Patient-specific simulation of Retinal Hemangioblastoma provides new perspectives on the role ofantiangiogenic therapy

Abstract

Retinal Hemangioblastoma (RH) is the most frequent manifestation of the von Hippel-Lindau syndrome (VHL), a rare disease associated with the germline mutation of the von Hippel-Lindau protein (pVHL). An emblematic feature of RH is the high vascularity, which is easily explained by the overexpression of angiogenic factors (AFs) arising from the pVHL impairment. The introduction of Optical Coherence Tomography Angiography (OCTA) allowed observing this feature with exceptional detail. However, our understanding of RH is limited by the absence of an animal model fully recapitulating the tumor. Here, we exploit a cancer mathematical model as an alternative way to explore RH development and angiogenesis. We derived our model from the agreed pathology for this tumor and compared our results with patient-specific OCTA images. Our simulations closely resemble the medical images, proving the capability of our model to recapitulate RH pathology. Our results also suggest that angiogenesis in RH occurs suddenly when the tumor reaches a critical mass, with full capillary invasion in the order of days. These findings open a new perspective on the critical role of time in antiangiogenic therapy in RH, which has resulted ineffective. Indeed, it might be that when RH is diagnosed, angiogenesis is already too advanced to be effectively targeted with this mean.