With a $3.4 million, five-year grant from the National Cancer Institute, UF Health Cancer Center researchers will study how a novel small-molecule drug could be used to enhance immunotherapy treatments for melanoma, the deadliest skin cancer.
The project builds on the team’s recent development of a compound called a proteolysis-targeting chimera (PROTAC) to target an intracellular protein in the tumor microenvironment that has been shown to contribute to tumor development and plays a vital role in suppressing the immune system’s ability to battle cancer.
The team found that the PROTAC effectively degraded the protein, nuclear receptor subfamily 4 group A member 1 (NR4A1), in laboratory and mouse testing in melanoma and colorectal cancer models. That finding indicated its potential as a small-molecule-based therapy to complement existing immunotherapy treatments or provide new options for patients who are resistant or do not respond to immunotherapy.
“The current grant will support our team effort in the development of novel NR4A1 PROTACs with better efficacy, lower toxicity and broader cancer treatment potential.”
– Weizhou Zhang, Ph.D.
The new project is co-led by Weizhou Zhang, Ph.D., the Dr. and Mrs. James Robert Spencer Professor of Pathology in the department of pathology, immunology and laboratory medicine in the UF College of Medicine, Guangrong Zheng, Ph.D., a professor in the department of medicinal chemistry in the UF College of Pharmacy, and Keiran Smalley, Ph.D., a professor and director of the Donald A. Adam Melanoma and Skin Cancer Center of Excellence at Moffitt Cancer Center.
The team aims to establish NR4A1 as a valid therapeutic target for melanoma and further develop the NR4A1 degrader using PROTAC technology.
Using living organism models and cancer specimens, the research team will determine the mechanisms underlying how the small-molecule drug works to promote an immune response and how the drug could ultimately be used as a single agent or in combination with other drugs to treat melanoma or other deadly cancers.
“The current grant will support our team effort in the development of novel NR4A1 PROTACs with better efficacy, lower toxicity and broader cancer treatment potential,” Zhang said. “Our goal is to develop one lead compound for potential translation in cancer immunotherapy for different cancer types such as melanoma, renal cancer and others.”
