Newswise — New Brunswick, N.J., May 14, 2012 – Investigators at The Cancer Institute of New Jersey (CINJ) and the Institute for Advanced Study (IAS) in Princeton, N.J., have identified and validated a drug compound that reactivates a primary function in a mutated form of the p53 protein – the ability to suppress cancer tumors. CINJ is a Center of Excellence of the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School.
More than three decades of research into the p53 protein has substantiated its role as one of the most important regulators of human cancer. P53 has been called “the guardian of the human genome” where it serves to recognize cellular stress and puts the brakes on cell proliferation to allow the cell to either recover from the stress or kill the cell if the damage is irreparable. Loss of p53 function is one of the most common ways that cancer cells escape this control and proliferate freely.
The gene encoding p53 is mutated in more than half of human cancers. Most of these mutations result in a small change in the amino acid makeup of the protein, rendering it nonfunctional. Research on animal models of cancer has shown that restoring p53 function has been both highly therapeutic and, in some cases, curative. Rescuing the function of p53 with a drug is seen as a highly attractive cancer therapeutic strategy, and currently no available drugs exist in the clinic that restore p53 function.
Researchers on this study include CINJ resident member Arnold J. Levine, PhD, professor of pediatrics and biochemistry at UMDNJ-Robert Wood Johnson Medical School and professor emeritus at the Simons Center for Systems Biology in the School of Natural Sciences at IAS, who co-discovered p53 more than 30 years ago. The team developed a computer screening methodology that identified a compound that selectively kills cancer cells with the p53R175 mutation, which is the third most frequent type of p53 mutation in human cancer. The findings are in the current online edition of the journal Cancer Cell (doi: 10.1016/j.ccr.2012.03.042).
Utilizing anticancer drug screen data from the National Cancer Institute, in which over 48,000 compounds have been tested across a panel of 60 human tumor cell lines, investigators identified the compound known as NSC319726 as one that restores “wild-type” structure and function to the p53R175 protein. This compound not only restores “wild-type” structure to p53, but also activates the protein to induce a program to kill the cell (known as apoptosis). This observation occurs at doses of the compound that are non-toxic to normal (non-cancerous) cells. When the compound was tested on human tumor cell lines with the mutation in experimental models, cell death was evident and tumor growth was blocked. The p53R175 mutant is nonfunctional because this mutant fails to bind zinc which is required for normal structure and function of p53 protein. One reason that may explain the specificity of NSC319726 for the p53R175 mutation (and not other mutations) is that NSC319726 binds zinc and affects intracellular zinc concentrations. The researchers hypothesize that NSC319726 may be working to restore the structure of the p53R175 mutant by providing a source of zinc ion to allow the mutant protein to revert to the normal p53 structure. Because of its ability to selectively kill cancer cells while leaving normal ones undisturbed, the authors say NSC319726 can be considered a lead compound for targeted drug development in p53 and may allow for the design of other compounds for different p53 mutations that fail to bind zinc.
“The R175 mutation is the third most common p53 mutation – resulting in some 32,000 affected people in the U.S. annually. While more research is needed, this is a large population that may find benefit from the NSC319726 compound in its ability to restore p53 tumor suppressor properties,” said Darren Carpizo, MD, PhD, surgical oncologist at CINJ, who is the senior author of the research. “Our findings support the growing trend in developmental therapeutics in which the efficacy of future cancer drugs will depend upon the knowledge of the patient’s tumor genotype,” noted Dr. Carpizo, an assistant professor of surgery at UMDNJ-Robert Wood Johnson Medical School, who also just received a $200,000 2012 Pancreatic Cancer Action Network-AACR Career Development Award to support continued early-phase development of NSC319726 as a potential anti-cancer drug.
Along with Carpizo, the author team consists of Xin Yu, CINJ and UMDNJ-Robert Wood Johnson Medical School; and Alexei Vazquez and Dr. Levine, both CINJ, UMDNJ-Robert Wood Johnson Medical School, and IAS.
The research was supported by CINJ (Carpizo), The Breast Cancer Research Foundation (Levine), and the National Institutes of Health (P01CA87497, Levine).
About The Cancer Institute of New JerseyThe Cancer Institute of New Jersey (www.cinj.org) is the state’s first and only National Cancer Institute-designated Comprehensive Cancer Center dedicated to improving the detection, treatment and care of patients with cancer, and serving as an education resource for cancer prevention. CINJ’s physician-scientists engage in translational research, transforming their laboratory discoveries into clinical practice, quite literally bringing research to life. To make a tax-deductible gift to support CINJ, call 732-235-8614 or visit www.cinjfoundation.org. CINJ is a Center of Excellence of the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School. Follow us on Facebook at www.facebook.com/TheCINJ. The CINJ Network is comprised of hospitals throughout the state and provides the highest quality cancer care and rapid dissemination of important discoveries into the community. Flagship Hospital: Robert Wood Johnson University Hospital. System Partner: Meridian Health (Jersey Shore University Medical Center, Ocean Medical Center, Riverview Medical Center, Southern Ocean Medical Center, and Bayshore Community Hospital). Major Clinical Research Affiliate Hospitals: Carol G. Simon Cancer Center at Morristown Medical Center, Carol G. Simon Cancer Center at Overlook Medical Center, and Cooper University Hospital. Affiliate Hospitals: CentraState Healthcare System, JFK Medical Center, Robert Wood Johnson University Hospital Hamilton (CINJ Hamilton), Somerset Medical Center, The University Hospital/UMDNJ-New Jersey Medical School*, and University Medical Center at Princeton. *Academic Affiliate
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