Dual Gene Therapy Inhibits Lung Cancer

Combination gene therapy delivered in lipid-based nanoparticles dramatically decreased the number and size of human non-small cell lung cancer tumors in mice, according to a new study.

Researchers from the University of Texas M.D. Anderson Cancer Center (Houston, TX, USA) and the University of Texas Southwestern Medical Center (Dallas, TX, USA) reported their study's findings in the January 15, 2007, issue of the journal Cancer Research.

Two tumor-suppressing genes administered intravenously reduced tumor growth separately but had their most noticeable effect when administered together, cutting the number of tumors per mouse by 75% and the weight of tumors by 80%. "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,” said Jack Roth, M.D., professor and chair of the M.D. Anderson department of thoracic and cardiovascular surgery, and a senior researcher on the study.

The genes were enveloped in the nanoparticles were p53, a well-known tumor suppressor that works by causing defective cells to commit suicide and is frequently inactivated or defective in cancer cells, and FUS1, a tumor-suppressor discovered by the research group that is deficient in most human lung cancers. Each nanoparticle carried one of the two genes.

The researchers reported that FUS1 works with p53 to induce the lung cancer cells to kill themselves--a process known as apoptosis. Additional examination revealed that the combination generated increased apoptosis because FUS1 suppresses a gene that expresses a protein known to quickly degrade p53, according to senior author Lin Ji, Ph.D., M.D. Anderson associate professor of thoracic and cardiovascular surgery.

The FUS1/p53 combination also activates a cell suicide pathway based in the cells' mitochondria, their energy powerhouse. Lab experiments first demonstrated that the gene combination decreased the number of viable cells in four lines of human non-small cell lung cancer by 70-80% 48 hours after treatment while leaving a control group of normal cells unaffected. The cancer cell lines treated with the gene combination had two to three times more cells killed by apoptosis than either gene nanoparticle had individually. The researchers then validated these findings in the mouse studies.

The nanoparticle delivery system, which the researchers have used for years, consists of a plasmid gene expression cassette loaded with DNA that encodes either the p53 or the FUS1 protein. This is wrapped tightly in a form of cholesterol to protect it from the body's defense processes. "You can't deliver naked DNA for cancer therapy,” Dr. Ji remarked.

The nanoparticles accumulate principally in the lungs, specifically in the tumors, according to Dr. Ji. The positively charged nanoparticles are delivered to the negatively charged cancer cell membrane and transported into the cell, where the genes repeatedly express either p53 or FUS1 tumor-suppressing proteins.

Dr. Roth expects the researchers to bring these combination therapies to clinical trials in the near future, either of genes or of genes with other biologic or chemotherapy agents. "We certainly hope this approach will be more effective but we also think it's likely to be much less toxic, with fewer side effects, than other types of combined cancer therapy,” Dr. Roth said. "These genes don't have much effect on normal tissue or normal cells when they are overexpressed. It's really just cancer cells where they seem to have their effect. Ultimately, the usefulness of this approach has to be proven in clinical trials.”

The FUS1 nanoparticles are being evaluated alone in a phase I safety and dose-escalation clinical trial at M.D. Anderson for patients with advanced non-small cell lung cancer that has metastasized to other organs.



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