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," said Victor Velculescu,
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 (74/234) of colon
cancer samples, as well as 27 percent (4/15) of
glioblastomas, 25 percent (3/12) of gastric cancers, 8
percent (1/12) of 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,"
Velculescu said. "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, 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, all of the Johns Hopkins Kimmel Cancer
Center and Howard Hughes Medical Institute.
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