UC Department of Environmental Health and Cincinnati Cancer Center (CCC) researchers were awarded grants from the United States Department of Defense to continue genetic research on metastatic prostate cancer.
Shuk-Mei Ho, PhD, Jacob G. Schmidlapp Professor and Chair of Environmental Health at UC and director of the CCC, says this federal funding, which is becoming hard to obtain for researchers across the country, is important to advance scientific findings and gain additional financial support.
"Prostate cancer is the most common cancer and the second leading cause of cancer deaths, after lung cancer, among men in the U.S.,” she says. "Studies like the ones being conducted by these researchers are needed to in order change these facts. I’m very pleased that our researchers were chosen to receive these competitive grants and hopefully make strides in the development and treatment of cancer.”
Targeting Drug-Resistant Prostate Cancer
Pheruza Tarapore, PhD, assistant professor in the Department of Environmental Health and a member of the CCC, was presented with the Idea Award, $375,000 over three years, to continue her research on treatment resistant prostate cancer.
"A substantial proportion of patients develop metastases after receiving primary-tumor therapy for prostate cancer, even if the primary tumor appears to only be in the prostate gland at first diagnosis,” she says. "Also, a large number of advanced prostate cancer cases have become androgen-independent, meaning that the cancer can thrive even through hormone therapy. There is an urgent need to come up with new treatment regimens for these patients.”
She says clinical trials with the drug abiraterone showed significant effects on these patients’ survival, leading to Food and Drug Administration (FDA) approval of this drug; however, patients do develop resistance.
"The identification of the markers responsible for blocking this drug is important for designing therapeutic interventions sensitizing prostate cancers to combination abiraterone therapies and for prognostic applications to monitor and predict relapse,” Tarapore continues. "Abiraterone inhibits CYP17A1—a critical enzyme in hormone biosynthesis—in the adrenals and has direct effects on prostate cancers. Therefore, in this study, we hope to use prostate cancer animal models to identify changes in expressions of microRNA during treatment with the drug.”
She adds that the team will develop a combination therapeutic approach to treat prostate cancer with Abiraterone and RNA therapy.
"The cell-surface receptor called prostate specific membrane antigen, or PSMA, is associated with a higher chance of tumor growth. It is currently used as a tumor marker for diagnosis, monitoring and prognosis of prostate cancer,” Tarapore says. "Elevated levels of PSMA are also used as an independent marker for predicting disease relapse. We will use an RNA aptamer—single-stranded RNA molecules that can bind to pre-selected targets, like prostate cancer cells—to deliver the microRNA with hopes of sensitizing tumors, and revealing the cause of abiraterone resistance.
"We also think that RNA therapy—restoring or targeting micro RNA—should increase sensitivity to the abiraterone-resistant tumors, allowing us to prolong treatments, and eventually, the life of a patient. We hope our findings will lead us toward a more targeted, tissue-specific approach to treating this type of cancer. This strategy could be a major breakthrough in RNA therapy, which could later be extended towards other target genes and cancers.”
Members of the research team also include Yuet-Kin (Ricky) Leung, PhD, assistant professor of environmental health at UC, and Ho.
Using MicroRNA-765 to Stop Prostate Cancer in Its Tracks
Ana Cheong, PhD, a post-doctoral fellow in Ho’s lab, received the Postdoctoral Training Award, totaling $115,000 over two years, to study ways microRNA-765 could be used to stop the progression of prostate cancer.
"Although early screening for elevated prostate serum antigen, a predictor of prostate cancer, improved the outcomes for patients, there is currently no cure for metastatic prostate cancer,” Cheong says. "The need for finding an approach for advanced metastatic prostate cancer-specific therapeutic strategies stirred my interest in the prostate cancer field, and my goal is to explore the use of microRNAs as a tool for prostate cancer-specific therapy.”
She says fulvestrant, an antiestrogen, drug approved by the FDA for treating metastatic breast cancer, has been shown to be beneficial and can increase the lifespan of metastatic prostate cancer patients in clinical trials. However, the effect doesn’t always last and may cause drug resistance.
"To address these issues, my project will focus on the tumor-suppressing ability of microRNAs associated with fulvestrant. MicroRNAs regulate expression of multiple cancer-causing genes. Some of our recent research shows that microRNA-765 inhibits prostate cancer cells from being aggressive and that it could be used therapeutically to control prostate cancer advancement and metastasis by changing the expression of multiple oncogenes,” she says.
Cheong says with her mentors, she will dissect the role of a set of microRNA-765 targeted genes to hopefully unveil how their change in expression alters prostate cancer cell growth and sensitivity to therapeutic drugs.
"Our next step is to design a therapeutic delivery vehicle to specifically deliver microRNA-765 to prostate cancer cells and stop tumor-causing functions,” Cheong says, adding that this research will be done in human cell cultures and animal models. "Findings from this study will reveal the tumor-suppressing effect of microRNA-765 during prostate cancer cell growth and metastasis by stopping expression of multiple oncogenes. The proposed outcome of a prostate cancer-specific microRNA therapy could revolutionize RNA therapeutic strategies for treating this cancer.”
Members of the mentor team include Leung, Tarapore, and Ho.