Researcher earns multiple R01 grants

Powered by four R01 grants from the National Cancer Institute, UK Markey Cancer Center researcher Xiaoqi Liu, PhD, is unraveling the secrets of a mysterious enzyme that may be to blame for hard-to-treat prostate cancer.

Liu, chair and professor in the toxicology and cancer biology department at the UK College of Medicine and the Lucille P. Markey Endowed Chair in Oncology Research, has spent his career researching the role that the enzyme polo-like kinase 1 (Plk1) plays in cancer, with the goal of developing novel treatments for patients with the disease. His current work, which focuses on enhancing therapy outcomes for patients with prostate cancer, is funded by four R01 grants from the NCI, totaling more than $1 million per year for five years in research support and making Markey a hub of innovative prostate cancer research.

“With almost all of the available therapies in prostate cancer, patients will eventually develop resistance,” Liu explained. “The goal of my research is to understand the basic mechanisms of this therapy resistance and then devise new approaches that enhance the efficacy or overcome the resistance of particular types of therapy.”

“The goal of my research is to understand the basic mechanisms of this therapy resistance and then devise new approaches that enhance the efficacy or overcome the resistance of particular types of therapy.” Xiaoqi Liu, PhD

All four of the R01 grants focus on uncovering how Plk1 – an important signaling pathway that is prominent in some tumors – can be targeted with new therapies to kill cancer cells, specifically in castration-resistant prostate cancer (CRPC) that is unaffected by a common type of drug called androgen signaling inhibitors (ASIs). Although ASIs are one of the current standards of care for CRPC, they have been shown to improve overall survival for patients for only several months.

Liu’s lab’s research is homing in on four distinct areas of focus:

• Overcoming drug resistance for CRPC: Under this grant, Liu and his team are attempting to define how Plk1 activates androgen receptor (AR) signaling and demonstrate its importance as a therapeutic target in CRPC.
• Improving chemotherapy for CRPC: This research is analyzing whether Plk1-associated activity impacts AR signaling, which, in turn, causes the prostate cancer to build up resistance to docetaxel – a current standard of care for metastatic CRPC. Liu’s team is testing whether a combination therapy with docetaxel plus a Plk1 inhibitor may improve patient survival.
• Treatment of CRPC: Through this grant, Liu’s team is investigating whether Plk1 plays a role in regulating the β-catenin pathway, which is known to cause significant genomic alterations in CRPC and can make the disease harder to treat. The research is examining the potential impact of combination therapy with a Plk1 inhibitor and a β-catenin pathway inhibitor in the treatment of metastatic CRPC.
• Enhancing anti-neoplastic activity of metformin in prostate cancer: Using the established and widely used diabetes drug metformin, which may inhibit the development of CRPC, Liu and his group are investigating whether combining it with a Plk1 inhibitor is helpful in treating ASI-resistant CRPC.

With prostate cancer being the most common cancer diagnosis and the leading cause of cancer death among men, Dr. Peng Wang, genitourinary and prostate cancer oncologist at Markey, says finding a new way to treat the disease is critical and targeting Plk1 could be a promising approach.

“In collaboration with Dr. Liu’s lab, we’re working to develop multiple clinical trials for our prostate cancer patients that will target Plk1 to see if it can either delay resistance or even resensitize patients to other treatment,” he said. “And this would be very, very helpful for our patients.”

R01 grants from the NCI support healthrelated research projects, covering most of the associated research costs for a three- to five-year span. Most scientists strive to earn R01 grants to support their research across their careers; having four selected for funding simultaneously is a significant accomplishment.

In 2018, more than 28,000 new R01 applications were reviewed by the National Institutes of Health, but fewer than 5,000 were awarded funding. As of October 2019, Markey has 72 active R01 grants through the NCI, and Liu serves as principal investigator for more than any other researcher on that list.