2 Potential New Drug Pathways to a Prostate Cancer Target

ACS grantee's discovery of two new pathways to the well-known protein target, EZH2, may lead to new treatments for prostate cancer.

Grantee: Qi Cao, PhD
Institution: Northwestern University Feinberg School of Medicine in Chicago
Area of Focus: Biochemistry and Immunology of Cancer
Term: 01/01/2016-06/30/2022

“The protein EZH2 is highly expressed in aggressive forms of prostate cancer, and cancer cells without the EZH2 gene cannot survive. Many pharmaceutical companies are developing drugs that target the enzymatic function of the protein EZH2 to silence certain genes that drive cancer. However, this strategy does not work well in solid tumors, like prostate cancer. My investigations focus on the novel functions of EZH2 in prostate cancers in order to find new insights about developing drugs to target the EZH2 protein.”

The Challenge: Proteins called androgen receptors (made by the AR gene) are inside cells of male reproductive tissue. In healthy cells, the male hormone androgen attaches to androgen receptors. Their bond helps guide the development of male sexual characteristics, like hair growth and sex drive.

In prostate cancer, the binding of androgen to androgen receptors causes cancer cells to grow.

Interestingly, though, some types of prostate cancer cells don’t have androgen receptors (AR negative), yet they grow more than those with the receptors. This type of prostate cancer is referred to as castration resistant. This growth suggests that there are other, unknown, factors that control cell growth in prostate cancer.

Understanding how these other unknown factors work to cause unrestricted cell growth has the potential to lead to new treatments for prostate cancer.

The Research: A recent American Cancer Society (ACS) research grantee, Qi Cao, PhD, collected tumors samples from men with prostate cancer that had varying characteristics and expected results after treatment (prognosis). He and his team studied the levels of certain genes in these tumor tissue samples and published their findings in Oncogene.

In the prostate cancer cells that didn’t have androgen receptors, they looked to see what was causing the cancer to grow. They identified that one gene involved in cell growth — CDCA8 — was present in higher levels. The gene CDCA8 codes for the protein CDCA8. Higher amounts of the protein CDCA8 have been reported in multiple types of cancer, and CDCA8 is strongly linked with how aggressive the cancer is and how well someone will do after treatment.

To test the role of CDCA8, Cao’s team decreased the amount of CDCA8 proteins in mice with prostate cancer. The result was that the cancer cells were less aggressive and did not grow tumors as well.  

To learn what caused the increase in CDCA8 proteins, Cao looked at a gene he’d studied beforeEZH2. The protein EZH2 has been studied for more than 10 years and has been linked with over 20 genes that control cell growth in cancer. In a previous study, his lab discovered that men who had prostate cancer with higher numbers of the protein EZH2 have shorter survival times compared with men with prostate cancer that has low numbers, or no amount, of, EZH2 in the tumor.

In this study, he found two different ways by which the gene EZH2 can increase levels of the protein CDCA8. Both ways should be studied as potential new targets for drugs that may to treat prostate cancer.

Why It Matters: Previous studies have found that that changing EZH2 can increase how frequently cells divide and how long they live. EZH2 has been found to be related to the start of cancer (initiation), the spread of cancer (metastasis), resistance to anti-cancer drugs, how cancer cells use energy, and how they affect the body’s immunity. So targeting EZH2 as a type of cancer treatment is a hot research topic and different types of EZH2 inhibitors have been developed for several types of cancer, including breast, kidney cancer, multiple myeloma, non-Hodgkin lymphoma, and ovarian cancer.

Cao’s finding that EZH2 can increase levels of CDCA8 in prostate cancer in two different ways suggests that scientists may be able to develop drugs that target EZH2 along two paths, which could more completely slow the production of CDCA8, and hopefully result in a more effective treatment.