Gene Therapy for Advanced Lung Cancer Tried in Mice and Men

HOUSTON, Jan. 15 -- Investigators here have begun a small clinical trial of gene therapy for advanced non-small-cell lung cancer.

The Phase I safety and dose-escalation trial at the University of Texas M. D. Anderson Cancer Center emerged from a study with mice that found that gene therapy with two tumor-suppressor genes combined sharply reduced the number of human non-small-cell lung cancer tumors.

The human trial, however, is with just one of the two genes that were used with the experimental mice. It is FUS1, a novel gene that is defective in a majority of non-small-cell lung cancers and almost all small-cell lung cancers, No data are available yet from the single-gene-therapy trial.

On the mouse trial, Jack Roth, M.D., of M. D. Anderson, one of the project's lead researchers, said, "In cancer treatment we have combination chemotherapy, and we also combine different modes of therapy -- surgery, radiation and chemotherapy. Now you've got the possibility of combined targeted gene therapy."

The two genes are p53, a well-known tumor-suppressor gene that is inactive on about half of all human lung cancers, and FUS1, Dr. Roth and colleagues reported in the Jan. 15 issue of Cancer Research.

The effect appears to be synergistic - the combination of the two genes is a better therapy than either administered alone, the researchers said.

Using mice prone to develop human non-small cell-lung cancer, the researchers administered the two genes in a nanoparticle delivery system, consisting of plasmid gene expression cassettes with either the p53 or the FUS1 gene.

The plasmids are protected by a form of cholesterol until they can merge with the target cells, according to senior researcher Lin Ji, Ph.D., also of M.D. Anderson.

"You can't deliver naked DNA for cancer therapy," Dr. Ji said.

In laboratory cell lines, the researchers had first shown that the combination of the two genes killed between 70% and 80% of cancer cells within 48 hours, while leaving normal cells alone.

The combination induced apoptosis in up to three times as many cells as did either gene alone, the researchers reported.

The results were then confirmed in mice, Dr. Roth and colleagues reported. The researchers divided the animals into four groups, which were given either the gene combination, one of the two genes alone, or a control gene, ?-galactosidase.

On average, the control mice developed 16 tumors per animal, compared with between five and eight for the single-gene groups and approximately two for the combination group.

A similar pattern was seen for total tumor weight, with control mice averaging about 475 mg, compared with about 200 to 250 mg for the single-gene groups, and about 50 mg for the combination group.

One explanation for the result is that FUS1 appears to block the action of murine double minute-2, a gene (MDM2) that degrades the p53 protein, resulting in an accumulation of the protein, as well as the activation of the apoptotic protease-activating factor 1 (Apaf-1)-dependent apoptotic pathway in human NSCLC cells, the researchers said.

The researchers did not report any financial conflicts. The study was supported by the National Cancer Institute, the Department of Defense, the M.D. Anderson Cancer Center, a W.M. Keck Gene Therapy Career Development grant, and a grant from the Texas State Legislature.