Researchers at The University of Texas M. D. Anderson Cancer Center and the University of Texas Southwestern Medical Center report in the Jan. 15 edition of Cancer Research, that two tumor-suppressing genes given intravenously reduced cancer separately but had their most powerful effect when administered together, cutting the number of tumors per mouse by 75 percent and the weight of tumors by 80 percent.
"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 project.
The genes wrapped in the nanoparticles were p53, a well-known tumor suppressor that works by causing defective cells to commit suicide and is often shut down 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 Cancer Research paper reports that FUS1 works with p53 to force the lung cancer cells to kill themselves - a process known as apoptosis.
Further analysis showed that the combination achieved greater cell suicide because FUS1 suppresses a gene that expresses a protein known to rapidly degrade p53, says 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 showed that the gene combination cut the number of viable cells in four lines of human non-small cell lung cancer by 70 to 80 percent 48 hours after treatment while leaving a control group of normal cells unaffected. The cancer cell lines treated with the gene combination had 2 to 3 times more cells killed by apoptosis than either gene nanoparticle had individually. The research team then confirmed 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 mechanisms. "You can't deliver naked DNA for cancer therapy," Ji says.
The nanoparticles accumulate mainly in the lungs, particularly in the tumors, Ji says. The positively charged nanoparticles are delivered to the negatively charged cancer cell membrane and taken into the cell, where the genes repeatedly express either p53 or FUS1 tumor-suppressing proteins.
Roth expects the research team to advance combination therapies to clinical trials in the coming years, 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," Roth says. "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."
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The FUS1 nanoparticles are being tested alone in a phase 1 safety and dose-escalation clinical trial at M. D. Anderson for patients with advanced non-small cell lung cancer that has spread to other organs. Charles Lu, M.D., associate professor in the M. D. Anderson Department of Thoracic, Head and Neck Medical Oncology, is conducting the clinical trial, which is funded by M. D. Anderson's and UT-Southwestern's joint National Cancer Institute Specialized Program of Research Excellence (SPORE) in lung cancer.
Co-authors with Roth and Ji are John D. Minna, M.D., Department of Internal Medicine and Pharmacology, Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center; first author Wu-Guo Deng, Ph.D., Hiroyaki Kawashima, M.D., Ph.D., Guanglin Wu, M.D., Gitanjali Jayachandran, Ph.D., and Kai Xu, M.S., all of the M. D. Anderson Department of Thoracic and Cardiovascular Surgery.
Research was supported by a National Cancer Institute SPORE grant, U.S. Department of Defense TARGET Lung Cancer Programs grant, W.M. Keck Gene Therapy Career Development grant, M. D. Anderson's Cancer Center Support Grant, and a grant from the Tobacco Settlement Funds appropriated by the Texas Legislature.
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