Personalized nanomedicine for gastrointestinal stromal tumors driven by rare mutations

Gastrointestinal stromal tumors (GISTs) are a common type of sarcoma that develops in the digestive system, mostly the stomach and small intestine. They are divided into two major types: KIT receptor-driven and platelet-derived growth factor receptor α (PDGFRα)-driven, the latter being the focus of this project. Both types are characterized by rapid cell growth and have a poor prognosis if not detected early. Avapritinib was approved by the U.S. food and drug administration (FDA) in 2020, a tyrosine kinase inhibitor designed specifically to inhibit the most common PDGFRα mutation. However, among the side effects reported by patients, were harsh neurological and cognitive effects that resulted in reduced dose and reduced quality of life. By using novel formulations of drug nano-aggregates coated and stabilized by polydopamine, we aimed to achieve a tumor targeted treatment with fewer side effects while maintaining the efficacy. In order, to further improve treatment efficiency and prevent the development of resistance, drug combination screen have been tested in-vitro and showed promising results of several combinations (including 17-AAG, Trametinib and ponatinib). We were able to formulate nanoparticles that encapsulated Avapritinib alone or other combinations of drugs with an encapsulation ratio of approximately 70% while maintaining their activity in-vitro.