NEW YORK – Canine cancer firm One Health Company, along with collaborators at the University of Georgia, has discovered the largest overlap in cancer-related mutational hotspots between human and canine tumor genomes to date and hopes to exploit this finding to improve human cancer therapy development.
Last year, the researchers published their study, which involved 708 spontaneous canine tumors across 23 cancer types in 96 common pet breeds, in a preprint in BioRxiv that is currently undergoing peer review.
"This means that drugs designed to target specific hotspot mutations in humans can be trialed in dogs," Elinor Karlsson, director of the Vertebrate Genomics Group at the Broad Institute and a member of One Health Company's scientific advisory board, said via email.
The analysis uncovered 20 canine genomic regions that are prone to carcinogenic mutations, 13 of which have direct counterparts in the human genome.
Oncogenes with shared mutational hotspots included PIK3CA, KRAS, NRAS, BRAF, KIT and EGFR, and hotspot mutations significantly associated with specific tumor types included NRAS G61R and PIK3CA H1047R in hemangiosarcoma, ERBB2 V659E in pulmonary carcinoma, and BRAF V588E in urothelial carcinoma.
"I think we always expected that dog cancers would be driven by mutations in many of the same genes as human cancers, but it is really intriguing to see how often they seem to involve exactly the same genetic change in those genes," Karlsson said.
One Health Company sees this research as a path toward improving canine and human cancer care simultaneously and is positioning itself at the forefront of a potential shift toward using more dogs in cancer research.
The company, based in Palo Alto, California, raised $5 million in a 2019 seed funding round and $10 million in Series A financing in 2020. Its flagship product, FidoCure, a canine cancer screening assay launched in 2019 to identify cancer-driving mutations in dogs and to help veterinarians prescribe more targeted therapies, was used to analyze all biopsies taken in the study.
Approximately 500 US veterinary clinics currently offer FidoCure, and the company plans to reach 10,000 clinics over the next two years. FidoCure has also contributed to over 8,000 targeted therapy orders for canine cancer cases, according to Christina Kelly Lopes, founder and CEO of One Health Company. The company has generated an internal database consisting of the full genomes of an undisclosed number of the 2,500 canine tumors it has tested with FidoCure so far.
Although One Health's database mainly correlates the genomics, drugs, and outcomes relevant to canine cancer, "we can make this whole database actionable for humans," Lopes said, "and that's the goal."
She remarked that One Health is in early talks with several large and small biotechs interested in collaborating on human cancer trials, although she could not yet name any potential partners.
Through collaborations with the University of Georgia, Stanford University, and others, Lopes now hopes to leverage FidoCure as a bridge between canine and human cancer studies.
Dogs are regularly used in cancer therapy research already, but their use lags behind that of mice. Lisa Moses, a bioethicist in the Vertebrate Genomics Group at the Broad Institute, attributed this in large part to requirements placed on researchers by grant funders and publishers.
"A lot of the way grant funders require studies to be done is by using particular historically used models," she explained. "Another hurdle is, publications also expect that certain kinds of researchers are going to use certain kinds of models, because that's what's always been done."
Add to this the greater costs associated with upscaling drugs and immunological reagents for preclinical studies in dogs, as well as with hiring the required personnel, such as veterinarians and technicians, and an inertia working against dogs as research models emerges. Nonetheless, Moses said a concerted push is underway to bring dogs more fully into the fold.
The regulatory landscape governing the use of dogs — and of individually owned dogs in particular — is complicated on the one hand by a general sparsity of regulations and by property rights sometimes superseding what regulations there are. Here as well, Moses explained, many institutions are pushing to create clearer rules and governing bodies.
At the biological level, some researchers think that dogs make a better model than mice for cancer research. "The genomic similarities between cancers that occur in dogs and humans is a critical component of what makes companion dogs an exquisite model for studying human cancers, both in terms of etiology and treatment," Audrey Ruple, an associate professor of veterinary medicine at Virginia Tech and member of the Dog Aging Project, said via email.
Living outside of laboratory conditions may also prove advantageous when extrapolating the effects of medicines in dogs to humans.
"Companion dogs who are living in the 'real world' replicate lifestyles that are much closer to what humans are living because they are living with us," Ruple said. "The heterogeneity of their experiences means that the impact of new therapies found in controlled trials conducted in dogs are more likely to hold true in human populations than are drugs that are found to impact cancers in mice in laboratory settings."
The fact that canine cancers arise over the course of a dog's life through similar genetic processes, in addition to shared environmental stressors and lifestyles, may also contribute to these cancers' greater genetic complexity, as compared to mice.
"In laboratory mice, the cancers are induced and tend to be genetically less complicated than in humans," Karlsson explained, which likely factors into the high failure rate of therapies tested in mice.
Nonetheless, Karlsson emphasized that dogs are unlikely to replace mice outright as a model organism for cancer research. "But by including dogs in the therapeutic development process," she said, "we think we can make the human drug development process more efficient and effective, while also helping dogs survive cancer."