13 activated the AKT signaling pathway, which is known to be involved in cancer development. This discovery suggests that combining the CDK12/CDK13 degrader with existing therapies that target the AKT pathway could result in a synergistic effect, further improving the destruction of malignant cells. This could be key in preventing the development of resistance, which is a common challenge in cancer treatment.
By focusing on the development of an orally bioavailable CDK12/13 degrader, researchers aim to take the next steps toward clinical trials. This promising research paves the way for potential new treatments that could change prostate cancer therapy entirely, providing new hope for both patients and physicians alike. The goal is to develop strategies that not only treat the disease effectively but also improve the quality of life for patients.
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Researchers reveal mechanisms of how CDK12 alterations drive prostate cancer development
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