SCIENCE sciencemag.org
ida. “That’s been the guiding therapeutic
principle for maybe 5 decades or more.”
For many traditional chemotherapies,
pauses in the highly toxic treatment were
unavoidable to allow a person to recover.
But newer targeted treatments, often less
punishing, could be—and often are—given
without a break.
A few labs, including Gatenby’s, are challenging that dogma. They are motivated by
theoretical models of cancer growth and evidence from animal studies suggesting that
temporarily stopping or cutting back a drug
dose can help keep the cancer cells from becoming resistant to the drug and can even
trigger some cells to die, extending patients’
lives. Periodically ceasing cancer therapy
can also be less toxic for the patient, says
Cooper’s oncologist, UCLA cancer researcher Antoni Ribas. Cooper has his own
take on the rationale. “It’s the idea of having a long enough break and starting again
anew, that the cancer cells wouldn’t develop
a defense against the drugs,” he says.
Trials are testing these new dosing strategies in cancer patients. Some stop the drug
altogether, then restart it on a fixed schedule;
others alternate high and low doses, and still
others wait until the tumor has shrunk significantly before dialing down treatment. Definitive results are a long way off, but Cooper’s
story is among those providing anecdotal encouragement. After nearly 2 years of taking
periodic drug “holidays,” he still has residual
tumors, but the most worrisome ones outside
his kidneys have shrunk by more than half—
a far better outcome, Ribas says, than most
advanced melanoma patients taking the pills
continuously could expect.
THE STUNNING SUCCESS of Gleevec, approved in 2001 for a form of leukemia driven
by a specific mutated protein, helped cement
the idea that targeted therapies should be
given continuously. For most patients, taking
the drug daily will result in a near-normal
life expectancy. Gleevec has led to a wave of
similar drugs that block mutated proteins
that transmit growth signals, including
BRAF and MEK inhibitors for melanoma—
the two drugs Cooper takes—and EGFR
and ALK inhibitors for lung cancer. But unlike the blood cancer originally treated by
Gleevec, the solid tumors they target are genetically complex, with subsets of cells that
carry every imaginable resistance mutation.
As a result, the drugs tend to stop working
within a year or so as a few drug-resistant
cells emerge and grow.
To help understand this resistance, re-
searchers at Novartis and UC San Francisco
(UCSF) several years ago created drug-
resistant melanoma cells by continually
dosing tumor-laden mice with a BRAF in-
hibitor until the tumors, which had initially
shrunk, resumed growing. When the re-
searchers then took the drug away, however,
the tumors unexpectedly shrank again. The
reason: The remaining tumor cells had
adapted to the drug by cranking out levels
of BRAF protein so high that it was lethal
to the cells if the drug wasn’t there, says
Martin McMahon, who worked on the study
at UCSF before leaving for the Huntsman
Cancer Institute at the University of Utah in
Salt Lake City.
By starting and stopping the drug in the
cancer-ridden mice, the Novartis-UCSF collaborators found they could keep the tumor
size under control and the mice alive for
nearly 7 months, the team reported in February 2013 in Nature. By comparison, most
mice on continuous dosing had such large
tumors that they had to be euthanized after
about 3.5 months.
Later that year came evidence that people
might benefit from the same effect. A team
of melanoma oncologists in the United Kingdom reported a study of 19 patients who had
stopped taking BRAF inhibitors because their
tumors became resistant. In 14 of them, scans
showed that the tumors grew more slowly
or even shrank, the oncologists reported at
a meeting. In follow-up work on tumor cell
lines, UCLA’s Roger Lo, together with Ribas,
showed that pausing treatment with a BRAF
and MEK inhibitor combination—the default
melanoma treatment—can also trigger death
of cancer cells.
Together those results encouraged the
National Cancer Institute to launch the
clinical trial Cooper joined. (He has since
dropped out of the trial officially but still
follows the on-off dosing schedule under
Ribas’s supervision.) The study has enrolled
135 of a planned 240 melanoma patients,
half of whom get intermittent therapy and
the rest continuous doses, and it could have
early results next year, says trial leader
Alain Algazi of UCSF. “At minimum we
should lengthen the time until genetic resistance develops” to the drugs, Ribas predicts.
U.K. researchers are finalizing plans for
a similar 2-year pilot study of on-off dosing
with 150 melanoma patients. They will col-
lect data on how patients’ tumors change
over time and do animal studies in parallel
to refine the dosing regimen before testing
the strategy in a larger group of patients,
says University of Oxford oncologist Mark
Middleton. He expects some “nervousness”
from oncologists and patients about using
less than maximum doses, even though that
should mean fewer side effects and cut drug
costs. “‘More is better’ is kind of hard-wired
in the oncological community. But you have
to follow the science,” Middleton says.
Researchers suspect the same dosing
strategy could work with targeted therapies
for other cancers. Like melanoma cells exposed to BRAF inhibitors, lymphoma cells
treated with an ALK inhibitor become dependent on it, Jonathan Schatz of the University of Miami in Florida has reported,
suggesting that intermittent dosing could
also help control a form of that cancer.
The original UCSF-Novartis finding, Schatz
says, “has opened a whole new way of thinking about some of these cancers and a new
way of identifying strategies” to treat them.
YET SIMPLE ON-OFF DOSING REGIMENS may
not always be the right approach, cautions
Franziska Michor, an evolutionary biologist
at the Dana-Farber Cancer Institute in Boston. She has used mathematical modeling
of tumor growth to study drug resistance
in non–small-cell lung cancer. About half
the time, EGFR inhibitors—the state-of-the-art targeted therapy for lung cancers with
mutant EGFR proteins—eventually stop
working because the tumor cells develop a
specific resistance mutation.
But tumors with this mutation are also
slower growing in the lab and in patients,
Michor and collaborators have found, suggesting that resistance has a fitness cost for
the cells. The result, according to modeling
that the team detailed in Science Translational Medicine in 2011, is that “it’s a really
bad idea to take a drug holiday,” Michor
says. That’s because stopping the drug allows the fitter, drug-sensitive cells to grow
very quickly. Instead, her team concluded
that patients should receive a high dose of
EGFR inhibitors twice a week, and a low
dose in between.
This model-guided “pulsatile” dosing
schedule has been tested in a small clinical
trial for advanced non–small-cell lung cancer. However, patients developed resistance
just as quickly as did those on continuous therapy. The researchers believe that’s
mostly because people absorb or metabolize
the pills differently than mice. “We couldn’t
get past a key peak [blood] concentration”
needed to stop resistant cells from emerging, says Helena Yu of Memorial Sloan Ket-
Chet Cooper, with oncologist Antoni Ribas, follows
an on-off drug dosing regimen for his melanoma.
“We’re not saying we know
this will work, but it makes
sense and we ought to test it.”
Paul Chapman, Memorial Sloan Kettering
Cancer Center
FRONTIERS IN CANCER THERAPY SPECIAL SECTION
17 MARCH 2017 • VOL 355 ISSUE 6330 1145
