Low dose AKT inhibitor miransertib cures PI3K-related vascular malformations in preclinical models of human disease

Abstract

Low-flow vascular malformations are congenital overgrowths composed by abnormal blood vessels potentially causing pain, bleeding, and obstruction of different organs. These diseases are caused by oncogenic mutations in the endothelium which result in overactivation of the PI3K/AKT pathway. Lack of robust in vivo preclinical data has prevented the development and translation into clinical trials of specific molecular therapies for these diseases. Here, we describe a new reproducible preclinical in vivo model of PI3K-driven vascular malformations using the postnatal mouse retina. This model reproduces human disease with Pik3ca activating mutations expressed in a mosaic pattern and vascular malformations formed in veins and capillaries. We show that active angiogenesis is required for the pathogenesis of vascular malformations caused by activating Pik3ca mutations. Using this model, we demonstrate that low doses of the AKT inhibitor miransertib both prevents and induces the regression of PI3K-driven vascular malformations. We confirmed miransertib efficacy in isolated human endothelial cells with genotypes spanning most of human low-flow vascular malformations.

Immunoregulatory subtype of dermal lymphatic endothelial cells at capillary terminals drives lymphatic malformations

“…In agreement with previous observations (7,16,41), proliferation was a common early response of venous ECs and LECs to oncogenic Pik3ca. However, proliferation was sustained selectively in LECs of advanced lesions.…”

“…Modelling of Pik3ca-driven venous malformations in the mouse retina recently uncovered that active angiogenesis is required for vascular overgrowth (41), similar to what has been reported in other types of vascular malformations (42)(43)(44)(45). Here, we observed a similar vascular response to Pik3ca H1047R expression in growing embryonic as well as quiescent postnatal dermal blood and lymphatic vessels.…”

Angiocrine polyamine production regulates adiposity

“…To elucidate endothelium-regulated systemic metabolic processes, we developed a model of enhanced EC-autonomous angiogenesis. Given that EC proliferation is primarily governed by PI3K signaling 11,13,14 , we studied the systemic consequences of sustained PI3K activity in the endothelium by Pten loss 14 . We bred Pten flox/flox mice 15 with PdgfbiCreER transgenic mice 16 (hereafter referred to as Pten iΔEC ), which enables the deletion of Pten in ECs in a tamoxifen-inducible manner.…”

“…Polyamines are polycationic metabolites synthesized from methionine and ornithine 38 . 13 C-methionine tracing revealed a remarkable increase in metabolites related to polyamine biosynthesis in isolated Pten-deficient ECs, including 13 C-labeled spermidine and spermine (Fig. 6g and Extended Data Fig.…”

“…ECs are exquisitely sensitive to PI3K fluctuations, with both too much and too little PI3K signaling resulting in defects in vascular development 11,12 . Analysis at single-cell resolution has shown that genetic manipulation of the PI3K/PTEN pathway primarily impacts cell proliferation 11,13,14 . Here we show that ECs, through the release of specific angiokines, regulate the function of WAT with systemic metabolic implications.…”