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A “Tail” of Two Species: New Canine Immuno-Oncology Research Offering.

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Laura Tabellini Pierre on March 1, 2021

NanoString has an unparalleled and longstanding tradition of developing best in class cancer research tools, thanks to an extensive knowledge accumulated in a decade of interrogating all aspects of the disease. Last fall, we welcomed a new addition to our collection of panels to support comparative oncology in canines, the nCounter® Canine IO Panel. The panel mirrors our human Immune Oncology collection’s content, but it was built with canine biology and genetics in mind. The panel enables Oncology researchers to potentially improve clinical trial success by translating findings from the treatment of spontaneous canine cancer to humans.

To create the Canine IO Panel, our scientists worked with the Consortium of Comparative and Veterinary Oncologists from the NCI Cancer Moonshot known as the PRECINCT consortium, and with the Freie University in Berlin – the largest veterinary center in Europe. Thanks to their expertise, they could add markers and biology tumor types common in canine cancers, ensuring a careful translation of human content to fit canine genomics and biology.

As this panel is designed to bridge knowledge between human and comparative biologists, we asked two experts in canine biology to share their experience. Vilma Yuzbasiyan-Gurkan, is professor of Microbiology and Molecular Genetics and Small Animal Clinical Sciences at Michigan State University, and Matthew Breen, is professor of Comparative Oncology Genetics in the Dept. of Molecular Biomedical Sciences at the NCSU College of Veterinary Medicine. This is an excerpt of the extended interview that you can find at the bottom of the page.

NSTG: What attracted you to comparative oncology, or how did you get into research in this area?

VYG: Because of its breeding structure, the dog world offers advantages from a genetics perspective. We have the best of both worlds as there is diversity in the variants existing within the dog genome. Yet, certain alleles have been concentrated in specific breeds giving us a cleaner genetic readout on how they contribute to a given disease or trait: the shortened life, the numerous individuals in a litter, the size, the multiple generations available for study; these traits allowed us to reach robust conclusions from a given set of families. This translates well to cancer and cancer genetics.

MB: I was working in the United Kingdom with a team that was developing new tools to identify dog chromosomes and determine which chromosomes were aberrant in canine cancer. It became very apparent that some chromosomes involved in both numerical and structural changes were conserved between canine and human cancers.

Those early observations fueled my interest in exploring the extent of genetic similarities in various other cancers shared between humans and dogs. About 25 years later, we have moved from just characterizing similarities at the chromosome level to now having the ability to identify shared mutational signatures.

This community of scientists is growing by the year. With the recent development of the integrated canine Data Commons group at the National Cancer Institute, we have the opportunity to appropriately curate canine similar to what was done with the human genome in clinical data with regards to cancers.

NSTG: Vilma, what do you consider to be the top challenges in cancer immunotherapy right now?

VYG: Immunotherapy is both a challenge and a great opportunity. We are in the very early stages of unleashing the power of our immune system against cancer, even if our understanding is just in its infancy. Right now, we have one major axis, the PD1-PDL1 and CTL4 that we can modulate and use as therapeutic targets. However, less than about 40% of patients can benefit from the modulation of that axis. We are just beginning to understand and characterize the players involved in the tumor micro-environment and its signals. Our ability to characterize them has been hindered by the tools and the samples we have. That’s why I am excited about the panels and queries we can make on samples that are relatively easy to get, such as the FFPE samples, or in small specimens that we can sequentially collect from patients.

NSTG: Matthew, what is it about dogs in particular that make them attractive in comparative studies of cancer?

MB: Both we as human beings and our dogs roughly developed the same kinds of cancers, but importantly we both do so spontaneously. And with so many dogs being diagnosed with cancer each year, there is a wealth of clinical data about naturally occurring cancers in dogs being gathered each year through their routine veterinary care.

