Cardio-Oncology: How New Targeted Cancer Therapies and Precision Medicine Can Inform Cardiovascular Discovery

Abstract

Cardio-oncology (the cardiovascular care of cancer patients) has developed as a new translational and clinical field based on the expanding repertoire of mechanism-based cancer therapies. Although these therapies have changed the natural course of many cancers, several may also lead to cardiovascular complications. Many new anticancer drugs approved over the past decade are "targeted" kinase inhibitors that interfere with intracellular signaling contributing to tumor progression. Unexpected cardiovascular and cardiometabolic effects of patient treatment with these inhibitors have provided unique insights into the role of kinases in human cardiovascular biology. Today, an ever-expanding number of cancer therapies targeting novel kinases and other specific cellular and metabolic pathways are being developed and tested in oncology clinical trials. Some of these drugs may affect the cardiovascular system in detrimental ways and others perhaps in beneficial ways. We propose that the numerous ongoing oncology clinical trials are an opportunity for closer collaboration between cardiologists and oncologists to study the cardiovascular and cardiometabolic changes caused by the modulation of these pathways in patients. In this regard, cardio-oncology represents an opportunity and a novel platform for basic and translational investigation and can serve as a potential avenue for optimization of anticancer therapies and for cardiovascular research and drug discovery.

Keywords: cardiotoxicity; drug evaluation; molecular targeted therapy; pre-eclampsia; protein-tyrosine kinases; translational medical research.

Figure 1

Depiction of Cardio-Oncology as a platform for investigation and comparison to human genetics and traditional “bottom up” basic science. Human genetics has been a rich source for discovery in part because the initial observation occurs at a human level. Genetic identification of a heritable phenotype leads to subsequent in vitro and animal studies as a means of novel drug development. On the other hand, traditional “bottom up” basic science starts at the level of a molecule with subsequent experimental models testing the relevance of the molecule in vivo with the hope that this will ultimately prove relevant to humans. The latter may not be the case for many reasons. On the other hand, cardio-oncology inspired drug discovery may prove more similar to genetics given that the initial observation occurs in humans.

Figure 2

An overview of pathways that are activated in cancer and regulate cardiovascular homeostasis. Example of different kinase inhibitors used in cancer treatment. Extracellular antibodies include receptor inhibitors (e.g. trastuzumab), dimerization inhibitors (e.g. pertuzumab) or ligand inhibitors (e.g. bevacizumab). Small molecule multi-target inhibitors include tyrosine kinase inhibitors (which often bind to more than one receptor tyrosine kinase) or other small molecule inhibitors. An emerging group of therapies includes drugs that modulate protein degradation machinery including drugs like immunomodulators (e.g. lenalidomide) that activate an E3 ubiquitin ligase targeting one or more proteins for proteasome-mediated degradation.

Figure 3

Cardiovascular Complications Associated with VEGF Signaling Pathway Inhibition: Similarities to cardiovascular complications that can occur during pregnancy. Central role for VEGF signaling in both models.

Figure 4

A schematic of cardio-oncology in the future which incorporates various aspects of a clinical cardiology division, as well as basic and clinical investigation.