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Study identifies a genetic driver of deadly prostate cancer



Study identifies a genetic driver of deadly prostate cancer

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

A new study has identified a new molecular driver for 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 can 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.

Men whose prostate cancer tumors are located typically survive many years after diagnosis, whether they have surgery, radiation therapy, 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 poor, with less than a third surviving five years after diagnosis. More than 29,000 men in the US die of prostate cancer each year, according to the American Cancer Society.

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

Freeman was the corresponding author of the multi-institutional study, published in the journal natural medicine. The first co-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 cancer patients in a large database. They found evidence of high activity of the Onecut2 molecule in tumors of patients whose prostate cancer resisted hormone therapy. Onecut2, a type of transcription factor, is required for the body to produce certain proteins.

The team found Onecut2 interfered with the activity of androgen receptor proteins, the targets of hormone therapy for prostate cancer. This process can allow the cancer to become less dependent on hormones for growth. At the same time, Onecut2 has led some of the cancer cells to switch to a more aggressive variety that resists hormone therapy. "These twin actions of Onecut2 may help explain how certain types of prostate cancer prevent hormone 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, which neutralized Onecut2. They showed that CSRM617 significantly reduced the size of prostate cancer metastases in mice. "Our research suggests that Onecut2 is a master regulator of lethal prostate cancer that can be a useful therapeutic target in up to one-third of patients whose cancer spreads and avoids hormone therapy," Freeman said.

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

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


Explore more:
Surgery and combination therapy optimize results in aggressive treatment of prostate cancer

More information:
Mirja Rotinen et al., ONECUT2 is a directional master regulator of lethal prostate cancer that suppresses the androgenic axis, natural medicine (2018) DOI: 101038 / s41591-018-0241-1


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