| NEW YORK
NEW YORK Dec 13 The cancer cells were not
behaving the way the textbooks say they should. Some of the
cells in colonies that were started with colorectal tumor cells
were propagating like mad; others were hardly multiplying. Some
were dropping dead from chemotherapy and others were no more
slowed by the drug than is a tsunami by a tissue. Yet the cells
in each "clone" all had identical genomes, supposedly the
all-powerful determinant of how cancer cells behave.
That finding, published online Thursday in Science, could
explain why almost none of the new generation of "personalized"
cancer drugs is a true cure, and suggests that drugs based on
genetics alone will never achieve that holy grail.
Scientists not involved in the study praised it for
correcting what Dr. Charis Eng, an oncologist and geneticist who
leads the Genomic Medicine Institute at the Cleveland Clinic,
called "the simple-minded" idea that tumor genomes alone explain
Calling the study "very exciting," she said the finding
underlines that a tumor's behavior and, most important, its
Achilles heel depend on something other than its DNA. Her own
work, for instance, has shown that patients with identical
mutations can have different cancers.
The core premise of the leading model of cancer therapy is
that cells become malignant when they develop mutations that
make them proliferate uncontrolled. Find a molecule that targets
the "driver" mutation, and a pharmaceutical company will have a
winner and patients will be cancer-free.
That's the basis for "molecularly targeted" drugs such as
Pfizer 's Xalkori for some lung cancers and
Novartis 's Gleevec for chronic myeloid leukemia. When
those drugs stop working, the dogma says, it is because cells
have developed new cancer-causing mutations that the drugs don't
In the new study, however, scientists found that despite
having identical genetic mutations, colorectal cancer cells
behaved as differently as if they were genetic strangers. The
findings challenge the prevailing view that genes determine how
individual cells in a solid tumor behave, including how they
respond to chemotherapy and how actively they propagate.
If DNA is not the sole driver of tumors' behavior, said
molecular geneticist John Dick of the Princess Margaret Cancer
Centre in Toronto, who led the study, it suggests that, to
vanquish a cancer entirely, drugs will have to target their
non-genetic traits too, something few drug-discovery teams are
Genomes are what cutting-edge clinics test for when they try
to match a patient's tumor to the therapy most likely to squelch
For their study, Antonija Kreso, Catherine O'Brien and other
scientists under Dick's direction took colorectal cancer cells
from 10 patients and transplanted them into mice. They infected
the cells with a special virus that let them track each cell,
even after it divided and multiplied and was transplanted into
another mouse, then another and another, through as many as five
Only one in 10,000 tumor cells was responsible for keeping
the cancer growing, the scientists found - in some cases for 500
days of repeated transplantation from one mouse to the next.
Genetically-identical tumor cells stopped dividing within 100
days even without treatment.
Tumor cells that were not killed by chemotherapy - the
scientists used oxaliplatin, a colon-cancer drug sold by
Sanofi as Eloxatin - had the same mutations as cells
that were. The survivors tended to be dormant, non-proliferating
ones that suddenly became activated, causing the tumor to grow
again. Yet the cells - dormant or active, invulnerable to chemo
or susceptible - had identical genomes.
"I thought we'd be able to look at the genetics that let
some cells propagate, or not be susceptible to chemotherapy, but
lo and behold there was no genetic difference," said Dick. "That
goes against a main dogma of the cancer enterprise: that if a
tumor comes back after treatment it's because some cells
acquired mutations that made them resistant."
That's true in some cases, he said, "but what our data are
saying is, there are other biological properties that matter.
Gene sequencing of tumors is definitely not the whole story when
it comes to identifying which therapies will work."
The results were surprising enough, Dick said, that experts
reviewing the paper for Science asked him to run additional
tests to make sure the cells that behaved so differently were in
fact genetic twins. He did, they were, and Science accepted the
Other experts also praised the work, saying it supported the
growing suspicion in the field that personalized cancer therapy
is oversimplistic, at least in how it's sold to the public.
"It's not as simple as just sequencing mutations to tailor
therapies to each tumor," said surgical oncologist Dr. Steven
Libutti of the Montefiore Einstein Center for Cancer Care in New
York City. "In my mind, the findings are not unexpected. Other
things besides genes matter: the environment in which a tumor is
growing, for instance, plays an important role in whether
therapy will be effective."
Rather than targeting DNA alone, the Toronto scientists
suspect, effective therapies would also take aim at what phase
of its cycle a cell is in (dormant, growing or dividing, for
example), which of its genes are activated, whether it sits in a
region of the tumor that is starved of oxygen, and other
Nudging tumor cells out of their dormant phase and into
their growth cycles, for instance, could make them more
susceptible to chemotherapy, which generally targets rapidly
"Our findings raise questions about the resources put into
sequence, sequence, sequence," said Dick. "That has led to one
kind of therapeutic" - molecularly-targeted drugs - "but not the
cures the public is being promised."