Johns Hopkins gene hunters pinpoint new cancer gene target

Scientists at the Johns Hopkins Kimmel Cancer Center and Howard Hughes Medical Institute have found mutations in a gene linked to the progression of colon and other cancers. The research findings, published online in the March 11 issue of Science, may lead to new therapies and diagnostic tests that target this gene.

The gene in which the mutations have been found, called PIK3CA, is part of a family of genes encoding lipid kinases, enzymes that modify fatty molecules and direct cells to grow, change shape and move. Although scientists have been studying the biochemical properties of this family of genes for more than a decade, until now, no study revealed that they were mutated in cancer.

Kinases have been the focus of recent drug development strategies, with some kinase-inhibiting compounds, such as Gleevec and Herceptin, already being used clinically to inhibit tumor growth.

“These findings open the door to developing specific therapies that may prove useful for the treatment of cancers with mutations in PIK3CA,” says Victor Velculescu, M.D., Ph.D., assistant professor of oncology and senior author of the research.

In their current experiments, the scientists sequenced the molecular code of the genes in this lipid kinase family and found mistakes in the nucleotides, or DNA building blocks, in one particular gene, called PIK3CA. Each mistake is a result of one nucleotide being switched for another. PIK3CA mutations were found in 32 percent of colon cancer samples (74/234), as well as 27 percent (4/15) of glioblastomas, 25 percent (3/12) of gastric cancers, 8 percent (1/12) breast cancers and 4 percent (1/24) of lung cancers. By studying 76 additional premalignant colon tumors, the scientists found that PIK3CA mutations may occur at or near the time a tumor is about to invade other tissues.

The investigators demonstrated that the mutations increase PIK3CA kinase activity, which can start a cascade of cellular events that spark a normal cell to grow uncontrollably and become cancerous.

“We envision future cancer therapy as personalized, based on gene mutations in each patient’s tumor,” says Velculescu. “This kind of information, gleaned from sequencing a patient’s tumor, means drugs could be targeted to just the right molecular pathway at just the right time and potentially be more effective with fewer side effects.”

Most of the PIK3CA mutations described in the current paper are located in two DNA cancer “hot spots,” thus making molecular diagnostic tests possibly easier to develop. “These mutations, added to a panel of existing markers for colon cancer developed in our laboratory, could help find cancers that would otherwise go undetected,” says Yardena Samuels, Ph.D., postdoctoral fellow and first author of the study.

The researchers are now looking more closely at the role of PIK3CA in tumor development and are working on identifying compounds that could target tumors with mutations in this gene.

This research was funded by the Ludwig Trust, the Benjamin Baker Scholarship Fund, the EMBO Fellowship Fund and grants from the National Institutes of Health.

Other participants of this research include Zhenghe Wang, Alberto Bardelli, Natalie Silliman, Janine Ptak, Steve Szabo, Gregory J. Riggins, Kenneth W. Kinzler and Bert Vogelstein of the Johns Hopkins Kimmel Cancer Center and Howard Hughes Medical Institute; Hai Yan of Duke University Medical Center; Adi Gazdar of UT Southwestern Medical Center; Steven M. Powell of the University of Virginia Health System; and James K.V. Willson and Sanford Markowitz of the Howard Hughes Medical Institute and Ireland Cancer Center, University Hospitals of Cleveland and Case Western University.