Researchers at the UC Davis Comprehensive Cancer Center have shown that the microRNA, miR-124, reduced tumor growth and increased cell death in castration-resistant prostate cancer. This small RNA fragment hit multiple targets, reducing androgen receptor signaling and reviving the potency of enzalutamide, a treatment for advanced prostate cancer. In addition, miR-124 impeded EZH2 and Src, proteins that contribute to treatment resistance. The research was published today in Cancer Research.
“Castration-resistant prostate cancer kills about 29,000 men in this country each year; it’s why men die from prostate cancer,” said Ralph de Vere White, director of the UC Davis Comprehensive Cancer Center and senior author on the paper. “But miR-124 shows great promise – you can give it systemically, it stops tumor growth and it makes enzalutamide more effective.”
Prostate cancer feeds on androgens, or male hormones, making androgen-deprivation therapy the mainline treatment for many men with metastatic prostate cancer. But over time, tumors learn to grow without androgens, requiring new treatments, such as enzalutamide, which inhibits androgen receptors.
This can work for a while, but prostate cancers soon develop resistance. Specifically, advanced tumors can produce androgen receptor splice variants (receptors with missing pieces) making it difficult for enzalutamide to hook on – like climbing a ladder after the bottom rungs have been removed. In addition, these mutations can promote cancer aggressiveness.
“Splice variants act like normal androgen receptors that are turned on all the time,” noted de Vere White.
The answer may be miR-124, a small, non-coding RNA that can block a number of targets associated with cancer resistance and aggression.
In the study, miR-124 was married to polyethylenimine nanoparticles, which helped deliver the molecules to human tumors in mice. Once inside the tumors, miR-124 successfully downregulated androgen receptors, including several splice variants, as well as oncoproteins EZH2 and Src. In addition, the microRNA helped boost anti-tumor protein p53 and increased apoptosis (programmed cell death).
Equally important, miR-124 rebooted enzalutamide against resistant cancer, providing a potent one-two punch. Enzalutamide alone was effective in 10 percent of resistant cells lines. However, the drug’s efficacy increased to 68 percent when combined with miR-124.
This work was supported in part by funding from NIH R01CA136597, Department of Defense grants PC080488 and PC111467, Stand Up To Cancer – Prostate Cancer Foundation-- Prostate Dream Team Translational Cancer Research Grant SU2C-AACR-PCF DT0812 and Medivation/Astellas.
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