New investigational gene therapy strategy very successful against human pancreatic cancer in animal model.

A molecularly engineered gene therapy selectively embeds a cancer-killing gene in pancreatic cancer that shrinks or eradicates tumors, inhibits metastasis, and prolongs survival with virtually no toxicity, researchers from The University of Texas M. D. Anderson Cancer Center report in the July 9, 2007 edition of Cancer Cell.

“This vehicle, or vector, is so targeted and robust in its cancer-specific expression that it can be used for therapy and perhaps for imaging,” notes senior author Mien-Chie Hung, Ph.D., professor and chair of M. D. Anderson’s Department of Molecular and Cellular Oncology.

The researchers call the system a versatile expression vector – nicknamed VISA. It includes a targeting agent, also called a promoter, two components that boost gene expression in the target tissue, and a payload – in this case a gene known to kill cancer cells. It’s all packaged in a fatty ball called a liposome and delivered intravenously.

Researchers are working with M. D. Anderson clinicians to move the system, developed and tested in mouse models of pancreatic cancer, to a Phase I clinical trial in people.

“This looks like a promising approach to gene therapy for pancreatic cancer and we are working to bring it to a clinical trial,” says James Abbruzzese, M.D., professor and chair of the M. D. Anderson Department of Gastrointestinal Oncology.

He estimates that it will take between one and two years to complete U.S. Food and Drug Administration requirements for a Phase I trial. Abbruzzese’s clinicians are working with Hung’s group to compile preclinical information for FDA review.

About 37,000 cases of pancreatic cancer are diagnosed annually in the United States. Early diagnosis is extremely difficult, so the disease is often discovered at a late stage after it already has spread, or metastasized. Fewer than 4 percent of pancreatic cancer patients survive five years after diagnosis, one of the lowest cancer survival rates.

In a test of the therapy against two aggressive lines of human pancreatic cancer cells in two different types of mice, researchers loaded the VISA system with a mutant version of a gene named Bik, which expresses a protein that naturally forces cancer cells to kill themselves. The team created the more lethal mutant and named it BikDD.

Untreated control mice in both experiments all died within 40 days. Mice treated with the mutant gene delivered via a less-targeted viral promoter driven expression system employing cytomegalovirus (CMV) all died within 90 days, most much earlier. In both trials, the VISA-BikDD mice lived longer, with at least half surviving for 14 months with no detectable sign of cancer recurrence.

The researchers tested both systems in the lab against all 13 human cell lines of pancreatic cancer available worldwide. BikDD killed cells in all lines, with the VISA-delivered gene destroying more cells in all but one case.

One test involved a pancreatic cancer line that spreads swiftly. In that case, live imaging showed that in control mice the cancer spread to the liver, spleen, kidneys, bladder, lungs, bone and intestines. Mice treated with the CMV BikDD showed only a few small tumors in nearby organs. There were no detectable metastases in mice treated with the VISA-BikDD combination, the authors report.

“All [conventional] cancer drugs have some toxicity and so cause side effects, which affects the dose that can be administered,” Hung says. The team looked for signs of acute systemic toxicity and of pancreatitis, a dangerous inflammation of the pancreas. While the cytomegalovirus-BikDD showed signs of both toxicities, the authors report “VISA-BikDD produces virtually no systemically acute toxicity or acute pancreatitis.” Hung’s team continues research on their gene expression vehicle, VISA. “VISA is versatile enough that if you change the promoter, you could target other cancers or even other diseases,” Hung says.

Abbruzzese says any clinical trial will advance under a National Cancer Institute Specialized Programs of Research Excellence (SPORE) grant in pancreatic cancer. SPORE awards are designed to translate scientific findings into the clinic.

“There are no good options for pancreatic cancer patients now,” says Abbruzzese, “That’s why we are trying new approaches such as this one as part of SPORE.” M. D. Anderson, the source of this news story, has filed for a patent on VISA-BikDD, which has been licensed to Alchemgen Therapeutics Inc. (ATI).