Researchers from Mount Sinai School of Medicine developed a cancer model built in the fruit fly Drosophila,
then used it to create a whole new approach to the discovery of cancer
treatments. The result is an investigational compound AD80 that
precisely targets multiple cancer genes. Tested in mouse models, the
drug proved far more effective and less toxic than standard cancer
drugs, which generally focus on a single target. This is the first time
that whole-animal screening has been used in a rational, step-wise
approach to polypharmacology.
The study appears online in the journal Nature.
Conventional drug design embraces the "one gene, one drug, one
disease" philosophy. Polypharmacology focuses on multi-target drugs and
has emerged as a new paradigm in drug discovery. The hope is that AD80
-- showing unparalleled effectiveness in fly and mouse models -- will be
tested in Phase I clinical trials.
"We've come up with one drug that hits multiple targets through
'rational polypharmacology,' and our approach represents a new concept
we believe will have great success in suppressing tumors," said Ross L.
Cagan, Ph.D., Professor and Associate Dean at Mount Sinai School of
Medicine, and senior author on the study. "Scientists are beginning to
recognize that single-target drugs can be problematic. I believe that,
within the next five years, we'll see more drugs entering clinical
trials that use rational polypharmacology as the basis of drug
discovery."
The study represented an unusual collaboration between fly
geneticists and medicinal chemists. Typically, scientists use human
tumor cell lines to screen for single target anti-cancer drugs. In this
project, Dr. Cagan, along with co-authors Tirtha Das, Ph.D, from Mount
Sinai and their collaborators Arvin Dar, PhD and Kevan Shokat, Ph.D.
from the University of California, San Francisco, used their fly cancer
models to screen a large chemical library for novel drug leads that
shrunk the tumors. They then combined classical fly genetic tools with
chemical modeling to develop second-generation drugs to better hit
specific targets.
"Many successful drugs now in the marketplace have, by chance, wound
up hitting several tumor targets, which is probably why they work," said
Dr. Cagan. "The intention of our research was to hit multiple targets
purposefully. By using fruit fly genetics we identified, step-by-step,
the targets we needed. To my knowledge, this has never been done before.
It's also a cost effective model and my prediction is there is going to
be more emphasis on whole animal polypharmacology approaches in cancer
drug research in the future."
For the study, investigators started out with Ret, the kinase that
drives the growth of medullary thyroid tumors in people whose Ret has a
cancer-activating mutation; a subset of lung cancer patients also have
activated Ret. Researchers engineered a cancer form of Ret into fruit
flies. The flies grew tumors wherever Ret was expressed. The
investigators then tested dozens of drugs with the goal of curing the
tumor.
One challenge is that Ret has many normal cellular roles and shutting
it down everywhere in the body would lead to toxicity, a major problem
with cancer drugs. "Our goal did not include the assumption that Ret
needed to be shut down," said Dr. Cagan. "We wanted to see what worked
on the tumors, and then figure out why it worked."
Researchers determined that their lead drug, AD57, suppressed several
cancer signals emanating from Ret. These signals include some of the
best-known cancer proteins such as Raf, Src, and Tor. Ret itself was not
entirely shut down, which suggested to scientists that a patient would
experience fewer side effects. The researchers then set out to improve
AD57. They manipulated genes in the presence of the original drug hit, a
process that had never been done before. As a result, they found that
if they lowered the amount of Raf signaling in the presence of AD57, the
drug would work even better.
Raf therefore was found to act as a desirable "target." Reducing Tor
made AD57 more toxic, so researchers christened Tor an "anti-target," a
new concept in drug discovery. Armed with an ideal target/anti-target
profile, the Shokat laboratory then developed a derivative of AD57
called AD80.
"When we fed AD80 to the fruit flies, it was like a super drug," said
Cagan. "It was remarkable how much AD80 you could give these flies and
they didn't mind. This drug wiped the tumors out in a way AD57 or any
other drug did not."
Tested in mice models with the same cancer, AD80 performed 500 times
better on human cell lines, and far better in mice with very low
toxicity, than a cancer drug that the FDA had recently approved for the
same cancer type. That drug, vandetanib, is an orphan drug for patients
with late-stage medullary thyroid cancer who are not eligible for
surgery. Vandetanib was validated in similar fly models from the Cagan
laboratory some years earlier.
"We hope that our research will influence the debate between those
who favor pursuing drugs that address single vs. multiple tumor
targets," said Cagan, who believes the rational polypharmacology model's
success in identifying AD80 will prompt scientists and drug companies
to pursue broader approaches to attack tumors.
Journal Reference:
- Arvin C. Dar, Tirtha K. Das, Kevan M. Shokat, Ross L. Cagan. Chemical genetic discovery of targets and anti-targets for cancer polypharmacology. Nature, 2012; 486 (7401): 80 DOI: 10.1038/nature11127
Courtesy: ScienceDaily
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