Saturday, September 7, 2024
9/7/2024
SUMMARY Slow flow vascular malformations, including lymphatic malformations (LMs) and venous malformations (VMs), have been shown to be caused by somatic mutations in genes that hyperactivate the PI3K/mTOR or RAS signaling. LM/VM patients have severe morbidities and even mortality, and there are no FDA-approved treatments. Current therapies provide partial response and are non-curative. There is an urgent need to identify effective, biologically targeted therapeutics. We have discovered protein homeostasis dysfunction in pathogenic endothelial cells (ECs) isolated from LMs (LMECs) and VMs (VMECs). We demonstrate that this dysfunction is downstream of PI3K/mTOR hyperactivation, which results in increased VECADHERIN and CD31 synthesis, cytoplasmic accumulation, and decreased expression at the cell surface. We proposed that the excess of VECADHERIN/CD31 in the cytoplasm overwhelms the proteasome and lysosomal degradation pathways, which in turn perturbs VECADHERIN/CD31 functions essential to the quiescent blood and lymphatic vasculature. Supporting this hypothesis, we identified a novel class of drugs, proteasome inhibitors (PIs) that inhibit proteasome degradation and preferentially target cells with protein homeostasis defects as more efficacious at suppressing LMEC/VMECs growth when compared to currently used therapies. We hypothesize that PI3K hyperactivation induces protein homeostasis defects that contribute to LM/VM pathology and that targeting this dysfunction serves as a new avenue of therapeutic intervention. In Aim 1, we will determine the mechanism by which PIs suppress abnormal LM and VM growth using patient derived LMEC/VMECs with PI3K and/or RAS pathway hyperactivation. Transgenic mouse models that express either PIK3CAH1047 or KRASG12D using EC and LEC specific drivers will be used to assess the efficacy of 2 PIs, oprozomib and bortezomib, with a goal of prioritizing which PI can be repurposed for the treatment of LMs and VMs. In Aim 2, we will determine the role of protein homeostasis dysfunction in VM/LM pathobiology. Primary human ECs that overexpress pathogenic PIK3CA or KRAS variants and patient ECs will be used to understand the consequences and mechanisms by which increased VECADHERIN and CD31 expression and cytoplasmic accumulation overwhelms proteasome and lysosomal degradation pathways. We will also determine if drugs that improve protein degradation can normalize LMEC/VMEC pathology. The goal is to better understand how common pathogenic variants in LM/VMs contribute to their pathogenesis and determine if therapeutics that target protein degradation defects can be repurposed for LM/VM patients.
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