Unconventional Cancer Therapies

06/24/2007

As dogs are living longer due to advances in preventive care and nutrition, the number being diagnosed with cancer continues to increase. More than half of dogs that live until the age of 10 will develop some form of cancer. The good news is that novel therapies and treatment options offer significant advances in canine cancer care.

Who would have thought 10 years ago that it would be possible to treat dogs with melanoma using a vaccine? Today, two vaccines offer promising results. One uses genetically modified cells to produce chemicals that activate white blood cells to attack tumor cells, and the other contains human DNA to trick the immune system into attacking the melanoma.

In studying lymphoma cancer, researchers learned that tumors need increased levels of vitamin B-12 to survive, and developed a method of delivering radiation directly to a tumor by attaching the radionucleatide to vitamin B-12. Trials are under way in humans and dogs to offer hope for this disease.

Perhaps most encouraging of all, researchers have developed a blood test to detect the presence of hemangiosarcoma, a cancer of the cells lining the blood vessels. In the future, as new treatments are discovered, susceptible breeds, such as Golden Retrievers, German Shepherd Dogs, Great Danes and Boxers, can be tested and ultimately treated even before clinical signs appear.

Maybe a Bee Sting

“Mack,” a 14-year-old Beagle, had lost his eyesight to glaucoma, but his keen sense of smell and the vigilance of his owners, Maggie and Gus Hoefling of Largo, Fla., helped him to get around safely. While administering eye drops one morning, Maggie noticed a small lump on Mack’s upper jaw.

“He was always poking under a bush, sniffing, so it could have been a bee sting,” she says. “But when I saw the swelling the next day, I knew something wasn’t right. I took Mack to the veterinarian, and he ordered a biopsy right away.”

While they were waiting for the biopsy results, the lump grew relentlessly. Within days the results came back: oral melanoma. The prognosis: three months to live. Maggie wouldn’t accept that. “Mack had almost died as a puppy, and was the most determined dog you could ever know. I was not about to give up on a dog that had already fought so hard to live. I had this nagging feeling that something was out there to help him if we could only find it in time.”

Relentlessly, Maggie searched the Internet and called veterinary teaching hospitals and research facilities across the country. She learned about the breakthrough research of Philip J. Bergman, D.V.M., Ph.D., DACVIM, head of the Donaldson-Atwood Cancer Clinic at The Animal Medical Center in New York, developing a vaccine containing human DNA for treating dogs with advanced malignant melanoma.

One glitch prevented Mack from receiving the therapy: Owners had to bring their dogs to AMC for frequent veterinary visits. Living in Florida, Maggie knew that was not an option. Meanwhile, Bergman helped to connect her with researchers at the University of Wisconsin School of Veterinary Medicine who were also working on a canine vaccine for melanoma. They were able to produce and ship the vaccine to a patient’s veterinarian. Mack was accepted into the clinical trial.

Less than two weeks after the lump first became visible, Mack was fading fast. The tumor had grown to three-quarters the size of a tennis ball, and Maggie had to carry Mack into the animal hospital the day the tumor was surgically removed. After 10 days of post-surgical recovery, Mack received the first dose of melanoma vaccine. He slept around the clock while war raged in his body. When he awoke 26 hours later, Maggie noted that he seemed brighter and more like his old self.

Each week Mack received another dose of vaccine and would go to sleep for an extended period. The tumor was visibly growing again and had become larger than a golf ball after three weeks had passed. The fourth dose of vaccine brought a marked and joyous change: The tumor had begun to shrink. By week six, it was smaller, and then two weeks later, only a tiny lump could be seen inside Mack’s mouth. He received his last shot of vaccine on Thursday, and by Sunday all signs of the tumor had disappeared.

After the initial treatment, Mack received monthly vaccine boosters. He enjoyed two more years of quality, cancer-free life before dying of heart failure at age 16. He was the first dog in the vaccine trial at the University of Wisconsin in which the tumor completely disappeared.

Two Melanoma Vaccines

Melanoma is a rapidly growing cancer in which the pigment-producing cells of the skin multiply erratically, eventually invading the surrounding tissues. Most canine melanomas that appear in areas with hair are benign, but when found on the toenails, lips or in the mouth, melanoma is nearly always malignant and aggressive. It also commonly spreads, or metastasizes, from the original tumor site to the lymph nodes, lungs, brain and/or liver, where additional tumors develop that ultimately cause death.

