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Genetic Factor Discovered in Metastatic Prostate Cancer

Cancer cells. 

Because prostate cancer cases are often localized and controlled, men can survive many years after diagnosis. However, that is not the case for metastatic castration-resistant prostate cancer (mCRPC): after diagnosis, less than a third of men survive five years.

In the treatment of prostate cancer, hormone therapy is commonly used to suppress androgen receptors in order to prevent testosterone from being produced, thereby killing the malignant tumor. Unfortunately, this does not work for mCRPC.

Michael Freeman, PhD, Co-Director of the Cancer Biology Program in the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai, stressed the importance of finding preventative measures for mCRPC: "We need fresh strategies to prevent prostate cancer from turning deadly for the thousands of men whose disease metastasizes and withstands hormone therapy."

Findings from a study by Dr. Freeman and colleagues, published in Nature Medicine, show that a potential treatment can emerge from identifying genetic drivers for mCRPC. The transcription factor Onecut2 (OC2) was found to be elevated in men with mCRPC. Onecut2 helps metastatic prostate tumors to grow by interfering with androgen receptors, making the cancer less dependent on testosterone for survival. In addition, OC2 transforms cancer cells into a more aggressive type that is able to resist hormone therapy.

Dr. Freeman explained, "These twin actions of OC2 could help explain how certain prostate cancers evade hormone therapy and turn more aggressive."

In mice, the researchers were able to identify a compound, CSRM617, that is capable of counteracting OC2. CSRM617 was able to reduce metastatic tumor size in mice. Further research will need to be conducted to confirm if this compound works in humans.

"Our research suggested that OC2 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," commented Dr. Freeman.

Dr. Freeman also worked on another study, published in Cancer Research, that found an instrumental way of determining prostate malignancies' level of aggression based on the shape of the nuclei of cancer cells and the presence of metastasized cells in the bloodstream. These new methods of measuring cancer aggression can lead to less invasive ways of detecting and monitoring prostate malignancies.

According to Dan Theodorescu, MD, PhD, Director of the the Samuel Oschin Comprehensive Cancer Institute, "These discoveries are emblematic of the paradigm-shifting work that is being carried out in cancer at Cedars-Sinai. They show how our investigators are bridging scientific discovery to clinical development of novel therapies that will impact patients."

For More Information

Reis-Sobreiro M, Chen JF, Novitskya T, et al (2018). Emerin deregulation links nuclear shape instability to metastatic potential. Cancer Res, 78(21):6086-6097. DOI:10.1158/0008-5472.CAN-18-0608

Rotinen M, You S, Yang J, et al (2018). ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis. Nat Med. [Epub ahead of print] DOI:10.1038/s41591-018-0241-1

Image courtesy of Dr. Cecil Fox

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