04.2020 | THE SCIENTIST 27Hunger games
About 15 years ago, while perusing
internet news, Robert Gatenby came
across an article about the diamond-
back moth, and the damage that this
pest species had been wreaking on
cabbages and other cruciferous plants
around the world for much of the last
century. Ecologists had realized, the
article explained, that by smothering
their crops in chemicals, farmers were
merely encouraging this fast-reproduc-
ing species to evolve insecticide resis-
tance, while killing off any competing
insects in the ecosystem that mighthave helped keep moth populations in
check. To Gatenby, a radiologist and
codirector of the Center of Excellence
for Evolutionary Therapy at the Mof-
fitt Cancer Center, the parallels to can-
cer were obvious. High doses of can-
cer therapy are “the same as high-dose
insecticide,” he says. “You’re selecting
for resistance, and you’re taking away
competitors.”
He says the story made him won-
der whether oncologists might harness
competition within the cancer ecosys-
tem—that is, among the various clonal
subpopulations making up a tumor—
to stave off the evolution of resistance.
A cancer cell with a resistance mech-
anism would have an advantage over
other cancer cells competing for space
and resources, but only when the rel-
evant drug was present, Gatenby rea-
soned in theoretical papers during the
2000s and 2010s. In the drug’s absence,
it would have no such edge—indeed, the
resistance mechanism might even come
with a cost, if the cell directs resourcestoward resistance instead of growth and
replication, for example.
This idea has been bolstered by years
of clinical data. For example, one small
2015 study of patients with colorec-
tal cancer who were receiving EGFR-
targeting drugs found that, soon after the
study started, several patients’ tumors
were taken over by cells with mutations
in KRAS, a well-known oncogene that
helps cancer cells bypass normal metab-
olism and confers drug resistance. Ye t
when clinicians stopped administering
the drugs, that same KRAS-mutated sub-
population took a hit, with liquid biop-sies showing declining numbers of these
cells with respect to other subpopula-
tions. The drug-resistant cells appeared
to be drug-dependent.
To turn the idea into a therapeu-
tic strategy, Gatenby proposed cycling
between providing a treatment and
withholding it, thus growing and
shrinking different cancer cell sub-
populations in a way that would limit
the overall size of the tumor and block
drug-resistant cells from taking over
completely. A team at Novartis tested
this strategy in the early 2010s using
patient-derived melanoma xenografts
in immunocompromised mice. The
researchers found that while a con-
tinuous high-dose treatment of mela-
noma tumors with the B-Raf inhibitor
vemurafenib led to lethal drug-resistant
disease in mice within a few months,
intermittent dosing on a four-weeks-
on, two-weeks-off schedule staved off
resistance for the full 200 days of the
study, and drastically slowed overall
tumor growth.^3A cancer cell with a resistance mechanism
would have an advantage over other cancer
cells competing for space and resources—
but only when the relevant drug was present.
LUCY
READING-IKKANDA