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.”
The collaboration between lung-cancer researchers at M. D. Anderson and UT Southwestern began in 1996 when the joint program was awarded a $4.5 million SPORE grant from the NCI to accelerate research and improve therapy for lung cancer.
Other researchers from M. D. Anderson who contributed to the study include lead author Dr. Lin Ji, Dr. Masahiko Nishizaki, Dr. Kai Xu, Dr. Nancy Yen, Dr. E. Neely Atkinson and Dr. Bingliang Fang. Other UT Southwestern researchers contributing to the study were Dr. Boning Gao, Dr. David Burbee, Dr. Masashi Kondo, and Dr. Craig Kamibayashi. Dr. Michael Lerman from the NCI also contributed to the research.
In addition to the NCI, the research was supported by Tenneco, Exxon, Tobacco Settlement Funds, a W. M. Keck Gene Therapy Career Development Grant and Introgen Therapeutics.