TKLs Studied In Mast Cell Cancers


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Oncologists foresee treatments from combined therapy research

Only lymphoma is more common in dogs than malignant mast cell skin tumors, making MCTs of great interest to veterinary oncologists.

 Up to 80 percent of mast cell tumors are grade II but can act as grade I or grade III, experts say, citing the need for a better way to accurately diagnose and treat the cancer.
 
Oncologists say being able to determine the path of a MCT earlier in treatment, along with a more clear-cut eradication method, would improve the odds for animal cancer patients.

“If you ask 10 oncologists how to treat a grade II mast cell tumor, you’ll get 11 different answers, counting the indecisive one,” says Rance Gamblin, DVM, Dipl. ACVIM (oncology), of Metropolitan Veterinary Hospital in Akron, Ohio. “With the current understanding on mast cells, there isn’t one treatment plan that can work in each patient.”

An added danger with MCTs is that they do not have a classic, easily identifiable appearance and can spread to additional skin sites, lymph nodes and the spleen, ultimately resulting in death.

“In 10 to 15 percent of MCT cases, a tumor appears in another region of a patient’s body after the initial tumor’s removal,” Dr. Gamblin says. “Animals diagnosed with internal mast cell tumors generally have a less optimistic prognosis than those with cutaneous tumors, but promising research may help us use a more focused treatment method.”

Gamblin says he’s especially interested in the outcome of research on tyrosine kinase inhibiting (TKI) drugs combined with the use of chemotherapy. He says some private practitioners, along with researchers at the collegiate level, are gathering information on this.

Role of miRNA

Cheryl London, DVM, Ph.D., Dipl. ACVIM (oncology), an associate professor at Ohio State University, is leading several projects looking at ways to improve the prognosis of canine patients that have mast cell tumors. One study, Dr. London says, is looking at the role of microRNAs (miRNAs), which are small nonprotein-coding RNAs involved in the initiation and progression of cancer in humans.
 
Specifically, miRNA expression is being examined to link aggressive mast cell disease and ways to define how the miRNA may promote the aggressive progression of tumors in dogs.

“Little is known about how mast cells transform from benign to malignant,” London says. “We’re looking for molecular targets in a transcriptional profiling study of mast cells to form more efficient treatments.
 
“Evidence suggests that in human and veterinary patients, tyrosine kinases (TKs) are often abnormally activated in malignant tumors. This may occur through mutation, overexpression, the generation of fusion proteins from chromosomal translocation or autocrine loops of activation through coexpression of growth factor and receptor.”

Drugs Could Help

A variety of small molecule inhibitors that target specific TKIs have been approved for the treatment of human cancer, London says. The drug class TKIs has only one Food and Drug Administration-approved pharmaceutical for veterinary use: Palladia (toceranib) by Pfizer. In a study of 150 dogs, tumors shrank or disappeared in 43 percent of those that received Palladia, compared with 8 percent that received a placebo.
“Palladia is an oral drug and can be used to treat different types of cancers,” London says.
 
“Masitinib, developed by European manufacturer AB Science, is a TK inhibitor that has been tested in canines and is awaiting FDA approval.”
 
It is available to U.S. veterinarians under the FDA personal import (compassionate use) program. Interested veterinarians can contact Albert Ahn, DVM, of AB Science at 973-218-2437.

Gleevec (imatinib mesylate) by Novartis has been successfully used in dogs, and more recently Gleevec in cats, according to London.

More Research

Ohio State veterinary student Bonnie Harrington is comparing and studying genes in low- and high-grade tumors under London’s watch. While removal of low-grade tumors might void the body of cancer indefinitely, MCTs of a higher grade require more aggressive treatment. Harrington, who has Morris Animal Foundation funding for her research, predicts that knowing how some low-grade tumors become high grade could lead to treatments for regulating tumor behavior.

“There’s no good direct comparison of mast cell disease found in dogs or cats with what is found in people,” London says. “Cats with mast cell tumors more commonly present with symptoms of weight loss, lethargy, loss of appetite or vomiting. Only upon exam is a diagnosis made through bloodwork and sampling. Dogs typically present with skin tumors and, if caught early enough, can be expected to have good treatment outcomes.”

London says mast cell tumors occur in dogs more frequently than any other species. While no canine breed is excluded, some tend to have a higher incidence. Golden retrievers, shar-peis, Labrador retrievers, boxers and pugs 8 or 9 years old have a higher disease incidence.
 
Kerstin Lindblad-Toh, Ph.D., co-director of the genome sequencing and analysis program at the Broad Institute, partnered with Ohio State researchers to map genes associated with MCTs.
The genomes of 88 golden retrievers with MCT were compared with those of more than 103 healthy golden retrievers serving as control subjects. The researchers identified and localized five candidate loci as genetic risk factors for mast cell tumors.
 
Researchers reported that the locus on chromosome 17 has the strongest association, suggesting that it is a major risk factor for the disease. Specific genes were not identified, but the search is narrowed. Determining these genetic mutations will allow for the development of genetic tests to identify dogs at risk for MCT, leading to better treatment strategies and breeding management.

Current Treatment

Oncologists generally agree that cytologic evaluation of fine needle aspirates is the most common method used to diagnose MCTs, with an excisional biopsy required for histologic grading of the tumor.

 “The mitotic index is used to measure the proliferation of the mast cell,” says Pedro A. Boria, DVM, Dipl. ACVIM (oncology), of Greater Cleveland Veterinary Internal Medicine and Oncology.“After a tumor grade has been determined, a treatment plan can be developed. Treatment of MCTs typically means removal of the mass with 2- to 3-centimeter margins if possible. If it isn’t possible to get this margin due to tumor location, I typically recommend radiation as well.”

If a tumor is too big for immediate removal or is of a higher grade, Dr. Boria says he may consider chemotherapy.

“My main concern with current treatment options is that radiation isn’t readily available in all areas,” Boria says. “In my case, clients must be willing to drive their pet to a location two or three hours away.”
How to prevent mast cell tumors is unknown, says Avenelle Turner, DVM, Dipl. ACVIM (oncology), of City of Angels Specialty Center and Veterinary Cancer Group in Culver City, Calif.

 “In cases of breed predisposition, research may reveal a way to detect an at-risk animal and deselect it for breeding,” Dr. Turner says. “Only about 5 to 10 percent of feline cancer patients present with mast cell tumors, and much less research is focused on the feline patient in this case.”

About 15 percent of dogs with a grade III mast cell tumor will live seven months postsurgically, Turner says.
 
“Once mast cell cancer has metastasized, dogs tend to die within six months from the symptoms of systemic illness,” Turner says. “We follow patients with low-grade tumors for 18 to 24 months postsurgically, but most become lifelong patients.”

Oncologists say early detection is the best hope. They urge primary care providers to remind clients to feel their pets’ skin and inspect it when something feels unusual.

“The worst mast cell tumor cases I’ve seen have been in shar-peis,” says Gamblin, of Metropolitan Veterinary Hospital. “It sometimes seems there are more questions than answers. We don’t know if there is a connection between shar-peis’ predisposition to allergic skin problems and the severity of mast cell tumor cases. This disease is both fascinating and frustrating.” 

 

 

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