Selected Grantee Publications
- Clear All
- 2 results found
- Cancer
- Spectrometry
- 2024
Identifying Mitigating Strategies for Endothelial Cell Dysfunction and Hypertension in Response to VEGF Receptor Inhibitors
Camarda et al., Clinical Science. 2024.
https://pubmed.ncbi.nlm.nih.gov/39282930/
Vascular endothelial growth factor receptor inhibitor (VEGFRi) use can improve survival in patients with advanced solid tumors, but outcomes can worsen because of VEGFRi-induced hypertension, which can increase the risk of cardiovascular mortality. The underlying pathological mechanism is attributed to endothelial cell (EC) dysfunction. The researchers performed phosphoproteomic profiling on human ECs and identified α-adrenergic blockers, specifically doxazosin, as candidates to oppose the VEGFRi proteomic signature and inhibit EC dysfunction. In vitro testing of doxazosin with mouse, canine, and human aortic ECs demonstrated EC-protective effects. In a male C57BL/6J mouse model with VEGFRi-induced hypertension, it was demonstrated that doxazosin prevents EC dysfunction without decreasing blood pressure. In canine cancer patients, both doxazosin and lisinopril improve VEGFRi-induced hypertension. This study demonstrates the use of phosphoproteomic screening to identify EC-protective agents to mitigate cardio-oncology side effects. Supported by ORIP (K01OD028205), NCI, NHGRI, and NIGMS.
Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in Response to Anti-PD-1 Immune Checkpoint Inhibitor Cancer Therapy
Racine et al., Journal of Immunology. 2024.
Myocarditis has emerged as a relatively rare but often lethal autoimmune complication of checkpoint inhibitor (ICI) cancer therapy, and significant mortality is associated with this phenomenon. Investigators developed a new mouse model system that spontaneously develops myocarditis. These mice are highly susceptible to myocarditis and acute heart failure following anti-PD-1 ICI-induced treatment. Additionally, the treatment accelerates skeletal muscle myositis. The team performed characterization of cardiac and skeletal muscle T cells using histology, flow cytometry, adoptive transfers, and RNA sequencing analyses. This study sheds light on underlying immunological mechanisms in ICI myocarditis and provides the basis for further detailed analyses of diagnostic and therapeutic strategies. Supported by ORIP (U54OD020351, U54OD030187), NCI, NIA, NIDDK, and NIGMS.