Drugs known as tyrosine kinase inhibitors can be an effective
treatment for many types of cancers, but they also have severe and
sometimes fatal side effects.
Using lab-grown heart cells, Stanford
researchers were able to assess the drugs' various effects on heart
muscle cells, including whether the cells survived, were able to beat
rhythmically and effectively, responded appropriately to
electrophysiological signals and communicated with one another.
‘Used heart muscle cells made from stem cells Stanford researchers ranked commonly used chemotherapy drugs based on their likelihood of causing lasting heart damage in patients.’
The researchers found that their assay can accurately identify those
tyrosine kinase inhibitors already known to be the most dangerous in
patients. In the future, they believe their system may prove useful in
the early stages of drug development to screen new compounds for
"This type of study represents a critical step forward from the
usual process running from initial drug discovery and clinical trials in
human patients," said Joseph Wu, director of the Stanford
Cardiovascular Institute and a professor of cardiovascular medicine and
of radiology. "It will help pharmaceutical companies better focus their
efforts on developing safer drugs, and it will provide patients more
effective drugs with fewer side effects."
A paper describing the research will be published in Science Translational Medicine
Wu, who holds the Simon H. Stertzer Professorship, is the senior
author. Former graduate student Arun Sharma is the lead author.
"We used multiple measurements to accurately predict which of the
tyrosine kinase inhibitors were the most cardiotoxic," said Sharma. "The
drugs with the lowest safety indices in our study were also those
identified by the Food and Drug Administration as the most cardiotoxic
to patients. Other drugs that are not as cardiotoxic performed much
better in our assays."
Validating the researchers' cardiac-safety test on drugs with
extensive clinical track records is necessary before the assay can be
used to predict with confidence the likely clinical outcomes of drugs
still under development.
Sharma, Wu and their colleagues created heart muscle cells called
cardiomyocytes from induced pluripotent stem cells, or iPS cells, from
11 healthy people and two people with kidney cancer. They grew the
lab-made cardiomyocytes in a dish and tested the effects of 21 commonly
used tyrosine kinase inhibitors on the cells.
They found that treatment with drug levels equivalent to those taken
by patients often caused the cells to beat irregularly and begin to
die. The cells also displayed differences in the electrophysiological
signaling that controls their contraction. The researchers used these
and other measurements to develop a cardiac safety index for each drug.
They found that those drugs known to be particularly dangerous to
heart function, such as nilotinib, which is approved for the treatment
of chronic myelogenous leukemia, and vandetanib, which is approved for
the treatment of some types of thyroid cancer, also had the lowest
safety indices based on the assay; conversely, those known to be better
tolerated by patients ranked higher on their safety index. Prescribing
information for both nilotinib and vandetanib contains warnings from the
FDA about the drugs' potential cardiotoxicity.
An activity increase in an insulin responsive pathway
Six of the 21 tyrosine kinase inhibitors tested were assigned
cardiac safety indices at or below 0.1 - the threshold limit at which
the researchers designated a drug highly cardiotoxic. Three of these six
are known to inhibit the same two signaling pathways: VEGFR2 and PDGFR.
The researchers noticed that cells treated with these three drugs
ramped up the activity of a cellular signaling pathway that responds to
insulin or IGF1, an insulin like growth factor.
This discovery, coupled with the fact that treatment with insulin or
IGF1 is known to enhance heart function during adverse cardiac events
such as heart attacks, led the researchers to experiment further. They
found that exposing the cells to insulin or IGF1 made it less likely
they would die due to tyrosine kinase inhibitors blocking the VEGFR2 and
PDGFR pathways. Although more research is needed, these findings
suggest it may be possible to alleviate some of the heart damage in
patients receiving these chemotherapies.
The current study mirrors another by Wu's lab that was published in
April 2016 in Nature Medicine. That research focused on the toxic effect
of a chemotherapy drug called doxorubicin on iPS cell-derived
cardiomyocytes. Doxorubicin, which indiscriminately kills any
replicating cells, is increasingly being replaced by more targeted,
cancer-specific therapies such as the tyrosine kinase inhibitors tested
in the current study.
"The switch from doxorubicin is a result of the paradigm shift in
cancer treatment to personalized, precise treatment as emphasized by
President Obama's 2015 Precision Medicine Initiative," said Wu. "Moving
even further, we're discovering that many tyrosine kinase inhibitors are
themselves significantly cardiotoxic, and some have been withdrawn from
the market. There is a critical need for a way to 'safety test' all
drugs earlier in development before they are administered to patients.
Our drug safety index is a step in that direction."