New target for treating wide spectrum of cancers

January 31, 2013

(Medical Xpress)—UC Irvine biologists, chemists and computer scientists have identified an elusive pocket on the surface of the p53 protein that can be targeted by cancer-fighting drugs. The finding heralds a new treatment approach, as mutant forms of this protein are implicated in nearly 40 percent of diagnosed cases of cancer, which kills more than half a million Americans each year.

In a study published online this week in Nature Communications, the UC Irvine researchers describe how they employed a computational method to capture the various shapes of the . In its regular form, p53 helps repair damaged DNA in cells or triggers cell death if the damage is too great; it has been called the "guardian of the genome."

Mutant p53, however, does not function properly, allowing the it normally would target to slip through and proliferate. For this reason, the protein is a key target of research on .

Within cells, p53 proteins undulate constantly, much like a seaweed bed in the ocean, making binding sites for potential difficult to locate. But through a called molecular dynamics, the UC Irvine team created a computer simulation of these physical movements and identified an elusive binding pocket that's open only 5 percent of the time.

After using a computer to screen a library of 2,298 small molecules, the researchers selected the 45 most promising to undergo biological assays. Among these 45 compounds, they found one, called stictic acid, that fits into the protein pocket and triggers tumor-suppressing abilities in mutant p53s.

While stictic acid cannot be developed into a viable drug, noted study co-leader Peter Kaiser, professor of , the work suggests that a comprehensive screening of small molecules with similar traits may uncover a usable compound that binds to this specific p53 pocket.

"The discovery and pharmaceutical development of such a compound could have a profound impact on cancer treatments," Kaiser said. "Instead of focusing on a specific form of the disease, oncologists could treat a wide spectrum of cancers, including those of the lung and breast." He added that there is currently one group of experimental drugs—called Nutlins—that stop p53 degradation, but they don't target protein mutations as would a drug binding to the newly discovered pocket.

The results are the culmination of years of labor by researchers with UC Irvine's Institute for Genomics & Bioinformatics and the Chao Family Comprehensive Cancer Center.

"It's been a large and complex multidisciplinary effort," said Richard Lathrop, professor of computer science and co-leader of the study. "We're working on the leading edge of what's possible, and a variety of skills and expertise is required to make progress. Hopefully, our research eventually will lead to drugs that target many different forms of cancer."

Hartmut Luecke, UC Irvine professor of molecular biology & biochemistry and physiology & biophysics, and Rommie Amaro, an assistant professor of computer science and pharmaceutical sciences who is now at UC San Diego, were other study co-leaders.

Explore further: New drug shrinks cancer in animals, study shows

Related Stories

New drug shrinks cancer in animals, study shows

April 6, 2011

A study led by researchers at the University of Michigan Comprehensive Cancer Center showed in animal studies that new cancer drug compounds they developed shrank tumors, with few side effects.

Drug kills cancer cells by restoring faulty tumor suppressor

May 14, 2012

A new study describes a compound that selectively kills cancer cells by restoring the structure and function of one of the most commonly mutated proteins in human cancer, the "tumor suppressor" p53. The research, published ...

A protein's role in helping cells repair DNA damage

November 1, 2012

(Medical Xpress)—In a new study, University at Buffalo scientists describe the role that a protein called TFIIB plays in helping cells repair DNA damage, a critical function for preventing the growth of tumors.

Cancer biology: Keeping bad company

January 16, 2013

The p53 tumor suppressor protein manages DNA repair mechanisms in response to genetic damage and kills off precancerous cells before they multiply. The loss of p53 due to mutation greatly increases risk of tumorigenesis. ...

Recommended for you

Combination therapy can prevent cytostatic resistance

November 26, 2015

Researchers at Karolinska Institutet have found a new way of preventing resistance to cytostatics used in the treatment of cancers such as medulloblastoma, the most common form of malignant brain tumour in children. The promising ...

Forecasting the path of breast cancer in a patient

November 23, 2015

USC researchers have developed a mathematical model to forecast metastatic breast cancer survival rates using techniques usually reserved for weather prediction, financial forecasting and surfing the Web.


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.