A collaborative research team from UC San Francisco and Stanford University has been awarded a Program Project Grant (PPG) from the National Institutes of Health (NIH) to investigate the mechanisms behind cancer treatment-induced cardiotoxicity. The study will focus on a novel class of cancer therapies known as covalent kinase inhibitors, which, while effective against certain cancers, can cause significant heart damage in some patients.
The research aims to understand why some individuals experience cardiotoxicity while others do not, with a focus on covalent kinase inhibitors. Javid Moslehi, MD, UCSF Section Chief of Cardio-Oncology and Immunology, will lead a UCSF team to identify specific signaling pathways associated with cardiovascular toxicities from these inhibitors. "Covalent kinase inhibitors are generally more specific and targeted than first generation of kinase inhibitors and yet we observe a myriad of unexpected cardiovascular toxicities," said Moslehi.
One notable example is ibrutinib, a covalent kinase inhibitor used to treat B cell malignancies. While transformative, ibrutinib can induce cardiac arrhythmias like atrial fibrillation. Moslehi's team will investigate whether these cardiotoxicities result from the drug's intended target (on-target effects) or unintended interactions with other molecules (off-target effects). The team will combine cell and animal models with clinical population studies, including data from VigiBase, the World Health Organization (WHO) international pharmacovigilance database, to identify patients with cardiotoxicity.
Genetic Causes of Cardiotoxicity
Joseph C. Wu, MD, PhD, director of the Stanford Cardiovascular Institute, will lead efforts to establish a "cell village" derived from patients experiencing cardiotoxicity after kinase inhibitor treatment. This project aims to study the genetic causes of cardiotoxicity using human induced pluripotent stem cells (hiPSC) to model cardiac disease. Wu's lab will employ a "clinical trial in a dish" approach, comparing cardiotoxic effects modeled in hiPSC-derived cells with patient and animal phenotype studies. Gene expression and epigenomic analysis will be conducted to identify target pathways affected by drugs like ibrutinib.
Drug Discovery Pipeline
Mark Mercola, PhD, professor of Cardiovascular Medicine at Stanford University, will lead a drug discovery project focused on epigenomic modifications of kinase inhibitors. This project aims to define genetic loci that confer susceptibility or protection against cardiotoxicity. "What is great about this PPG is interconnectedness and the collaboration across the aims of the project," said Wu. Mercola’s project will be supported by the genetic identification of susceptibility loci and animal mouse models.
The UCSF Cardio-Oncology & Immunology Program was created to minimize heart-health risks for patients during and after their cancer treatment. The program includes a team of cardiovascular specialists collaborating with doctors and researchers at UCSF Bakar Cancer Hospital, as well as the UCSF Cardiovascular Research Institute and other medical centers worldwide. The program treats patients with heart-related side effects from cancer treatments, newly diagnosed cancer patients who already have cardiovascular issues, people with inflammatory heart conditions, patients with metabolic issues or disorders and cancer survivors.
