NCI researchers develop gene delivery system that targets tumor blood vessels in dogs with cancer

Delivery method could aid in the design of human clinical trials

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BETHESDA, Md.—A recent study led by researchers at the National Cancer Institute (NCI) produced a gene delivery system that targeted tumor blood vessels in pet dogs with naturally-occurring cancer, providing valuable information the researchers hope will aid in the design of future clinical trials, prevent drug toxicity, increase drug efficacy and ultimately, forge a developmental path for new therapies for cancer in humans.

The study, published in the March 30 issue of the peer-reviewed journal PLoS ONE, was the first endeavor by the Comparative Oncology Trials Consortium (COTC), a network of 18 veterinary teaching hospitals across the United States. The COTC's studies are centrally managed by the NCI's Comparative Oncology Program (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 COTC team 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 seen at five different veterinary oncology centers across the country. First, they established the safety and optimal dose of the vector for delivery of the TNF-a gene into dogs that had various types of cancer. Next, the researchers administered the targeted vector to another group of tumor-bearing dogs weekly for four weeks. Data were reported to a central electronic database, which allows principal investigators at the NCI to oversee patient care and trial management contemporaneously.

The delivery method was well tolerated, and in some dogs, the size of tumors decreased or remained stable. 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 non-cancerous tissues, including the skin, muscle, lung, liver, spleen and gastrointestinal tract of treated dogs.

The COTC study provided valuable and necessary data to complete the design of first-in-man studies, says one of the study's lead authors, Dr. Anita Tandle of the CCR's Surgery Branch.

"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," Tandle says.

The COTC team notes that studying dogs with cancer can effectively contribute to the development of new cancer drugs, but scientists must gain a clearer understanding of the types of tumor targets, treatment agents, therapeutic approaches and disease entities that are most suitable to this approach. Further studies will need to continue to focus on specific questions needed to advance the development path of new drugs, they say.

"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," adds another of the study's lead authors, Dr. Melissa Paoloni of the NCI-CCR Comparative Oncology Program.

According to the NCI, experiments involving pets with cancer provide a win-win opportunity for cancer researchers. Although mouse models of cancer are useful tools for studying the biology and biochemistry of particular pathways involved in cancer development and progression, they are limited in their representation of some features of human cancer; however, the nearly six million dogs that are diagnosed with cancer each year in the United States have much in common with humans suffering from cancer, including tumor genetics, molecular targets, biological behavior and response to conventional therapy.

In addition to giving scientists a more effective animal model for cancer research, this method also gives pets access to new treatments that may increase their survival rate, the researchers say.

"In addition to serving as a model that may help humans, consortium studies could aid veterinary cancer patients, which is an important added benefit," says Paoloni

In addition to Paoloni and Tandle, the study was co-led by Dr. Chand Khanna of the NCI-CCR Comparative Oncology Program and Dr. Steven K. Libutti, formerly of the CCR.

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