Therapy Destroys Pancreatic Cancer in Mice
CancerWise - September 2007
A molecularly engineered therapy tested in mice embeds a gene in pancreatic cancer that shrinks or destroys tumors, stops the spread of cancer and prolongs survival. The experimental treatment also has minimal toxicity, researchers reported in the July 9 edition of Cancer Cell.
Significance of results
"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 M. D. Anderson's Department of Gastrointestinal Oncology.
The study also resulted in an effective tool in monitoring tumor growth in animals through imaging, notes senior author Mien-Chie Hung, Ph.D., professor and chair of M. D. Anderson's Department of Molecular and Cellular Oncology.
The key ingredient to the therapy is a gene called Bik, which produces a protein that forces cancer cells to kill themselves. In the study, researchers genetically modified the gene to make it more lethal and named the gene mutation BikDD.
BikDD was given intravenously through an expression vector (a genetic design that allows a killing agent to target cancer cells and not healthy cells). Researchers developed the vector and nicknamed it VISA.
To reach the tumor, VISA was coupled with a liposome (fatty ball) that carried it through the blood stream.
VISA is essentially a DNA that contains:
A cancer-specific promotor – Also called a cancer-specific design, which allows the gene of interest to be produced in cancer cells.
Two gene-boosting components – These proteins increase the expression of genes in the targeted tumor.
A payload – The payload (anti-cancer agent) in this study consisted of BikDD.
Researchers tested the VISA-BikDD delivery system against two aggressive lines of pancreatic cancer. They also tested VISA-BikDD against CMV-BikDD, a less-targeted viral promoter delivery system using cytomegalovirus (CMV).
In addition to disease progression and survival, researchers studied side effects of acute systemic toxicity (poisoning throughout the body) and pancreatitis, a dangerous inflammation of the pancreas.
The more aggressive line of pancreatic cancer had these results in:
Control (untreated) mice – Live imaging showed that cancer in mice that were not treated spread to the liver, spleen, kidneys, bladder, lungs, bone and intestines. In both experiments all died within 40 days.
Mice treated with CMV-BikDD – Mice in this group had only a few small tumors in nearby organs. They experienced signs of both toxicities, and all died within 90 days.
Mice treated with VISA-BikDD – There was no sign of cancer in this group, and the mice experienced virtually no toxicities. They also lived longer, with at least half surviving for 14 months with no detectable sign of cancer recurrence.
Hung's team addressed obstacles to gene therapy for pancreatic cancer:
Lack of a targeted system that hits cancer and spares normal tissue – Researchers created a new gene delivery system called C-VISA and compared its effectiveness to the CMV-BikDD system against all 13 available human cell lines of pancreatic cancer available worldwide. CMV-BikDD killed cells in all lines, and the C-VISA system destroyed more cells in all but one case.
The C-VISA system spared healthy tissue while CMV-BikDD destroyed healthy cells.
Need for a live animal model (molecularly engineered mice) for imaging – Researchers solved the problem by modifying two lines of pancreatic cancer to release the bioluminescent agent that lights up fireflies. This allowed live imaging of the mice to monitor cancer progression.
The researchers already had developed several components of the gene expression system.
Abbruzzese 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.
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," Abbruzzese says. "That's why we are trying new approaches such as this one as part of SPORE."
Hung's team continues research on a gene delivery vehicle. "VISA is versatile enough that if you change the promoter, you could target other cancers or even other diseases," Hung says.
– From staff reports