Basic Research in Hemangioma and Vascular Malformations
Laboratory research at Cincinnati Children’s provides the foundation for innovations in the treatment of hemangiomas, rare vascular tumors, and vascular malformations.
Our research currently focuses on:
Learning More About Venous Malformation (VM)
Vascular anomalies are birthmarks caused by defects in the vascular system affecting capillaries, arteries, veins or lymphatics (or a combination of these) and involve increased number or vessels and / or vessels that are enlarged and sinuous. Our laboratory is investigating venous malformation (VM). VMs are slow-flow lesions composed of ectatic veins with irregular smooth muscle cell coverage. VMs cause deformity, pain, local intravascular coagulopathy, and they expand with time. Activating mutations in the endothelial cell tyrosine kinase receptor TIE2 and PIK3CA genes are a common cause of these lesions. We recently generated a model of VM by injecting human umbilical vein endothelial cells (HUVECs) expressing the most frequent VM-causing TIE2 mutation TIE2-L914F into immune-deficient mice. TIE2-L914F-expressing HUVECs formed VMs with ectatic blood-filled channels that enlarged over time.
Targeted pharmacological therapies are not available for the treatment of VM, therefore we used our murine VM model to test candidate drugs for their efficacy in preventing lesion growth. The mTOR inhibitor rapamycin effectively prevented VM growth through its ability to reduce mutant TIE2-induced AKT signaling.
Our VM model allows evaluation of potential therapeutic strategies; an ongoing prospective clinical pilot study demonstrated that rapamycin provides clinical improvement in patients with venous malformation. In six patients with difficult–to-treat venous anomalies, rapamycin reduced pain, bleeding, lesion size, functional and esthetic impairment, and intravascular coagulopathy. Read the full article.
Currently we are testing an array of FDA-approved drugs for their effects on TIE2 mutant endothelial cells and on murine VM growth and regression to identify a drug that can be used alone, or in combination with rapamycin, to increase clinical improvement in patients. Read the full article.
Generating a Murine Model of GNAQ-related Vascular Anomalies
A class of life-threatening vascular tumors are associated with the p.Q209L mutation in the guanine nucleotide-binding protein G(q) subunit alpha (GNAQ) gene family causing excessive, uncontrolled activity of the protein encoded by this gene. A roadblock to finding effective, non-invasive treatments has been the lack of animal models for the study of disease development and targeted treatment. Our laboratory has developed a murine model of GNAQ mutant vascular tumors that recapitulate important steps of the patients’ disease progression and complications. We showed the mutation results in excessive proliferation of the vascular cells which is linked to the hyperactivation of the MAPK signaling pathway. This model allows for groundbreaking preclinical studies. With this model, we showed that targeted treatment with the MAPK inhibitor Trametinib can improve survival by reducing cell proliferation and preventing the development of the coagulopathy complication. Read the full article. Currently we are screening for additional signaling molecules crucial for the tumor formation and growth, our goal is to identify additional targets for therapy. Additionally we are investigating the molecular pathways driving the life-threating coagulopathy (Kasabach-Merritt Phenomenon, KMP) that can develop in patients. We hope this will help the development of effective targeted therapeutic strategies that can be used in patients in the near future.
Associated Research Labs
The goal of our research is to investigate the underlying mechanisms and identify potential new therapies for vascular anomalies, especially lymphatic malformations in children and adults. A major area of our focus is understanding the disease-causing pathways in patients with Kaposiform Lymphangiomatosis (KLA), a rare but devastating lymphatic anomaly. Our work focuses on the role of somatic gene mutations, signaling pathways, and vascular growth factors. Our approach is to use use human endothelial cells in culture and genetic mouse models to better understand the disease and test potential new therapies.
Biomarkers for Vascular Anomalies
Our group also utilizes patient blood and tissue samples to identify disease biomarkers that can used for diagnostic testing, monitoring responses to therapies, and potentially gain further insights into the pathobiology of these diseases. One of our most recent biomarker discoveries is that angiopoietin-2 (ANGPT-2), a pro-angiogenic protein/factor, is increased in the blood (serum) of patients with KLA and Kaposiform Hemangioendothelioma (KHE). This led to a clinical test that can be used to help in diagnosis and monitoring response to therapies - The ANGPT-2 test is available through our Hemostasis Thrombosis Laboratory (HTL) clinical lab.
Associated Research Labs
Once a month, researchers from basic science labs meet with clinicians to discuss the latest findings during the Vascular Translational Research Conference to create a bench-to-bedside and bedside-to-bench pipeline of ideas to benefit patients with these rare conditions.
Current clinical research includes:
- Clinical trials involving new investigational treatments, including medications.
- Data collection and chart reviews for research registries that will help us better understand the disease processes.
- Lab collections for future analysis and studies in Research Repositories.
See the full list of ongoing research studies and clinical trials specific to hemangiomas and vascular malformations at Cincinnati Children’s Hospital.