46 | New Scientist | 7 March 2020
evolves. In a 2012 study, Swanton’s team
sequenced multiple samples from four
people’s kidney cancers, and found the cells
diverged over time – the way different animal
species branched off from each other over
millions of years. “It’s not linear evolution,
it’s branching evolution,” says Swanton.
Within each person, two-thirds of the
mutations weren’t shared across all their
tumour cells. This showed that it could be
misleading to take one small sample from
a cancer to predict which targeted therapy
to use. “Depending on where you put your
biopsy needle, you’re going to get different
results,” says Swanton.
Since then, several other studies have
launched with the goal of drawing up
detailed evolutionary trees for individual
cancers, exploiting our new DNA sequencing
capacity. The largest is the one that has
recruited Knott. However, the only way to get
enough tumour samples from each person is
to collect them after death, otherwise it would
be too destructive, says Mariam Jamal-Hanjani
at the Francis Crick Institute, who co-leads the
study along with Swanton.
The team is working with hospitals around
the UK to find 500 people with many different
types of cancer. While some doctors are
hesitant, says Jamal-Hanjani, “almost always,
these patients are incredibly willing to donate
their bodies knowing it will benefit others”.
As Knott says: “I want to help other people
and it seemed to be a logical next step. And
when you’re gone, you’re gone.”
The 2012 kidney cancer paper was seen as
bad news for targeted therapies, but it also
showed that within each person, about a
third of the mutations were present in all the
tumour samples they took. These mutations
must have arisen when the tumour was small,
before its cells had diverged much, and are
sometimes called “trunk mutations”, meaning
they are in the stem of the evolutionary tree,
not its branches. Any therapies targeting trunk
mutations should in theory kill all cancer cells
and so be less likely to trigger resistance.
Swanton thinks that the best way of doing
this is by weaponising the patient’s immune
system. People with cancer usually have some
immune cells active against their tumour – but
most target branch mutations. If someone’s
immune cells could be directed at their trunk
mutations, this could be enough to get rid of
all the malignant cells from their body.
Swanton has co-founded a firm called
Achilles Therapeutics, which is due to start two
small trials of this strategy this year in lung and
skin cancer. When people have their tumourresistance in insects. “They learned 50 years
ago you can’t eradicate with huge doses of
pesticide – all you do is you get resistance.”
Treating intermittently is a better approach,
and might work on cancers too, he says.
“If you treat a little bit then take it away, the
tumour will regrow over months or years.
But when it comes back, there has been no
selection for resistance.”
Gatenby’s institute recently found
encouraging signs from an initial small test
of this strategy in prostate cancer. Researchers
there have now started or are planning five
larger trials to put this “adaptive therapy” to
a more rigorous test, by comparing it with
standard treatment in prostate cancer and
three other types of tumours.
In a related tactic, another team at the
Moffitt Cancer Center plans to tackle a rare and
aggressive form of muscle cancer by switching
from one drug to a second one rather than
using a single drug intermittently.
The current approach for this is to give a
certain drug combination for 10 months and
then wait for the cancer to recur with drug-
resistant cells, which it nearly always does. At
that stage, people are given a second therapy.
The new idea is to give the first therapy for justCRED
IT“ Targeting
certain tumour
mutations
should in
theory kill all
cancer cells”
New therapies will help
immune system T-cells
better target tumourscut out, the firm will sequence many of its cells
to identify the trunk mutations. Researchers
will also extract immune cells from within
the tumour and select those that target these
mutations. The firm will then multiply the
immune cells in the lab, so that many can
be injected back into the patient.Great adaptations
Achilles is by no means the first to try to
exploit people’s immune response against
their cancer. The idea has a long history and
has been recently turned into a treatment
called CAR-T therapy for leukaemia and
lymphoma, cancers that occur when blood
cells turn malignant. Using this approach
against solid tumours has proved more
difficult, though. Several groups have tried
and failed at this – although so far none has
tried genetically identifying trunk mutations
as Achilles is doing, says Swanton.
Whether or not this approach works, a focus
on evolution may lead to other treatment
avenues, such as tweaking the way we use
existing anti-cancer drugs. Gatenby sees
parallels between the evolution of drug
resistance in cancer cells and that of pesticide