Clinical trials for the vaccine that made Mack’s tumor disappear have been under way since 1998. In about 20 percent of dogs, the tumor shrinks, and another 10 to 20 percent experience up to six months of remission. In roughly 12.5 percent of cases, the tumor completely disappears. The vaccine works by stimulating dogs’ immune systems to attack and destroy tumor cells.

In developing this vaccine, researchers at the University of Wisconsin grew cells from an “allogeneic” melanoma tumor (tumor from an unrelated dog) in the laboratory, irradiated the cells so they could not reproduce, and then genetically modified them to produce a growth factor that attracts and activates white blood cells. Ultimately, these altered melanoma cells are injected into patients through the vaccine. In effect, the combination of irradiated melanoma cells and the growth factor stimulates the immune system to recognize and kill the melanoma tumor cells.

Meanwhile, at The Animal Medical Center, Bergman’s vaccine uses DNA from humans to increase survivability in dogs with malignant melanoma. Mouse studies had demonstrated that xenogeneic (from a different species) DNA vaccination with genes encoding tyrosinase family members (a family of proteins used to make black pigment) can induce antibody and cytotoxic T-cell responses, resulting in tumor rejection in both preexisting and future tumors. These studies provided the rationale for a trial of xenogeneic DNA vaccination in canine malignant melanoma using the human tyrosinase gene.

One patient treated with the human DNA vaccine survived more than four years and is still alive today. “Jake,” a Rottweiler/Labrador Retriever cross, was diagnosed with melanoma on his toe in October 2000. After surgery, his owner, Kristen Ludwikow of Canton, Conn., was referred to Bergman for enrollment in the clinical trial. Jake’s success in the treatment and his contributions to advancing research led to his being named the Connecticut Veterinary Medical Association Pet of the Year in 2002.

“Jake showed us what the immune system is capable of,” Bergman says. “He also donated blood that helped us to develop a serum test to determine if the proper immune response has occurred.” Currently, The Animal Medical Center is working with the U.S. Department of Agriculture to obtain a license to distribute the DNA vaccine to veterinarians for treating dogs outside the New York area. Additionally, studies on the DNA vaccine in dogs had such a good safety and efficacy record that human trials using the vaccine began much quicker than usual.

Vitamin B-12 and Lymphoma

Canine lymphoma is one of the five most common tumors seen in dogs. Lymphoma describes a tumor that grows in lymph nodes and arises from lymphocytes or white blood cells that fight disease. The most noticeable signs are usually big masses around the neck, in front of the shoulders or behind the knees. Occasionally lymph nodes that are not visible or palpable from outside the body, such as inside the chest or abdomen, are affected.

Swollen nodes may cause other health problems. Large masses in a dog’s neck may cause problems breathing or eating, and masses in the chest may make it hard to breathe so animals become tired or lethargic. Cancerous lymphocytes may also infiltrate organs such as the gastrointestinal tract, spleen, liver or kidneys, leading to signs such as weight loss, vomiting, diarrhea or kidney failure. Malignant lymphocytes in bone marrow may cause a dog to become anemic and lethargic.

Realizing that lymphoma tumors need increased levels of vitamin B-12 to survive, Sue Lana, D.V.M., DACVIM, associate professor of medical oncology at Colorado State University Animal Cancer Center, has begun a collaborative research effort working on ways to target tumor cells and stop tumor growth. The study involves attaching a radioisotope called Indium-111 to vitamin B-12. This work began at the Mayo Clinic. Continued support from an anonymous donor whose relative is battling lymphoma allowed Lana and her research colleagues at CSU to conduct their own study.

“Because tumors are more metabolically active and have an increased need for vitamin B-12, we hope that the lymph nodes will take up the B-12, allowing delivery of a therapeutic dose of radiation directly to the tumor,” Lana says. “This study will also help us determine the highest dosage of the radioisotope that can be safely administered to lymphoma patients.”

A Test for Hemangiosarcoma

For more than a year, Cortney Corral of Wellington, Ohio, saved her money to buy a Golden Retriever. Her mother, Julie Corral, finally said she could. “Kaycee” proved to be a patient dog, helping Cortney learn to be a junior handler. Just before her 9th birthday, Kaycee refused to eat her breakfast for the first time ever. Julie looked at her gums. They were very pale.

They went straight to the veterinarian, who performed blood work, an ultrasound and took a radiograph. The only thing he found was a small amount of blood in Kaycee’s abdomen. The Corrals took Kaycee home, and she seemed fine. At a follow-up visit the next week, a more extensive ultrasound was performed. This time, the veterinarian found a tumor on the dog’s spleen and more blood in the abdomen.

