Repositioning sitagliptin for treating cutaneous capillary malformations - Project Summary Cutaneous capillary malformation (CM, a.k.a, Port Wine Birthmark, PWB) is a defect of primitive capillaries in the skin during development. It mainly appears on the face with an estimated prevalence of 0.3-0.9% in newborns and is highly associated with many complicated types of vascular malformations and outgrowth syndromes, such as Sturge-Weber syndrome (SWS), Parkes-Weber syndrome, Klippel-Trenaunay syndrome, arteriovenous malformations (AVM), and CLOVES syndrome. Photobiological-based modalities, such as pulsed dye laser (PDL) or photodynamic therapy (PDT), are the common treatment options for CM; unfortunately, complete removal occurs in less than 10% of patients treated. In addition, about 20% of lesions have no response to laser, e.g., laser-resistant (PDL- or PDT-resistant) CM. The inadequate outcomes are unmet clinical barriers. This study will tackle these challenging clinical barriers by repurposing an FDA-approved anti- diabetic medicine sitagliptin to target laser-resistant CMs. In this proposal, a series of clinically relevant in vitro and in vivo models including CM-derived inducible pluripotent stem cells (iPSCs), their induced endothelial cells (iECs), vascular organoids (VOs), and mouse models with xenograft of CM iECs will be used. We will determine the therapeutic window of sitagliptin on laser-resistant CM iECs in vitro. We will dissect sitagliptin-mediated inhibition of antioxidant pathways as a novel mechanistic action to sensitize CM lesions. We will characterize how sitagliptin-modulated GPX activity, GSH and ROS levels in response to PDT. We will test if sitagliptin improves the outcomes of laser therapy on VOs in vitro and determine if oral administration of sitagliptin at non-toxic doses enhances the efficacy of PDT in xenograft mouse models. This study is highly translational. First, sitagliptin is among the top list of compounds generated through our data-driven drug repurposing pipline using the multiome datasets of CM iPSCs, iECs and patients’ biopsies. Second, sitagliptin is an FDA-approved drug, thus repurposing sitagliptin would be easier, cheaper, and more feasible than other candidate compounds. Third, PK/PD, safety, and real-world data of sitagliptin are available for its’ repurposing. Third, sitagliptin shows efficacy in nanomolar ranges, displaying a wide therapeutic window for pediatric patients. The successful completion of this proof-of-concept study will serve as a milestone and basis for a Go/No-Go decision for the further repositioning sitagliptin for off-label trials in patients.
