Antiangiogenic Therapy for Canine Cancers

Cancers in dogs depend on angiogenesis to survive and proliferate. Tumors create new blood vessels that supply them with oxygen and nutrients, allowing them to grow in size and spread throughout the body. Antiangiogenic therapy cuts off these new blood vessels, effectively starving tumors and preventing their growth. Cancers may be controlled with effective doses of antiangiogenic drugs.

Angiogenesis inhibitors are designed to attack tumors by depriving cancer cells of their blood supply. A number of steps along the angiogenesis pathway in cancers can be targeted by drugs:

• Angiogenic growth factors or growth factor receptors on blood vessel cells
• Migrating, dividing, or attaching endothelial cells
• Matrix metalloproteinases (MMPs) that clear the way for invading blood vessel cells
• Endothelial progenitor stem cells (EPC) that contribute to new vessels
• Blood vessel maturation

Some antiangiogenic drugs may also be combined in order to hit multiple targets and improve their effectiveness.

Antiangiogenic therapy offers a number of advantages over traditional therapies for cancer:

• Tumor cells often mutate and become resistant to chemotherapy. Because antiangiogenic drugs only target normal endothelial cells, these cells are less likely develop acquired drug resistance.
• All tumors rely upon host vessels. Antiangiogenic agents are therefore effective against a broad range of cancers.
• Conventional chemotherapy and radiotherapy indiscriminately attacks all dividing cells in the body, leading to side effects such as diarrhea, mouth ulcers, hair loss, and weakened immunity. Antiangiogenic drugs selectively target dividing blood vessels and cause fewer side effects.
• Antiangiogenic drugs are relatively nontoxic and work at levels well below the maximum tolerated dose, so may be given in lower doses over longer periods of time.
• Antiangiogenic treatment may take weeks or even months to exhibit its full beneficial effect, but this allows for continuous, chronic control of disease.
• Antiangiogenic drugs may also serve as a powerful supplement to traditional chemotherapy or radiation therapy.

The Angiogenesis Foundation is leading research on angiogenesis and antiangiogenesis in canines. In a study taken in conjunction with the National Cancer Institute, Foundation researchers studied the presence of angiogenesis growth factors in canine serum and found abnormally elevated levels of VEGF in dogs with lymphoma. The Foundation is also actively developing antiangiogenic treatments for pet dogs, and has created a series of protocols containing different combinations of angiogenesis inhibitors. This combinatorial approach is considered by cancer researchers to be advantageous by hitting multiple targets simultaneously for maximum pharmacological effect.

The Foundation has also tested drugs that are already FDA-approved and available for angiogenesis inhibitory properties, and hopes to develop practical antiangiogenic treatments based on drug availability. One approach, known as the 'Navy Protocol' (OLCAT-007), uses COX-2 inhibitors along with inhibitors of blood vessel cell proliferation and invasion. The Navy protocol was named after a 2-year-old golden retriever who was the first canine cancer patient to be successfully treated with antiangiogenic therapy. So far, more than one dozen dogs have received the Navy protocol. The Foundation is working with the Cleveland Metroparks Zoo and other leading institutions to study these protocols.

Another area under study at the Angiogenesis Foundation is the role of diet in controlling canine cancer. Foundation researchers have been testing green tea and soy incorporated into dog food as a way of dietary cancer suppression. Both green tea and soy are food substances that contain natural angiogenesis inhibitors. This approach may complement drug therapies.

Biopharmaceutical companies are also now developing antiangiogenic therapy for veterinary application. The drug company Bayer has tested an antiangiogenic pill called Tanomastat (Bay 12,9566) in dogs with lymphoma. The University of California at Davis has tested a drug called tetrathiomolybdate (TM), which lowers copper levels in the bloodstream, along with circulating levels of angiogenesis growth factors that tumors rely upon to create their own blood supply. TM has also been used successfully in human breast cancer patients. The angiogenesis inhibitor angiostatin has also been tested in a dog at the Angell Memorial Hospital in Boston. Currently, the pharmaceutical company Abbott is testing an intravenous angiogenesis inhibitor called ABT-510 in canines with cancer. The drug is an analog of a natural molecule called thrombospondin, which is one of the body's natural angiogenesis inhibitors.