Federal Project Grant Award Summary

The National Heart, Lung, and Blood Institute (NHLBI), under its Cardiovascular Diseases Research program (CFDA 93.837), awarded The Leland Stanford Junior University $770,603 on July 15, 2026, to identify druggable targets for mitigating cancer therapy-induced cardiotoxicity. The project addresses cardiovascular adverse events—including hypertension, thrombosis, arrhythmia, and heart failure—associated with proteasome inhibitors (PIs) such as bortezomib, carfilzomib, and ixazomib used in multiple myeloma treatment. Through completion on March 31, 2030, Stanford will deliver research outputs across three coordinated objectives: characterization of PI-induced cytotoxicity profiles using patient-specific induced pluripotent stem cell-derived cardiomyocytes and endothelial cells (iPSC-CMs and iPSC-ECs); delineation of aberrant cellular crosstalk mechanisms using three-dimensional cardiac organoids, mouse models, and single-cell multi-omics approaches; and execution of a large-scale CRISPR interference/activation (CRISPRi/a) druggable target screen employing customized lentiviral short guide RNA libraries.

Deliverables include functional validation and molecular characterization of the two lead gene targets identified through the screening pipeline, supported by molecular docking studies and drug candidate confirmation conducted in both in vitro and in vivo systems. These research activities are designed to uncover cardiovascular protective mechanisms applicable to targeted cancer therapies, addressing a critical gap in understanding proteasome inhibitor-induced cardiovascular toxicity through mechanistic, cell-type-specific analysis and translational validation.