Researchers
Find 3 Tumor Suppressor Genes that Reduce Lung Cancer in Mice
Researchers at The University of Texas M. D. Anderson Cancer Center
and The University of Texas Southwestern Medical Center at Dallas
have identified three lung-cancer tumor suppressor genes on chromosome
3 that dramatically reduced human lung cancer growth in mice and for
which gene therapy trials with humans will begin within a year.
Researchers at both UT institutions,
working under a joint National Cancer Institute Specialized Program
of Research Excellence (SPORE) in Lung Cancer grant, published their
findings in the May 1 issue of Cancer Research.
Dr. John Minna, senior author
of the study, director of the Nancy B. and Jake L. Hamon Center
for Therapeutic Oncology Research at UT Southwestern and principal
investigator for the UT SPORE in Lung Cancer, said this research
has been under way for 10 years. Working from a set of about 20
genes previously identified as possible tumor suppressors, UT Southwestern
researchers homed in on a small region of chromosome 3, where they
identified eight possible tumor-suppressor genes.
Under the direction of Dr.
Jack Roth, chairman of the Department of Thoracic and Cardiovascular
Surgery at M. D. Anderson and co-principal investigator for the
UT SPORE in Lung Cancer, M. D. Anderson researchers tested six of
the genes' effectiveness as tumor suppressors using their new adenovirus
technology. They found three genes -- 101F6, NPRL2 and FUS1 -- that
not only inhibited tumor growth and metastasis, but induced human
lung cancer cell death.
Dr. Roth said the discovery
of this chromosomal 3p region is the earliest genetic change detected
in the process of lung cancer development. The significance of the
finding could be far-reaching, he said, with greater opportunity
for earlier detection, diagnosis, prevention and treatment of lung
cancer.
"Discovering a region
on a chromosome, as opposed to a single gene, that contributes to
cancer development is novel," said Dr. Roth. "This is
the earliest genetic change yet identified in lung cancer, a change
that can take place in normal-looking lung tissue."
Dr. Minna, who also directs
the W.A. "Tex" and Deborah Moncrief Jr. Center for Cancer
Genetics, said, "We saw that the 3p genes triggered apoptosis,
the natural process of cell death, in cancer cells. But putting
the same genes in normal human lung epithelial cells didn't kill
those cells."
The 3p genes were used to treat
human lung cancers growing in mice, and the treatment caused a dramatic
regression of the tumors, Dr. Minna said. The researchers also introduced
cancer systemically -- injecting malignant cells intravenously into
mice and allowing them to form tumors around the body as metastases
-- then introduced the 3p gene therapy in the same fashion. They
found that the systemic therapy also was effective in reducing the
metastatic tumors. A virus genetically engineered to be harmless
was used to deliver the genes.
"We used Dr. Roth's adenovirus,"
Dr. Minna said. "There was no toxicity, and it looks like we
can deliver enough tumor suppressor genes to cure the mice."
One of the genes pinpointed
in the study, FUS1, will be brought forward into a Phase I clinical
trial led by Dr. Roth, a world leader in gene therapy of lung cancer
and director of the W. M. Keck Center for Cancer Gene Therapy at
M. D. Anderson. The clinical trial, recently approved by the National
Institutes of Health Recombinant DNA Advisory Committee, will be
conducted jointly at M. D. Anderson and UT Southwestern. In that
trial, expected to start in about six months to a year, patients
with lung cancers will receive the gene therapy, delivered in a
lipid "capsule" that is injected and binds to tumors in
the body.
"This study, another
productive collaboration with Dr. Minna and his team at UT Southwestern,
is an excellent example of translational research," Dr. Roth
said. "The team in Dallas identified the region on the chromosome,
while the M. D. Anderson group analyzed the function of the genes,
and together we are using the information to develop and improve
treatment strategies for patients."
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