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Study identifies a genetic driver of fatal prostate cancer

Study identifies a genetic driver of fatal prostate cancer

The graph shows the elevated activity of a transcription factor network that includes the Onecut2 molecule in tumors of patients whose hormone therapy resistant to prostate cancer (above the purple bar) compared to other types. (Michael Freeman, Ph.D.) Credit: Nature Publishing Group

A new study has identified a new molecular controller of lethal prostate cancer, along with a molecule that could be used to attack it. The findings were made in laboratory mice. If confirmed in humans, they could lead to more effective ways to control certain aggressive types of prostate cancer, the second leading cause of cancer death in men in the US. UU

Men whose tumors of prostate cancer are localized generally survive many years after diagnosis, whether they have surgery, radiotherapy or no treatment. But for a minority of men whose cancer spreads to other parts of the body and resists hormone therapy, the prognosis is bad and less than a third survive five years after diagnosis. According to the American Cancer Society, more than 29,000 men in the US UU They die of prostate cancer every year.

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

Freeman was the corresponding author of the multi-institutional study, published in the magazine. Natural medicine. The co-first authors were the project scientist Mirja Rotinen, Ph.D., and Sungyong You, Ph.D., assistant professor of Surgery and Biomedical Sciences, both at Cedars-Sinai.

For the research, the team analyzed genetic and molecular data from patients with cancer in a large database. They found evidence of elevated activity of the Onecut2 molecule in tumors of patients whose prostate cancer withstood hormone therapy. Onecut2, a type of transcription factor, is necessary for the body to produce certain proteins.

The team found that Onecut2 interfered with the activity of androgen receptor proteins, the targets of hormone therapy for prostate cancer. This process may allow the cancer to become less dependent on growth hormones. At the same time, Onecut2 led some of the cancer cells to become a more aggressive variety that resists hormone therapy. "These twin Onecut2 actions could help explain how certain prostate cancers evade hormone therapy and become more aggressive," said Freeman, professor of Surgery and Biomedical Sciences.

In additional experiments with human tissue samples, pharmaceutical databases and laboratory animals, the researchers identified a compound, CSRM617, which counteracted Onecut2. They showed that CSRM617 significantly reduced the size of prostate cancer metastases in mice. "Our research suggested that Onecut2 is a master regulator of lethal prostate cancer that may be a useful therapeutic target in up to a third of patients whose cancer spreads and evades hormone therapy," Freeman said.

Freeman was also the corresponding author of a recent study in the journal. Cancer research who identified a new method to measure the aggressiveness of prostate cancer. This method is based on the stability of the cell nuclei forms of cancer. Instability was associated with cancers that spread. The researchers also found that they could detect the instability of the nuclei in the bloodstream through the cells removed by the tumor. These findings could lead to less invasive techniques to identify potentially dangerous prostate cancer and monitor its progression through blood samples, the research team said.

"These discoveries are emblematic of the paradigm shift work that is taking place in cancer at Cedars-Sinai," said Dan Theodorescu, MD, Ph.D., director of the cancer institute. "They show how our researchers are bringing scientific discovery closer to the clinical development of novel therapies that will impact patients."

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More information:
Mirja Rotinen et al, ONECUT2 is an orientable master regulator of lethal prostate cancer that suppresses the androgen axis, Natural medicine (2018). DOI: 10.1038 / s41591-018-0241-1

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