Hegde Research Lab: Therapeutically targetable molecular pathways in cancer and pulmonary hypertension
We use a combination of animal models, single-cell transcriptomics, mechanistic biochemistry and structure-aided drug design to elucidate mechanisms that promote, and interventions that prevent, the proliferation of cells under conditions of oxidative stress.
Current research in the Hegde Lab focuses on two areas: cancer biology and pulmonary arterial hypertension.
Cancer Biology: Biomarker-informed treatment for Ewing Sarcoma
Ewing sarcoma is a rare pediatric cancer of the bone and surrounding soft tissue. If detected early (before metastasis), radiation and surgery followed by chemotherapy can be effective. However, for patients with metastasis or with recurrent disease there is no standard treatment protocol, and the prognosis is very poor. Furthermore, heterogeneity among patient tumors makes for varied responses to newer targeted therapeutics. Hence, there is an urgent need to devise strategies that prevent incurable recurrences, and match patient tumors with the appropriate targeted therapeutics. This is the overall objective of this project.
We work closely with our clinical collaborators in the Sarcoma Program at Cincinnati Children's Hospital Medical Center to obtain patient tumor samples, establish both in vivo (patient-derived xenografts) and in vitro (tumor organoid) models for the analyses of tumor-specific signaling pathways that can be therapeutically targeted. In recent work we have shown that Ewing sarcoma tumors can be classified into two groups – one in which replication stress levels are high and IGF1R is membrane-associated, and another in which replication stress levels are low and IGF1R is nuclear. These distinct molecular signatures correlate with differential sensitivity to drugs targeting the replication stress response ad IGF1R kinase activity. In ongoing studies, we are further refining biomarkers of treatment response and attempting to match them with targeted therapeutic regimens. This project utilizes numerous techniques including in vivo tumor models, 3D tumor models, biochemical and cell-based analyses of cell signaling pathways, drug screening, phospho-proteomics and single-cell transcriptomics.
Pulmonary Arterial Hypertension
Targeting vascular remodeling in Pulmonary Arterial Hypertension
Pulmonary Hypertension (PH) is a pathophysiologic condition characterized by elevated pressure in the pulmonary arteries. Pulmonary arterial hypertension (WHO Group I PH; PAH) is a particularly severe form of PH frequently associated with right heart failure and premature death. There is no cure, and treatments only target the symptoms. Approximately 50% of PAH patients die within five years of diagnosis. There is therefore a compelling, unmet need for new therapeutic strategies.
Pulmonary vascular remodeling is the defining pathological feature of PAH. It leads to occlusion of distal pulmonary arterioles, with accompanying increase in pulmonary vascular resistance. Vascular remodeling is promoted by the survival and proliferation of pulmonary arterial vascular cells under conditions of oxidative stress and in the presence of DNA damage. We have shown that the Eyes Absent protein (EYA3) promotes survival of DNA damaged cells facing a survival-versus-apoptosis decision. EYA3 is a druggable and mechanistically unique protein tyrosine phosphatase (PTP) present at elevated levels in pulmonary arterial smooth muscle cells isolated from PAH patients. In proof of principle studies, we show that transgenic mice harboring an inactivating mutation in the EYA3 PTP domain are significantly protected from vascular remodeling in a chronic hypoxia model, and that inhibitors of EYA3 PTP activity reverse vascular remodeling in a rat model of experimental angio-obliterative PH.
The overall goal of this project is to establish the EYA3-PTP as a disease-modifying target whose function in the pathophysiology of PAH can be targeted by available inhibitors. This will be a critical milestone in pre-clinical drug target validation and will be achieved through genetic and pharmacological approaches.