Radiation Therapy “By inhibiting miR-21 in localized prostate cancers, we could potentially reduce the amount of radiation needed for primary or salvage radiation therapy – or achieve a greater cancer-killing effect with standard radiation doses.”

In the search for better treatments for prostate cancer, protein-coding genes – genes that make proteins that cancer needs to grow and spread – have been a major focus of scientific attention. “Proteins are often good targets for cancer drugs,” says scientist Shawn Lupold, Ph.D., the Catherine Iola and J. Smith Michael Distinguished Professor in Urology, “because they contain unique features that can be specifically targeted with tiny molecules or antibody-based therapies. However, there is an entirely different class of genes that contribute to prostate cancer growth but do not encode a single protein.”

These non-coding genes “are proving to be novel biomarkers and therapeutic targets for cancer,” explains Theodore DeWeese, M.D., a pioneer professor of radiation oncology and molecular radiation sciences, who brought the first gene therapy for prostate cancer to clinical trial at Hopkins. Instead of proteins, these genes make RNA molecules, “which are more difficult to target with small molecules and antibodies.” Lupold and DeWeese are developing strategies for prostate cancer radiation therapy aimed at specific RNA molecules, called microRNAs.

For more than 20 years, Lupold’s laboratory has been studying microRNAs in prostate cancer – particularly, one promising microRNA gene: miR-21 “This microRNA is highly active in multiple types of cancers, and is believed to drive cancer development, growth, metastasis, and resistance to treatments,” Lupold says. In previous studies, Lupold and colleagues showed that miR-21 is upregulated in prostate cancer, associated with high Gleason grade, and capable of driving resistance to hormonal therapy. Lupold and DeWeese recently made another discovery about miR-21: it plays an important role in how prostate cancer cells respond to radiation therapy. “We were looking to identify microRNAs that inhibited DNA repair and enhanced the cell-killing effects of radiation therapy,” says DeWeese, “but we found that miR-21 caused the opposite effect. Cells that received miR-21 appeared resistant to radiation therapy, with almost three times more cancer cells surviving radiation treatment!” Shireen Chikara, a postdoctoral fellow working with Lupold and DeWeese, has validated these findings in several different prostate cancer cell models. Importantly, her work found that inhibiting miR-21 made radiation therapy even more effective.

Chikara has used two different strategies to block miR-21 in prostate cancer: natural chemicals that prevent cells from making miR-21, and RNA-based miR-21 inhibitors. “By directly injecting miR-21 inhibitors, I have been able to significantly reduce the levels and activity of miR-21 in human prostate tumors grown in mice,” she says. Chikara’s work has exciting implications for radiation therapy, notes DeWeese: “Radiation resistance is a significant factor contributing to the progression of localized prostate cancers following unsuccessful primary or salvage radiation therapy. By inhibiting miR-21 in localized prostate cancers, we could potentially reduce the amount of radiation needed for primary or salvage radiation therapy – or achieve a greater cancer-killing effect with standard radiation doses.”