Common targetable biomarkers in canine hemangiosarcoma and human angiosarcoma

Rare cancers are globally responsible for almost one fourth of the total cancers in EU and have worse prognosis than common cancers. Consequently, their social and economic burden is extremely elevated in absolute terms. However, pharma companies usually focus on diseases of higher potential economic interest and basic research is hampered because the relatively limited number of available patients obstructs both the investigation of the involved biological mechanisms and the development of effective pharmacological therapies. The shortcoming of appropriate animal models that would recapitulate human features is another critical issue. Under these inferior conditions, tumor surgical excision is the only curative option but the scarce availability of reagents for precise imaging of primary and metastatic tumor lesions often limits its effectiveness. Pet dogs have been proposed as animal model for oncological diseases since they develop spontaneous tumors with characteristics sufficiently similar to those of humans and are often suitable for translational studies. From the perspective of the One Health initiative, the canine-based comparative oncology has already successfully contributed to the understanding of molecular and clinical features of some rare human cancer diseases and the development of diagnostic reagents and therapeutic solutions suitable for both species. Projects of molecular profiling of canine patients have already been undertaken to enable direct comparison with human subjects and to maximally exploit the information inferred from canine cancers for improving Personalized Medicine trials in humans. Once the similarities between canines and humans will have been established for a specific tumor type, the path will be paved to develop reagents, possibly cross-reacting, and to perform studies in parallel in the two species. Angiosarcoma (AS) is a rare (1 case/1 million people, corresponding to roughly 1% of all yearly diagnosed sarcomas), genomically complex and aggressive vascular sarcoma. The limited availability of patients impaired the development of effective therapies and consequently, the survival rate is dramatically poor. Dogs spontaneously develop histologically similar neoplasia, hemangiosarcoma (HSA) that is relatively common, representing 5-7% of all canine malignant tumors with an incidence that is significantly higher in breeds such as German shepherd and boxer. Both AS and HSA are considered to originate from hematopoietic endothelial progenitor cells. Despite the fact that AS is predominantly cutaneous in humans and HSA visceral in dogs, metastasis are mostly localized in lungs and liver in both models and comparative genomic analyses confirmed strong similarities between AS and HSA as well as the high but convergent heterogeneity within and between patients of both species. At protein level, immune histochemical and gene expression analyses indicated the overexpression of CD31, VEGFR1, VEGFR2, VEGFR3, PDGFRA/B, MUC18, CD117 (c-Kit) and FGFR1 in at least part of the evaluated samples and consequently such receptors could serve as HSA membrane, accessible markers. Data relative to AS cell surface targetable biomarkers are more limited in number but suggest overexpression of VEGF receptors as well as of c-Kit. The HSA prevalence and the prior knowledge justifies the interest for exploring HSA as a tractable model for studying human AS, developing drug and immunotherapies as well as testing experimental therapies in clinical trials. The project general aim is to isolate a set of immunoreagents suitable for the characterization, diagnostics and, potentially, therapy of HSA in dogs. They should target biomarkers exposed at the cell surface, allowing the selective targeting of the corresponding cells in tissues. Furthermore, they could serve as reagents for implementing similar diagnostic protocols in human AS.