Discovery
January 22, 2016

Your dishwasher is broken again. You've kept it going, but maybe you've fixed it too often; maybe it needs to go. On the molecular level, your body faces similar dilemmas all the time when it comes to fixing damaged DNA. DNA is a precious thing, and the body works hard to keep it in good shape, but there's a delicate balance, explains Brady scientist Shawn Lupold, Ph.D., the Frank Hinman Scholar: "Too little DNA repair can lead to an accumulation of changes — to uncontrolled cell growth, cancer development, or even cancer progression. On the other hand, too much DNA repair can be detrimental, too, if it helps cancer cells resist treatment like chemotherapy or radiation.”

Although cancer biologists know a lot about how to work with and around some of the body's DNA-fixing mechanisms, there's a new repairman in town, genetically speaking: A newly discovered class of genes called microRNAs. Lupold has been studying these genes and their role in the development and progression of prostate cancer with other Brady scientists, including Theodore L. DeWeese, M.D., Ph.D., the Sidney Kimmel Professor and Director of Radiation Oncology and Molecular Radiation Sciences. Although what microRNAs do is very complicated and is still not fully understood, basically they send messages that produce action. "Each microRNA gene encodes a short RNA transcript" that results in "selectively turning off the synthesis of specific proteins and enzymes," says Lupold.

In a recent study with DeWeese and Koji Hatano, a visiting urologist and fellow from Osaka University in Japan, Lupold learned more about how microRNAs regulate DNA repair pathways in cancer cells. "Using a novel and high-throughput screening strategy, our team evaluated more than 800 different human microRNAs," says Lupold. They were looking for microRNAs that seemed especially adept at inhibiting DNA repair and sensitizing prostate cancer cells to radiation therapy — for a new weapon that would not only make radiation therapy more powerful against prostate cancer, but would also hinder the cancer cells' ability to recover from the attack. This work was published in April in the journal, Nucleic Acids Research. Hatano, who was first author on the paper, identified miR-890 as "one of the most potent radiation-sensitizing microRNAs in the study," says Lupold. This particular microRNA "inhibited the ability of cancer cells to repair the most lethal type of DNA damage, double-stranded breaks. This led to an over 50-percent increase in prostate cancer cell sensitivity to ionizing radiation. Most importantly, we demonstrated that miR-890 specifically targets and inhibits the expression of multiple DNA repair genes and pathways."

In laboratory studies, the team injected the microRNA into established prostate tumors in mice, and two days later treated the animals with radiation therapy. "The tumors treated with miR-890 were significantly reduced in size and growth when compared to controls," says Lupold. The next step, currently being worked on by Lupold and DeWeese, is to find the best way to deliver these microRNAs to prostate cancers, "with the ultimate goals of selectively sensitizing prostate cancer tumors to radiation and chemotherapy, while sparing the healthy tissues right next to the cancer." In other studies of microRNAs, Lupold's lab is exploring the role of these genes in other aspects of prostate cancer, such as androgen signaling.