04.2020 | THE SCIENTIST 29says, “physicians as a group did not like
it. [At conferences] the usual comment
was, ‘This is bullshit. Just give me better
drugs.’” Now, with clinical trials under-
w ay, Gatenby says, there’s more interest
in these sorts of approaches for cancers
that are all but untreatable.
Greaves says he agrees that con-
trolling, rather than curing, aggres-
sive cancers may be a sensible goal. But
there’s still “a bit of a gap between the
modeling and the clinical practice,” he
notes. Current theory can’t produce
clear treatment recommendations for
individual patients, he continues. “We
aren’t there yet.”
Blocking evolution
Efforts to herd or otherwise manipu-
late cancer evolution assume that the
emergence of drug resistance is inevi-
table, and is thus best directed in order
to achieve clinical benefit. But some
researchers are interested in how a can-
cer gets to be so adaptable in the first
place, and whether that process itself
might be blocked or slowed down. The
ke y, Rossanese explains, is the hetero-
geneity of the cancer cell population.
“When you increase heterogeneity,
you’re giving evolution a bigger sub-
strate to act upon,” she explains. “So
what if we could reduce some of the
ways cancers generate heterogeneity?”
Although research shows that some
cancer-related mutations arise as a
result of treatment itself, most DNA
errors are generated spontaneously as
cells in the tumor multiply. Data on
when and where these mutations usu-
ally arise are pouring in from research
projects, such as the Pan-Cancer Analy-
sis of Whole Genomes (PCAWG), that
sequence and analyze tumor DNA. For
example, researchers working on the
TRAcking Cancer Evolution through
therapy (TRACERx) project, which
Swanton leads, have sequenced tumors
from hundreds of NSCLC patients in the
UK to explore how mutation patterns
change as cancer progresses. (Swan-
ton also cofounded a company, Achilles
Therapeutics, to develop personalized
T cell therapies targeting antigens iden-
tified by mutations in patient sequenc-
ing data.) Among other things, such
data can help identify particular types of
mutations in a tumor that are associated
with elevated genetic diversity overall,
and thus identify potential targets for
evolution-stalling therapies.
One such target generating interest
among oncologists is the apolipoprotein
B mRNA-editing catalytic polypeptide-
like (APOBEC) protein family, a group
of enzymes that modify nucleic acids by
changing cytosine bases to uracil and
are thought to be involved in the innate
immune response. A 2019 study using
TRACERx and other datasets contain-
ing genomic information on various lung
and thoracic cancers found a strong cor-
relation between APOBEC-driven muta-
genesis and overall tumor heterogeneity,
suggesting that APOBEC activity may be
a significant contributor to the diversi-
fication of cancer cell subpopulations.^7
Other research has linked the proteins
to tumor diversity and disease progres-
sion in head and neck, breast, and blad-
der cancer, among others. “We know it’s
an active process that’s driving heteroge-
neity in cancer,” says Rossanese.
APOBEC3B in particular appears
to be upregulated in at least half of all
known cancers, and ICR researchers are
currently in the early stages of devel-
oping small-molecule inhibitors of the
enzyme, Rossanese tells The Scientist.
“The idea is to test the hypothesis that
reducing mutational load and hetero-
geneity will in fact delay drug resis-
tance,” she explains. Researchers in
New Zealand, meanwhile, are target-
ing the protein using oligonucleotides.
In work published last fall, a team at
Massey University described an oligo-
nucleotide drug that selectively inhib-
ited APOBEC3B in vitro.^8
Like other evolution-based approaches
to therapy, the strategy has limitations.
At diagnosis, most cancer patients have
already accumulated substantial within-
tumor heterogeneity. While better cancer
screening could help tackle that problem
from a public health perspective throughearlier diagnosis, therapies targeting APO-
BEC or as-yet-undiscovered evolution-
driving proteins might have little effect
on late-stage disease, notes Gatenby. “I
think once the horse is out of the barn, it’s
going to be very hard to suppress evolu-
tion,” he says, adding that cancer cells may
well find new escape routes that research-
ers can’t predict. According to the axiom
attributed to evolutionary biologist Leslie
Orgel, “Evolution is cleverer than you are,”
Gatenby says. “I take that to heart.”
Rossanese isn’t dissuaded. She notes
that evolution-stalling therapies would
probably be used in conjunction with
more-traditional approaches. Even for a
patient who already has high tumor het-
erogeneity, “a lot of times, a primary ther-
apy is going to take out 99 percent of the
cancer cells, and that 1 percent that’s left is
going to have to adapt its new condition,”
she says. “We’re trying to hobble those
remaining cells as much as possible.” gReferences- B. Zhao et al., “Exploiting temporal collateral
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