Comparative oncology for tackling rare cancers

Rare cancers are responsible for almost one fourth of the total cancers in EU, have worse prognosis than common cancers and consequently their social and economic burden is extremely elevated in absolute terms. The limited number of available patients for each single disease sub-type renders difficult both the investigation of the involved biological mechanisms and the development of ad hoc effective pharmacological therapies. Also the design and test of complementary therapies is often slowed down by the absence of appropriate animal models which would recapitulate the human features. Pet dogs have been proposed as optimal animal model for oncological diseases since they develop spontaneous tumors with characteristics sufficiently similar to those of humans and are highly suitable for translational studies. Our programme aims at creating a powerful network of expertise to improve the quality of care for both, canine and human patients. Its major reference is the highly acknowledged US consortium for Comparative Oncology (https://ccr.cancer.gov/Comparative-Oncology-Program; Canine Comparative Oncology and Genomics Consortium (CCOGC) - www.ccogc.org) for which no similar counterpart exists at EU level. The three proposer groups wish to further innovate the idea by proposing a platform for the isolation of immunoreagents suitable for both diagnostic and therapy, able to recognize both canine and human antigens and to be applied to oncological diseases that are neglected by basic research and pharmaceutical development because of their rarity. The UNG group is a leading lab in ligand technology (phage display, in vitro panning, nanobodies, alternative scaffolds, antibody fragment functionalization), whereas the VLU is the absolute national reference for canine oncology and the OI group has international reputation in oncological therapy. In this perspective, our proposal would represent an ambitious and exclusive challenge, not only at the national level, but the participant quality will render feasible the goal accomplishment.

A major bottleneck in the development of new drugs is represented by the use of animal models that do not represent conveniently the characteristics of the disease in humans. This is typically the case of artificial tumors grafted into immunosuppressed mice. In contrast, dogs represent an excellent translational model since develop spontaneous tumors that share many clinical and epidemiologic features with human cancers including histologic morphology, tumor genetics, molecular targets, biologic behavior and response to conventional therapies. Cancer in pet dogs develops naturally in the context of an intact immune system, which is characterized by tumor growth over long periods of time within a syngeneic host and tumor microenvironment, developing recurrence and metastasis to relevant distant sites. Dogs have hepatic enzyme capacities similar to humans and the large body size of canines facilitates the collection of tissue biopsy and biological samples from the same patient during treatment exposure. However, with respect to humans, the shorter canine lifespan and more rapid disease course provide earlier results in terms of disease progression compared to human trials. In the case of rare tumors, the common problem of the clinical trials is that the low number of cases questions the statistical significance of the results. These discouraging limitation might be overcome by Comparative Oncology, namely the synergized use of data collected in human and canine patients sharing the same kind of tumor. This opportunity can be exploited to better understand the physiological bases of the disease as well as for the development of new curative strategies. In this sense, a programme dedicated to Comparative Oncology represents an unmet chance to progress in research fields that otherwise will remain neglected.

The research subject we propose is not the lowest common denominator among groups with independent interest. At the opposite, it originates in a strongly cooperative framework where different partners with complementary expertises, sharing the same aim, will participate. The output is an ambitious vision that lay the groundwork for a project of comparative oncology aimed at increasing the treatment effectiveness for rare cancers for which no cure is available. The patients will be the first to benefit from this project, alongside the pet dogs suffering of similar pathologies, which will be provided with improved care. Furthermore, we had the rare chance to establish in Slovenia a leading platform at EU level, since no systematic Comparative Oncology programme has been yet established. This accomplishment would increase the international visibility of Slovenian research and improve its capacity to attract international research funds.