The five-year relative survival for all cancer sites has been steadily improving since the 1980s. Because cancer is becoming increasingly treatable, there is a growing focus on managing the side effects that have a strong negative effect on quality of life. 15% of cancer patients experience deteriorated heart function and 2.5% experience heart failure. Side effects of decreased cardiac function include shortness of breath, heart palpitations, and fluid retention. Clinically this has traditionally been identified and tracked by measuring the deformation of the heart while beating. This was done previously using an EKG or MRI. Newer methods use an Ultrasound for speck tracking echocardiography. An even newer method uses elevated Troponin levels in the blood to track cell death.
Doxorubicin, Trastuzumab, and Pembrolizumab are three examples of critically important anticancer agents that damage the heart as a side effect of treatment. Doxorubicin and its family of drugs have been a mainstay of treatment since its approval in the 70s. It causes cardiac damage through the generation and buildup of free radicals. But it is not just older treatments that can cause cardiac problems. Targeted therapies like Trastuzumab and immunomodulators like Pembrolizumab result in damage to the heart either by inhibition of important molecular pathways or from direct damage to the heart by cytotoxic T cells.
To preclinically identify potential cardiotoxic effects, we have developed a suite of cell-based assays of increasing complexity to investigate cardiotoxicity and mimic the relevant clinical endpoints. Primary neonatal cardiomyocytes can be induced to beat in time. Primary cardiomyocytes grown as a spheroid will spontaneously beat in time. After treating either model with a potential therapeutic there are a plethora of useful endpoints to investigate. Live cell imaging of calcium flux provides rate and amplitude of contractility. Reactive oxygen species generation, cell viability, and cytoskeletal rearrangement can all be analyzed using small molecule fluorescent probes. Troponin levels can be monitored by ELISA and PCR. Fluorescent immunohistochemistry can be added to identify cell subpopulations and protein expression.
If you are ready to begin counter screening for cardiotoxic effects, reach out to a Visikol Scientist today to discover which model is appropriate at your stage of drug development.