Some breeds of dogs are more likely to be diagnosed with certain types of cancer than others, suggesting the existence of genetic factors associated with breeds that are potentially putting them at elevated risk. This provides us an opportunity to work with “at-risk” breeds. There are also greater opportunities for dogs to engage in clinical trials earlier in the course of their disease.

In addition to cancer’s genetic basis, our dogs live in our homes, drink the same water, sleep on the same couch, and eat some of the same foods. If we take them to the park, they run across the same herbicide and pesticide-treated grass that will walk across. It seems logical then that if natural or humanmade environmental influences are associated with cancer, we share those same daily exposures. Combining these two sides provides us with a tremendous opportunity to consider the impact of the genetic and environmental factors across both species.

NSTG: Vilma, what has been your experience with translating molecular findings into useful diagnostic or prognostic tools and do you have any insight to share on how their use of these canine models has enhanced human oncology research?

VYG: One of our early successes was identifying mutations in the c-kit locus in mast cell tumors (mastocytoma).

Our studies and others clearly showed that response to treatment and overall survival in dogs and humans depended on the presence or absence of c-kit mutations. This also served as the first molecular targeted therapy established for canine cancer. The response to Toceranib – the dog equivalent of Gleevec in humans – is still studied, but whether the c-kit mutation status of dog patients is an important variable is still under investigation.

But we work very closely with human medicine colleagues to understand how mastocytoma patients with a very indolent disease turns on and becomes a hard to treat and eventually a fatal disease. Indeed, dogs have the mutations, but not the aggressive disease: we are trying to understand what else happens in the tumor to turn into an aggressive and terminal cancer, hoping to be able to translate it to humans.

NSTG: Matthew, how do you see pet owners playing a role in helping your group advanced cancer research that may benefit dogs as well as people?

MB: I think we all have to remember that the dogs are the patients and the owners are the clients, and certainly over the past 20 years, we have been working with dog cancer specimens from literally thousands of dogs, each one of those specimens has been submitted to the lab at the request of the owners through the veterinarian. It never ceases to amaze me how, especially at times of great personal distress, dog owners have the courage to ask the veterinarians to take a piece of a tumor from their beloved companion and submit it to the NC State University or anywhere else so that the research community can investigate the specifics of that particular dog’s cancer. It is a very personal decision for dog owners, and it’s incredibly humbling when, in many cases, what we will learn from that particular specimen may not help that particular dog at all. But the dog owners know that by collecting data from numerous dogs, as a community, we can work together to find patterns that will help us to develop new ways to detect and hopefully identify new treatments for dogs in the future.

Many dog owners have told me that they derive quite a lot of comfort from knowing that their dog has contributed to helping other families avoid the pain and distress that their families are experiencing at that time. Without the commitment and collaboration of dog owners across the nation in these complex research projects, there wouldn’t be such a robust field of comparative oncology.

NSTG: How hard is it to do clinical trials and oncology in terms of permits on dogs.

VYG: It’s important for the audience to realize that dogs are our patients. We do have institutional animal care and use committees that oversee the research carried on dogs and do those with informed consent given by the owner. We have the very same concerns that we would have in launching human trials: what is the benefit, what is the rationale, what are the risks, and the outcomes. We are very frank and open with the owner. However, one aspect is quite different from the human world: the opportunity to carry out a clinical trial – if justified – on naive patients: we don’t have to wait for the standard of care failed to enlist that dog in a clinical trial.

It depends on the rationale for the scientific question and the potential benefit to the dog: the owner must understand the benefit/risk ratio appropriately.

Indeed, we have a significant opportunity: to test novel treatments on dogs at the early stages of their disease and not just at the very late stages, whereas most human trials can be launched once patients have failed the standard of care.

The dog serves the human oncology field by de-risking novel approaches and novel treatments, providing the drug development team important information about efficacy and safety in the human patient.

You can listen to the full interview here.

For Research Use Only. Not for Use in Diagnostic Procedures

Post by Laura Tabellini Pierre