Targeted therapy for KRAS-driven vascular malformations – TRAS

Arteriovenous malformations (AVMs) are debilitating conditions caused by genetic mutations, which can be either inherited or somatic when acquired during embryonic development. KRAS gain-of-function mutations are frequently observed in sporadic AVMs, particularly those involving the brain vasculature. The mechanisms of disease progression in KRAS-driven AVMs are not well characterized, and there are no approved treatments available. Interestingly, KRAS mutations are commonly found in both vascular malformations and cancers, indicating a shared genetic link between the two conditions and providing an opportunity for cancer drug repositioning in patients with KRAS-driven vascular malformations. In two recent proof-of-concept studies published, we demonstrated that we can create mouse models carrying vascular malformations due to somatic mutations, identify and successfully reposition drugs under development in oncology, and quickly move toward clinical application. In this proposal, we aim to transform the outcomes and medical care of patients with KRAS-driven AVMs. Within this project, we will develop new preclinical models of KRAS-driven AVMs, decipher the mechanisms of disease development and progression, and identify new targeted therapies to provide personalized medicine for patients. By the end of the project, we will have established a world-leading position in KRAS-driven AVM patient care and drug repositioning.