Gene Delivery System Targets Blood Vessels In Dogs With Cancer
In a preliminary study of pet dogs with naturally occurring cancer, researchers have developed a way to target delivery of a gene to tumor blood vessels, where the gene product damages the vessels, disrupting blood flow to the tumors but not to the surrounding tissue. The delivery method was well tolerated, and in some dogs, the size of tumors decreased or remained stable. This study provides valuable information that may aid in the design of future clinical trials. These are the first results of the Comparative Oncology Trials Consortium (COTC), a novel multicenter network sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health, to integrate cancers that naturally develop in dogs into the developmental path of new therapies for cancers in humans. The study, led by NCI researchers, was published in the March 30, 2009, issue of PLoS ONE.
In the study, the researchers evaluated whether a targeted system, based on a bacteriophage vector, or delivery vehicle, that was designed to target tumor blood vessels could effectively deliver the TNF-alpha gene to the blood vessels of naturally occurring tumors in dogs. A bacteriophage is a virus that normally infects only bacteria, but can be engineered to target and infect specific mammalian cells, namely tumor blood vessel cells. The TNF-alpha gene directs the production of a protein called tumor necrosis factor-alpha (TNF-alpha), which stimulates the immune system and has antitumor effects. Because of the TNF-alpha protein’s toxicity it cannot be administered through the bloodstream, and efforts have focused on methods to achieve targeted delivery of tumors. Previous studies in mice showed that delivery of the targeted vector directly to tumor blood vessels, the expression of the TNF-a gene in tumors and their blood vessels, and inhibition of tumor growth.
Despite evidence of a drug’s effectiveness in mouse models of cancer, many potential drugs fail in human clinical trials because of toxicity or lack of effectiveness. Mouse models are excellent tools for studying the biology and biochemistry of particular pathways involved in cancer development and progression, but they are limited in their representation of some features of human cancer.
Naturally occurring, or spontaneous, cancers in dogs offer many advantages over mouse and other animal models. Canine cancers are complex and share many features with human cancers, including tumor genetics, molecular targets, biological behavior, and response to conventional therapy.
In the current study, the researchers first established the safety and optimal dose of the vector for delivery of the TNF-a gene into dogs that had various types of cancer. The range of cancers found in dogs is similar to those found in humans and include prostate and mammary cancers, non-Hodgkin lymphoma, melanoma, and some types of bone cancer.
"Because of the similarities, studying cancer that develops naturally in dogs provides additional information about the safety and effectiveness of novel therapies that can aid in the design of studies for humans," said Anita Tandle, Ph.D., of CCR, one of the study’s lead authors. Another study author, Melissa Paoloni, D.V.M., of CCR added, "The comparative approach allows us to ask specific and important questions about cancer therapies and evaluate biological effects within a tumor after treatment in ways that are difficult or not possible in human trials."
The COTC team next administered the targeted vector to another group of tumor-bearing dogs weekly for four weeks. Dogs had a variety of cancers including those of the bone, skin, and immune system. The dogs were seen at five different veterinary oncology centers throughout the United States. Data were reported to a central electronic database, which allows principal investigators at the NCI to oversee patient care and trial management contemporaneously.
The researchers found that in 14 dogs that completed treatment, which consisted of four weekly doses of the vector, tumors shrank in two dogs, remained stable in size in six dogs, and grew in six dogs. Tumor biopsy specimens taken before, during, and after treatment showed that the targeted vector was located in tumor blood vessels only. The researchers did not detect the vector in noncancerous tissues, including the skin, muscle, lung, liver, spleen, and gastrointestinal tract of treated dogs.
"In addition to evaluating the gene delivery method, the current study showed that the COTC is a well-organized multi-site effort that allows us, in a very sophisticated way, to inform the drug development path for human cancer patients," said Paoloni. "In addition to serving as a model that may help humans, Consortium studies could aid veterinary cancer patients, which is an important added benefit." In addition to Paoloni and Tandle, the study was co-led by Chand Khanna, D.V.M., Ph.D., of the NCI-CCR Comparative Oncology Program and Steven K. Libutti, M.D., formerly of CCR.
The COTC is a network of 18 veterinary teaching hospitals across the United States. COTC studies are centrally managed by CCR and are intended to assess multiple factors including safety, biology, and clinical activity of novel treatments that can be directly incorporated into the design of early phase human clinical trials. The study data are maintained in a central database at NCI.