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The p53 protein — a protein that controls cell division and plays a key role in the prevention of tumor growth — is the most commonly mutated protein across all cancer types, found in more than half of all tumors. When p53 is mutated, it either loses its ability to block cancer progression or transforms into a driver of disease.

Yuesheng Zhang, M.D., Ph.D., the Harrigan, Haw and Luck Families Chair in Cancer Research and a member of the Developmental Therapeutics research program at VCU Massey Cancer Center, was recently awarded $1.8 million through an R01 grant from the National Cancer Institute. The five-year grant will fund Zhang’s work studying the reactivation of the tumor-fighting functions of mutated p53 proteins through the manipulation of their interactions with another protein.

“This research is significant because it may bring about a paradigm shift in the understanding of the biology and regulation of p53 mutants, which in turn may offer innovative cancer treatment strategies,” said Zhang, who is also a professor in the Department of Pharmacology and Toxicology at the VCU School of Medicine.

Zhang and his research team previously determined that a protein called peptidase D (PEPD) — which is involved in collagen metabolism — naturally binds to the p53 protein and its mutants in cells. Additionally, they found that breaking this natural interaction by temporarily shutting off PEPD production activates p53 and also restores the tumor-suppressing function of the mutated forms of p53.

The project will seek to understand why and how the reactivation of mutated p53 occurs and if various reactivated p53 mutants regain their abilities to fight cancer. Findings could inform the development of novel treatment strategies that target PEPD in an effort to restore the antitumor properties of p53 mutants in many forms of cancer.

“We hope to bring to light a critical reactivation process inherent in p53 mutants, which may have far-reaching implications in p53 research and may break ground for new cancer therapies,” Zhang said.

Written by: Blake Belden