04:53pm Monday 23 October 2017

Using Stem Cells to Predict Toxicity of Chemotherapy Drugs

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Immunofluorescence image of a cardiomyocyte — heart muscle cell — derived from human-induced pluripotent stem cells.

A team of scientists has developed a new safety index for a common group of chemotherapy drugs, by using a stem cell model to screen such therapies for their potential to damage patients’ hearts.

The study, published in Science Translational Medicine, was co-authored by Paul Burridge, PhD, assistant professor of Pharmacology.

Tyrosine kinase inhibitors (TKIs), a class of chemotherapy drugs, have become increasingly important in treating many types of cancer. But almost all TKIs are also associated with cardiovascular side effects — ranging from arrhythmias to heart failure — and there has not yet been an effective tool to predict this cardiotoxicity.

In the current study, the scientists demonstrated that human-induced pluripotent stem cells can be used to model how TKIs might affect the hearts of patients receiving chemotherapy.

To do so, the scientists took stem cells from both a control group and patients with cancer and reprogrammed them to become cardiomyocytes, or heart muscle cells. Using high-throughput screening, they then evaluated how the heart cells responded to treatment with 21 different FDA-approved TKIs, looking at factors like cell survival, signaling and alterations in their ability to beat properly.

With the stem-cell data, the scientists were able to create a “cardiac safety index,” which ranks the TKIs on their likelihood of inflicting heart damage. That index correlates with the toxicity that has been observed in patients clinically — a validation that suggests the screening system might be a powerful tool in predicting toxicity before therapies are ever administered to patients.

Paul Burridge, PhD, was a co-first author of the study, which used a stem cell approach to evaluate the cardiotoxicity of a class of chemotherapy drugs.

Future research could establish even more specific predictions, by comparing the genomes of patients who might experience a certain drug side effect, such as atherosclerosis, with those who don’t. “Long-term, what my lab is interested in is taking a patient’s whole genome and, based on the work we’ve done in the past, being able to predict whether a patient will have an adverse drug event,” said Burridge, also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “This is the whole idea of pharmacogenomics, or precision medicine: Everyone is going to have a different response to a drug, and that response — good or bad — is already encoded in all of us.”

In the study, the scientists also discovered that administering insulin or insulin-like growth factor 1 alongside TKIs seemed to protect against some of the heart damage associated with the drugs. “While it’s still early, this is the first step toward opening up a whole new field of identifying cardioprotectants to reduce the toxicity of these drugs,” Burridge said.

The research was supported by the National Institutes of Health (NIH) grants K99/R00 HL121177, 14BGIA20480329, R01 HL132875, R01 HL130020, R01 HL128170, R01 HL123968, and R24 HL117756; the NIH Director’s Pioneer Award; the American Heart Association Predoctoral Fellowship; the American Heart Association Beginning Grant-in-Aid; American Heart Association Grant-in-Aid; the American Heart Association Established Investigator Award; the National Science Foundation Graduate Research Fellowship; the Endowed Faculty Scholar Award of the Lucile Packard Foundation for Children and Child Health Research Institute at Stanford and Burroughs Wellcome Foundation Innovation in Regulatory Science.

Northwestern University Feinberg School of Medicine


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