New Study Looks at Why Cancer Treatments Cause Heart Damage

New drugs and therapies have become indispensable for treating an array of cancers. Unfortunately, they can also cause damage to the heart, a side effect that has led to the development of a new discipline in medicine, called cardio-oncology. 

Now teams from UC San Francisco and Stanford University will study why certain cancer treatments cause cardiotoxicities for some patients but not for others. Under the auspices of a Program Project Grant (PPG) from the National Institute of Health (NIH), the teams will combine resources from both universities, undertaking three interconnected projects that integrate multiple scientific disciplines and clinical and basic research programs to better understand toxicities associated with a novel class of cancer therapies called covalent kinase inhibitors. 
 
Javid Moslehi, MD, William Grossman Distinguished Professor in Cardiology and UCSF Section Chief of Cardio-Oncology and Immunology, will lead a team at UCSF that will identify specific signaling pathways associated with cardiovascular toxicities from covalent kinase inhibitors – a type of enzyme inhibitor that can block the function of these enzymes and have proven effective for treating certain cancers (Project 1).

“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 example of a covalent kinase inhibitor is ibrutinib, which inhibits B cell signaling and has been transformative in treating B cell malignancies; however, ibrutinib can cause cardiac arrhythmia like atrial fibrillation.

Moslehi and his team will focus on whether these cardiotoxicities are due to the intended target kinase (so called “on-target”) or due to an “off-target” effect. “We will combine cell and animal models developed in my laboratory with clinical population studies,” Moslehi adds.

An example of the latter is VigiBase, the World Health Organization (WHO) international pharmacovigilance database that provides access to patients with cardiovascular toxicities. The UCSF clinical cardio-oncology program, in combination with an extended network of collaborators, will be leveraged to identify actual patients with cardiotoxicity.

What are the genetic causes for developing cardiotoxicity?

In addition to Moslehi’s team at UCSF, Joseph C. Wu, MD, PhD, professor and director of Stanford Cardiovascular Institute, will establish a pooled “cell village” from patients experiencing cardiotoxicities after kinase inhibitors to study the genetic causes for developing cardiotoxicity (Project 2). Wu will also serve as the overall Principal Investigator of the PPG. Wu’s laboratory has a been a pioneer in modeling cardiac disease from patients using human induced pluripotent stem cells (hiPSC) in a technique called “clinical trial in a dish.” Cardiotoxicities can be modeled using innovative platforms and will be compared to patient and animal phenotype studies in Moslehi’s part of the study. Gene expression and the epigenomic state of each patient will help detect a target pathway that is affected by Ibrutinib. 

Mark Mercola, PhD, professor of Cardiovascular Medicine at Stanford University, who has pioneered the use of hiPSC-derived cardiac cells for therapeutic targets and early-stage drug discovery, will lead Project 3. Mercola’s project will be a pipeline for drug discovery based on epigenomic modifications of kinase inhibitors that will be exploited to define susceptibility and protective genetic loci.

“What is great about this PPG is interconnectedness and the collaboration across the aims of the project,” says Wu. “Dr. Mercola’s goals in Project 3 will be supported by the genetic identification of susceptibility loci in Project 2 and by animal mouse models in Project 1.”

“Our assembled group collectively introduces synergies that will significantly impact the field of cardio-oncology and make translationally actionable inroads to decrease the burden of adverse effects of chemotherapeutics,” said Moslehi.

About UCSF Cardio-Oncology and Immunology:
The UCSF Cardio-Oncology & Immunology Program was created with the goal of minimizing heart-health risks for patients during and after their cancer treatment. Because of the complex nature of these issues, UCSF has a diverse 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. There are also clinics focused on treating specific conditions, including: amyloidosis, carcinoid heart disease, myocarditis, and clonal hematopoiesis of indeterminate potential (CHIP).
 

About UCSF Health: UCSF Health is recognized worldwide for its innovative patient care, reflecting the latest medical knowledge, advanced technologies and pioneering research. It includes the flagship UCSF Medical Center, which is a top-ranked specialty hospital, as well as UCSF Benioff Children’s Hospitals, with campuses in San Francisco and Oakland, Langley Porter Psychiatric Hospital and Clinics, UCSF Benioff Children’s Physicians and the UCSF Faculty Practice. These hospitals serve as the academic medical center of the University of California, San Francisco, which is world-renowned for its graduate-level health sciences education and biomedical research. UCSF Health has affiliations with hospitals and health organizations throughout the Bay Area. Visit www.ucsfhealth.org. Follow UCSF Health on Facebook or on Twitter.