How Canine cancers may lead to gene-based treatments for both dogs and humans
Carolyn Duregger, D.V.M., has known her dog Parker since his birth. The veterinarian witnessed the Wheaten terrier’s birth while visiting a breeder, and took the fluffy-soft pup home a few weeks later, after weaning.
Her family had two good reasons to name the puppy Parker — husband, Dan, is a devotee of jazz saxophonist Charlie Parker while son, Dylan, is a big fan of comic superhero Spiderman, aka Peter Parker.
For nearly 10 years, Parker has generated a lot of love. So, it came as a shock to Dr. Duregger when, during a routine oral exam, she saw the telltale signs of melanoma in Parker’s upper right gums.
“My stomach dropped. I literally gasped,” she said, recalling the moment she noticed the 1-centimeter-diameter discolored lump, and suddenly realized Parker might be in big trouble. “It’s an aggressive cancer with poor prognosis that I’ve seen many times.”
Dr. Duregger surgically removed the cancerous node, and started Parker on radiation and an immunotherapy drug: “We’re hopeful he’ll get to live his normal lifespan.”
Current therapies don’t always last, but Dr. Duregger sees hope in the molecular-level research into canine cancers led by TGen. She’s intrigued by the notion that the similarities in dog and human cancers may lead to discoveries in human cancer research that could also help pups like Parker.
“The genetic research is so promising for fine-tuning the disease treatments and understanding the disease process,” she said.
In the most comprehensive study of its kind, TGen and its collaborators from across the nation recently used multiple genomic analysis techniques to identify several gene mutations that could be the keys to what drives melanoma in dogs. Following the path from human melanoma, the findings of recurring molecular changes in canine melanoma can help veterinary physicians pinpoint potential new treatments for dogs. Likewise, human physicians will view these changes in light of the type of melanoma that occurs in non-sun exposed areas (as in the case of Parker) in the mouth, or other mucosal surfaces.
In August, following a multi-year study, researchers reported identifying mutations in the PTPRJ gene —a tumor suppressor gene-— in the open access journal PLOS Genetics.
A Genomic Bridge Between Dogs and People
“This mutational landscape of canine melanoma resembles that seen in human melanoma subtypes found in sun-shaded areas of the body, such as the nose and mouth, which remain difficult to treat. This similarity means that we have a genomic bridge across which understanding of the disease in either species can inform the other,” said Dr. Will Hendricks, a TGen Assistant Professor of Integrated Cancer Genomics, and the study’s lead author.
While melanoma is commonly associated with skin cancer, different types of melanoma can originate in different parts of the body, and it often spreads to the lungs, lymph nodes, bones and brain.
The study examined several dog breeds with a propensity for melanoma, including Cocker Spaniels, an English Cocker Spaniel and a Labrador retriever. The paper — Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis — notes that an expanded study of breed-specific groups will be critical for further understanding of melanoma among dogs.
New Treatment Promising for Canine Lung Cancer
Now, TGen and The Ohio State University are leading a new study of lung cancer in dogs, funded in part by the Petco Foundation.
The study, which could have implications for people who have never smoked, builds on previous findings by TGen and Ohio State that neratinib — a drug that has successfully been used to battle a type of human breast cancer — may also work for many of the nearly 40,000 dogs in the U.S. that annually develop the most common type of lung cancer, known as canine pulmonary adenocarcinoma, or CPAC.
Neratinib inhibits a mutant cancer-causing form of the gene HER2, which is common to both CPAC and certain types of human breast cancer.
“With our colleagues at Ohio State, we have found that this novel HER2 mutation occurs in nearly half of dogs with CPAC, which presents an immediate therapeutic opportunity for a large proportion of dogs with this type of lung cancer,” Dr. Hendricks said.
As part of the study, a clinical trial using neratinib is planned for dogs with naturally occurring lung cancer that have the HER2 mutation.
First Precision Medicine Canine Lung Cancer Trial
“This study is groundbreaking because it not only identified a recurring mutation in this canine cancer that had never been found before, but it actually led directly to a clinical trial. This clinical translation from dog to human and back is the holy grail of comparative cancer research — findings in the dog helping people and findings in people helping dogs,” said Dr. Jeffrey Trent, TGen President and Research Director.
CPAC is an aggressive disease that clinically resembles human lung cancer among never-smokers. There is no standard-of-care treatment for CPAC and — prior to the work performed by the TGen-Ohio State team — little was known of the disease’s genetic underpinnings. While more than 30,000 human cancer genomes have been sequenced, fewer than 300 canine cancer genomes have undergone similar profiling.
“This is the first precision medicine clinical trial for dogs with lung cancer. That is, the selection of cancer therapy for a particular patient is based on the genomic profile of the patient's tumor and matched with agents that are known to specially target the identified mutation,” said Dr. Wendy Lorch, an Associate Professor in the Department of Veterinary Clinical Sciences at The Ohio State University College of Veterinary Medicine, who also will run the study’s clinical trial.
Studying how lung cancer can be better treated among dogs could provide insights into better treatments for humans with lung cancer, the leading cause of cancer death in the
U.S., annually taking the lives of more than 154,000 Americans.