have long known that treating patients with multiple cancer drugs often
produces better results than treatment with just a single drug. Now, a study
from Massachusetts Institute of Technology (MIT) shows that the order and
timing of drug administration can have a dramatic effect.
the new paper, published in Cell, the researchers showed that staggering
the doses of two specific drugs dramatically boosts their ability to kill a
particularly malignant type of breast cancer cells.
researchers, led by Michael Yaffe, the David H. Koch Professor of Biology and
Biological Engineering at MIT, are now working with researchers at Dana-Farber
Cancer Institute to plan clinical trials of the staggered drug therapy. Both
drugs—erlotinib and doxorubicin—are already approved for cancer treatment.
and postdoctoral researcher Michael Lee, lead author of the Cell paper,
focused their study on a type of breast cancer cells known as triple negative,
meaning that they don’t have overactive estrogen, progesterone or HER2
receptors. Triple-negative tumors, which account for about 16% of breast cancer
cases, are much more aggressive than other types and tend to strike younger
triple-negative breast cancer cells, there is no good treatment. The standard
of care is combination chemotherapy, and although it has a good initial
response rate, a significant number of patients develop recurrent cancer,” says
Yaffe, who is a member of the David H. Koch Institute for Integrative Cancer
Research at MIT.
For the past eight years, Yaffe has been studying the complex cell-signaling
pathways that control cells’ behavior: how much they grow, when they divide,
when they die. In cancer cells, these pathways often go haywire, causing the
cells to grow even in the absence of any stimulus and to ignore signals that
they should undergo cell suicide.
became intrigued by the idea that drug-induced changes in these signaling
pathways, if staggered in time, could switch a cancerous cell into a less
malignant state. “Our previous systems-biology work had primed us to the idea
that you could potentially drive a cell from a state in which only a fraction
of the tumor cells were responsive to chemotherapy into a state where many more
of them were responsive by therapeutically rewiring their signaling networks in
a very time-dependent way,” he says.
he and Lee thought it might be possible to sensitize cancer cells to
DNA-damaging drugs—the backbone of most chemotherapy—by first giving them
another drug that shuts down one of the haywire pathways that promote
uncontrollable growth. They tested different combinations of 10 DNA-damaging
drugs and a dozen drugs that inhibit different cancerous pathways, using
different timing schedules.
thought we would retest a series of drugs that everyone else had already tested,
but we would put in wrinkles—like time delays—that, for biological reasons, we
thought were important,” Lee says. “I think had it not worked, we would have
gotten a lot of pushback, but we were pretty convinced that there was a lot of
information being left on the table by everyone else.”
all combinations they tried, they saw the best results with pretreatment using
erlotinib followed by doxorubicin, a common chemotherapy agent. Erlotinib,
approved by the FDA to treat pancreatic cancer and some types of lung cancer,
inhibits a protein found on cell surfaces called the epidermal growth factor
(EGF) receptor. When constantly active, as it is in many cancer cells, the EGF
receptor stimulates a signaling pathway that promotes uncontrolled growth and
researchers found that giving erlotinib between four and 48 hrs before
doxorubicin dramatically increased cancer-cell death. Staggered doses killed up
to 50% of triple-negative cells, while simultaneous administration killed about
20%. About 2,000 genes were affected by pretreatment with erlotinib, the
researchers found, resulting in the shutdown of pathways involved in
of looking like this classic triple-negative type of tumor, which is very
aggressive and fast-growing and metastatic, they lose their tumorigenic quality
and become a different type of tumor that is actually quite unaggressive, and
very easy to kill,” Lee says.
if the drugs were given in the reverse order, doxorubicin became less effective
than if given alone.
This treatment worked not only in cancer cells grown in a laboratory dish, but
also in mice with tumors. When treated with a one-two punch of erlotinib and
doxorubicin, the tumors shrank and did not grow back for the duration of the
experiment (two weeks). With chemotherapy alone, or when the two drugs were
given at the same time, the tumors initially shrank but then grew back.
combination of high-throughput measurements and computer modeling was used to
reveal the mechanism for increased tumor killing, and to identify a biomarker
for drug response. The researchers found that the treatment was most effective
in a subset of triple-negative breast cancer cells with the highest levels of
EGF receptor activity. This should allow doctors to screen patients’ tumors to
determine which would be most likely to respond to this novel treatment.
research is “groundbreaking in its demonstration that the principles of order
and time are essential to the development of effective therapies against
complex diseases,” Rune Linding, research group leader at the Technical
University of Denmark, and Janine Erler, associate professor at the University
of Copenhagen, wrote in a commentary accompanying the paper in Cell. “As
disease researchers, we must consider network states, and this and other
studies serve as a model for a new generation of cancer biologists.”
concept of staggering drug treatments to maximize impact could be very broadly
applicable, Yaffe says. The researchers found similar boosts in tumor killing
by pretreating HER2-positive breast cancer cells with a HER2 inhibitor,
followed by a DNA-damaging drug. They also saw good results with erlotinib and
doxorubicin in some types of lung cancer.
drugs are going to be different for each cancer case, but the concept that
time-staggered inhibition will be a strong determinant of efficacy has been
universally true. It’s just a matter of finding the right combinations,” Lee
findings also highlight the importance of systems biology in studying cancer,
Yaffe says. “Our findings illustrate how systems engineering approaches to cell
signaling can have large potential impact on disease treatment,” he says.