Surgery was performed in June to remove Kaycee’s spleen. Although her appetite never fully recovered, she seemed much like her old self, just slower. Rather than bounding up the stairs as in the past, she needed a little help. In October, Kaycee seemed too tired to go on. She was euthanized quietly at home, but some of her blood was collected and sent to the University of Colorado at Denver and Health Sciences Center, where researchers are studying hemangiosarcoma.

Hemangiosarcoma affects the cells that line the blood vessels, called the endothelial cells. If the cancer is found early when the tumor is easiest to treat with surgery and chemotherapy, a dog may survive seven to eight months. Without treatment, life expectancy is about two months.

Jaime Modiano, V.M.D., Ph.D., associate professor of immunology at the University of Colorado at Denver and Health Sciences Center, and an AKC Canine Health Foundation funded researcher, describes hemangiosarcoma as being extremely indolent. It develops slowly and is essentially painless, so clinical signs are usually not evident until the advanced stages when the tumor is resistant to most treatments.

Longtime research by Modiano and his colleagues has led to the development of a blood test to detect hemangiosarcoma. The University of Colorado recently applied for a patent on the test, which Modiano says is “just the first step on a long road toward conquering the disease.”

“We will have to complete additional work to determine how early the blood test can detect disease, and what to do if it is found on the test,” he says. “Without knowing where the bad cells live, it makes decisions regarding therapy difficult if not impossible. These efforts are just beginning.”

Inhibiting Mast Cell Cancer

Mast cell tumors are the most common skin tumor in dogs, affecting up to 20 percent of dogs. Unpredictable, some tumors exhibit benign behavior, while others are extremely aggressive. Aggressive tumors often spread to the lymph nodes and then throughout the body. In addition, they can mimic other types of tumors.

Part of the immune system, mast cells are normally found all over the body, especially in the skin, lungs and intestines. They help the body fight infection but also are responsible for allergic reactions. Breeds at increased risk for mast cell tumors include Golden Retrievers, Cocker Spaniels, Schnauzers, Boxers and breeds descended from the Bulldog.

Cheryl London, D.V.M., Ph.D., associate professor at The Ohio State University, has been studying canine mast cell tumors for many years. Her work began and was funded in part by the AKC Canine Health Foundation when she was at the University of California-Davis. While there, her research team began to focus on a gene called c-kit that codes for a protein called Kit, which is expressed on the surface of all mast cells. Signaling through Kit promotes the development and survival of normal mast cells.

The researchers began to investigate canine mast cell tumors for evidence of c-kit mutations. “We expected to find mutations similar to those that had already been identified in people, however we found a different form of mutation, called an internal tandem duplication,” London says. “While the mutation in dogs is different than that found in people, the ultimate effect is the same. They both cause uncontrolled activation of Kit and contribute to the development of mast cell cancer.”

The researchers learned that c-kit mutations account for approximately 30 to 50 percent of malignant mast cell tumors. They began working with a pharmaceutical company to explore using a novel tyrosine kinase inhibitor in the treatment of canine mast cell tumors. The inhibitor blocks Kit function and disrupts the ability of the malignant mast cells to grow.

In a clinical trial, 57 dogs with a variety of different cancers were treated with the kinase inhibitor. All signs of cancer disappeared in six dogs, while 10 dogs experienced tumor reduction of at least 30 percent. Of 22 dogs diagnosed with mast cell cancer, 11 experienced tumor shrinkage, and nine of these had mutations in c-Kit.

Following completion of this phase-one trial, a multicenter study of the kinase inhibitor in mast cell tumors was conducted. The results are pending, but London and the researchers are optimistic that the Food and Drug Administration will approve the kinase inhibitor for use in dogs with mast cell cancer.

Surviving Canine Cancer

Thanks to these new treatments and novel therapies, the odds of a dog surviving cancer today have changed dramatically from 30 years ago. Though much remains to be learned about what causes the uncontrolled cell growth and proliferation that occurs in cancer, progress is being made.

With the completion of the canine genome sequencing, researchers now know the correct and healthy sequence of genes. This information is critical in finding gene mutations in all diseases, including cancer. These advances along with the work of dedicated researchers may one day help to reduce the risk of canine cancer. 

1 Preyer NK, Lee LB, Zadovaskaya R, et al. Proof of Target for SU11654: Inhibition of KIT Phosphorylation in Canine Mast Cell Tumors. Clinical Cancer Research. 2003:9:5732.

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