New potential tyrosine kinase inhibitors (TKIs) for the treatment of canine mast cell tumors (MCTs)

• Grant number: 24/03600-3
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Start date: August 01, 2024
• End date: January 31, 2025
• Field of knowledge: Agronomical Sciences - Veterinary Medicine - Animal Pathology
• Principal Investigator: Ricardo de Francisco Strefezzi
• Grantee: Fernanda Ramalho Ramos
• Supervisor: Emir Hadzijusufovic
• Host Institution: Faculdade de Medicina Veterinária e Zootecnia (FMVZ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Ludwig Boltzmann Gesellschaft, Austria
• Associated to the scholarship: 23/00296-9 - Evaluation of CD30 expression in canine cutaneous mast cell tumours and its relation to prognosis, BP.MS

Abstract

Mast cell tumors (MCTs), being the third most common tumor subtype in dogs, are a significant focus in veterinary oncology due to their prevalence and diverse clinical behaviors. The prognosis relies on clinical staging and histopathological grading. While well-differentiated MCTs can be cured by applying wide-margin surgery, a high percentage of less differentiated tumors are either inoperable or recur after surgery. In addition to the destruction caused by neoplastic proliferation, neoplastic mast cells (MC) often lead to severe paraneoplastic syndromes due to the release of chemical factors such as histamine and heparin. The causes of MCTs are still unknown. However, mutations in the KIT receptor proto-oncogene (KIT) represent a prevalent occurrence in MC tumorigenesis. This research aims to assess the impact of novel tyrosine kinase inhibitors (TKIs), such as avapritinib, ripretinib, nintedanib, and bezuclastinib, which are used or tested for treatment of human neoplastic MC disorders, on canine neoplastic MC in vitro. The objectives include evaluating individual and combined effects of TKIs on proliferation, survival, and activation of canine neoplastic MC, including investigating their potential to reduce IgE-mediated histamine release. Two canine MC lines (C2 and NI-1) will be used in this project. Furthermore, we will analyze cells isolated from primary canine MCTs. This research seeks to contribute valuable insights into the potential of novel TKIs as an improvement in the treatment of canine MCTs. In the future, the goal is to test the most promising candidate in a follow-up multi-cancer clinical study in dogs suffering from MCTs.