Prospective identification and potential amelioration of cardiotoxicity is a critical component of contemporary drug development, particularly for targeted therapies (e.g., tyrosine kinases) in oncology that are designed to inhibit critical signaling pathways shared by both the tumor cell and the cardiac myocyte (e.g., HER2 and C-Abl). Current preclinical approaches to cardiac safety, which often focus primarily on ion channel testing (e.g., hERG), need to broaden the in vitro test menu to assess other cellular functions that are critical to cardiac cell health. Accordingly, effective nonclinical cardiotoxicity screening programs need to be implemented earlier in the development process.
Stem-cell technologies offer induced pluripotent stem-cell-derived (iPSC) cardiac myocytes that are pure, functionally relevant (exhibit electrical profiles in culture and are amenable to patch-clamp-like studies that monitor electrical potentials and voltage-gated ion channel function), and are human in origin. The following would comprise an effective preclinical cardiac safety testing program utilizing iPSC-derived cardiac myocytes:
- Determining influences on key cardiac metabolic pathways focusing on AMPK;
- Evaluating changes in fatty acid beta-oxidation;
- Measuring changes in mitochondrial health , reactive oxygen species production, and ATP levels;
- Assessing drug-induced apoptosis;
- Survey potential off-target effects using a comprehensive kinase profiling platform.
In addition to the above, the preclinical program should identify compounds that demonstrate cardio-protective effects with regard to mitochondrial health and energy homeostasis.
ABL1 = a proto-oncogene which encodes a cytoplasmic (C-ABl) and nuclear protein tyrosine kinase. Implicated in processes of cell differentiation, cell division, cell adhesion, and stress response.
AMPK = a metabolic sensor of cellular ATP. Controls fatty acid oxidation and glucose uptake in skeletal muscle, heart, and liver.
ATP = adenosine-5′-triphosphate, a multifunctional nucleoside triphosphate used in cells as a coenzyme. Responsible for intracellular energy transfer.
HER2 = “Human Epidermal growth factor Receptor 2,” a receptor required for healthy heart function.
hERG = the human Ether-à-go-go Related Gene. Codes for a potassium ion channel protein.
Source – Drug Discovery and Development