Maximizing the dual benefit of pet dogs in cancer trials

Abstract

Pet dogs with cancer have catalysed the translation of preclinical discoveries to first-in-human trials, highlighting the unique power of comparative oncology to study veterinary and human patients with cancer in parallel. However, the full potential of this approach has yet to be harnessed. Here we highlight accomplishments in oncology due to trials in dogs and discuss the next steps to advance comparative oncology.

In 2024, across the USA, two million new cases of cancer were anticipated in people and upwards of four million new cases of cancer were predicted in dogs^1,2. Naturally arising tumours in pet dogs are considered to be one of the most organic settings in which to study oncology for human benefits, as they (1) occur in immunologically intact yet genetically diverse hosts, (2) share genotypic and phenotypic overlap with human tumours, (3) arise in environments cohabitated by humans, and (4) are responsive to a multimodal arsenal of treatments, including those used for human patients³. However, despite the frequent diagnosis of dogs with cancer and numerous comparative oncological advantages, the mutually beneficial potential of studying these parallel patient populations is yet to be fully realized.

The status quo of comparative oncology

Small-scale studies in veterinary patients conducted by independent groups highlight the utility of naturally occurring malignancies in dogs to assess investigational treatments and inform early phase human trials. For example, Mendez-Gomez et al.⁴ enrolled pet dogs with glioma into a study to validate the use of RNA aggregates for transforming the tumour microenvironment, which ultimately expedited translation of a novel immunotherapy from mouse studies to a phase I clinical trial. If this therapy successfully progresses through the subsequent cascade of clinical trials and is ultimately approved in humans, these veterinary patients will have tangibly contributed to the advancement of a critically needed new treatment. The reciprocal benefit of advanced human therapeutics entering veterinary clinics as established therapies requires equivalent large-scale prospective trials in dogs with cancer. However, the current lack of adequately powered multi-centred, prospective studies in veterinary oncology has resulted in few universally accepted standard-of-care approaches to treat cancer in pets.

Given the incidence of cancer in animals and the dedication of many owners to the wellbeing of their pets, the lack of large-scale clinical trials in veterinary medicine cannot be solely ascribed to absence of opportunity. Although it is possible to perform randomized, prospective studies at individual veterinary institutions, such trials can take 5 years or longer to complete⁵. This prolonged duration for patient accrual hinders the progress of veterinary oncology and limits the translational value of the canine model, which centres on the ability to generate clinical data more rapidly than can be done in human hospitals. Notably, when multi-centred approaches are utilized, veterinary trial completion can be expedited. The US Food and Drug Administration (FDA) recently granted full approval of rabacfosadine for canine lymphoma following a pivotal clinical field study, enrolling over 150 dogs with lymphoma across 7 sites within a 10-month period⁶. Although this agent did not progress past a phase I/II human trial (NCT00499239), it has been quickly incorporated into veterinary clinical practice and welcomed by veterinary oncologists as an effective agent for dogs with lymphoma. This also provides financial incentive to pharmaceutical companies to consider repurposing drugs that failed in humans to confer benefit in other species.

The Comparative Oncology Trials Consortium (COTC) comprises 19 academic veterinary sites across North America and is managed by the Comparative Oncology Program (COP) of the Center for Cancer Research, National Cancer Institute (NCI), US National Institutes of Health (NIH). This initiative has been at the vanguard of coordinating over 23 prospective veterinary trials and will be central to the success of future trials. While the COP provides scientific leadership for these trials, study sponsors and veterinary centres must provide the resources and staffing to execute case enrolment. As providing these resources can be cost-prohibitive, infrastructure to streamline clinical data and biospecimen collection, as well as funding to support patient enrolment, is needed to garner the maximal potential of pet dogs as a comparative model. Currently, such support is provided through initiatives such as the NCI Cancer Moonshot programme, but often restricts appraisal of novel therapeutic interventions to academic research centres. However, there is a vast number of private referral practices employing veterinary specialists who also provide expert-level oncological care to pet dogs. To date, engaging veterinarians working in private referral practice remains an underutilized opportunity for expanding networks of translational investigators.

Collaboration, coordination and education can help advance comparative oncology

Historically, research in dogs has been hindered by the lack of reagents specialized for dogs with cancer, such as antibodies, that have advanced cancer studies in both rodents and humans. Bespoke assays are now available, such as the nCounter Canine IO panel, enabling in-depth studies of tumour samples from dogs⁷. Other investigators have leveraged multiple omics approaches to generate large comparative datasets from dogs and human patients with glioma⁸. While such technological progress generates substantial amounts of data that could be shared amongst the research community, data sharing requires a substantial level of coordination. This need has been met in part by the establishment of the Integrated Canine Data Commons (ICDC), a harmonized and open access resource to shared datasets from dogs with cancer. In addition, the Pre-medical Cancer Immunotherapy Network for Canine Trials (PRECINCT) provides infrastructure and oversight to a selected network of clinicians and researchers.

The forethought of prior groups, such as the Canine Comparative Oncology and Genetics Consortium, which organized a biorepository of clinical samples from nearly 2,000 cancer-bearing dogs, collected at 8 sites across the country⁹, has laid the groundwork for biobanking in the comparative oncology community. However, ensuring that patient samples are properly stored and fully annotated with linked clinical outcomes requires centralized oversight, storage facilities and personnel support. Promoting the sustainability of such infrastructure is crucial to ensure unique samples are fully utilized. Similarly, efforts to increase the accessibility of PRECINCT’s key objectives, including data management and biostatistical support to the community at large, will be invaluable when designing and implementing next-generation comparative studies. Although several independent veterinary clinical trial websites do exist, the development of a central site equivalent to the NIH website for human trials would be beneficial for the timely dissemination of canine clinical trial information and thus enrolment, benefitting both veterinary professionals and dog owners.

Designing, coordinating and administrating large comparative oncology trials requires a highly educated workforce. Although veterinary residency programmes afford advanced clinical training to prospective oncologists in America and Europe, these medical programmes are frequently the final step in post-graduate veterinary education. It is approaching half a century since Wyngaarden¹⁰ first proclaimed medical clinical investigators to be an “endangered species”, yet the current status of veterinary clinician-scientists could be considered even more precarious. Thus, attempts to remedy the shortfall of scientists with clinical training, who are ideally positioned to translate preclinical research into veterinary trials, are of high value. This is exemplified by the noteworthy work performed by The Clinical Translational Science Award One Health Alliance, which facilitates advanced fellowship training for veterinarians. The recent launch of the American College of Veterinary Internal Medicine Fellowship Programs provides another exciting opportunity for training of veterinary specialists to maximize the performance of well-designed, multi-centre, prospective studies in the realm of comparative oncology. Integration of practicing veterinary oncologists into cutting-edge basic and translational cancer research involving multiple species will further inspire future generations of veterinary clinician-scientists. Nurturing this currently small group by expanding support of fellowship training at institutional and federal levels will enable the growth of a critical mass of veterinary clinician-scientists needed to fulfil the substantial potential of comparative oncology (Fig. 1).

Fig. 1 |. Harnessing the reciprocal benefits in comparative oncology to maximize the value of trials across both species.

The needs to further advance this strategy are shown in red boxes.

Conclusions

Small, yet intricate, trials of dogs with cancer are bridging the gap between conventional preclinical work and human patients with cancer, yet the true power of comparative oncology has yet to be realized. Collaborative development of infrastructure and training networks are required to maximize the dual benefit of comparative oncology trials and comprehend the many lessons that we may yet learn from our canine companions.