Study Identifies Genetic Engine for Fatal Prostate Cancer

A new study has identified a new molecular engine for deadly prostate cancer, as well as a molecule that could be used to attack it. The results were made in laboratory mice. If they are confirmed in humans, they could lead to more effective ways to control some aggressive types of prostate cancer, the second leading cause of cancer death in men in the United States.

Men whose prostate cancer tumors are localized usually survive many years after diagnosis, whether they undergo surgery, radiation, or any treatment. But for a minority of men whose cancer spreads to other parts of the body and resists hormone therapy, the prognosis is bleak, with less than one-third of them surviving five years after diagnosis. According to the American Cancer Society, more than 29,000 men in the United States die each year from prostate cancer.

"We need new strategies to prevent prostate cancer from becoming fatal for the thousands of men whose metastatic disease and resistance to hormone therapy," said Michael Freeman, Ph.D., co-director of the Cancer Biology Program at the Samuel Oschin Cancer Research Institute in Cedars-Sinai. Hormone therapy blocks the activity of male hormones, which fuel the growth of the most prevalent type of prostate cancer.

Freeman was the corresponding author of the multi-institutional study, published in the journal Medicine of nature. The co-lead authors were Mirja Rotinen, Ph.D., project researcher, and Sungyong You, Ph.D., assistant professor of surgery and biomedical sciences, both of Cedars-Sinai.

For research, the team analyzed the genetic and molecular data of cancer patients in a large database. They demonstrated high activity of the molecule Onecut2 in tumors of patients whose prostate cancer was resistant to hormone treatment. Onecut2, a type of transcription factor, is needed by the body to make certain proteins.

The team discovered that Onecut2 had interfered with the activity of androgen receptor proteins, targets of hormone therapy for prostate cancer. This process could allow cancer to become less dependent on hormones for growth. At the same time, Onecut2 has caused some cancer cells to turn into a more aggressive variety that resists hormone therapy. "These twin shares of Onecut2 could help explain how some prostate cancers escape hormonal therapy and become more aggressive," said Freeman, a professor of surgery and biomedical sciences.

In additional experiments involving human tissue samples, pharmaceutical databases, and laboratory animals, the researchers identified a compound, CSRM617, that counteracted Onecut2. They showed that CSRM617 significantly reduced the size of prostate cancer metastases in mice. "Our research suggests that Onecut2 is an important regulator of deadly prostate cancer, which could constitute a useful therapeutic target in nearly one-third of patients whose cancer is spreading and eluding hormone therapy." "said Freeman.

Freeman was also the corresponding author of a recent study in the journal Research against cancer who has identified a new method to evaluate the aggressiveness of prostate cancer. This method is based on the stability of the forms of the cancer cell nuclei. Instability was associated with the types of cancer that spread. Investigators also discovered that they could detect the instability of the nuclei in the blood through the cells cleared by the tumor. These results could lead to less invasive techniques to identify potentially dangerous prostate cancer and monitor its progression on blood samples, the research team said.

"These findings are emblematic of the paradigm shift work being conducted in the field of cancer at Cedars-Sinai," said Dan Theodorescu, MD, Ph.D., director of the Cancer Institute. "They show how our researchers are linking scientific discovery to clinical development of new treatments that will impact patients."

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More information:
ONECUT2, Mirja Rotinen et al. Is a leading regulator targeting deadly prostate cancer that removes the androgen axis, Medicine of nature (2018). DOI: 10.1038 / s41591-018-0241-1