As evidence implicating stem cells in cancer mounts, drug makers are taking notice. GlaxoSmithKline (GSK) in December formed a strategic alliance worth up to $1.4 billion
with OncoMed Pharmaceuticals, of Redwood City, California. The deal
gives GSK an option to license four of OncoMed's antibody candidates
developed to target cancer stem cells, one of which is scheduled to
enter clinical trials in June.
The GSK-OncoMed pact is the first
major deal focused on cancer stem cell R&D, which is undergoing
explosive growth. John Bates, the director of Biopharm Reports, in
Cambridge, UK, says the number of companies devoted to this research
has grown from 17 in April 2007 to nearly 40 today. What's more,
patents covering developments in cancer stem cells doubled to about 70
in 2007, he adds. The problem is that not everyone even believes that
targeting cancer stem cells will yield therapeutic benefits.
Schreiner, CEO with Raven Biotechnologies in San Francisco, attributes
the burst of commercial interest to recent evidence of cancer stem
cells in solid tumors. Scientists have suspected since the 1950s that
the cells play a role in blood tumors, such as acute myeloid leukemia,
but their existence in solid tumors became evident only in 2003. That's
when Michael Clarke, currently associate director of Stanford
University's Institute for Stem Cell and Regenerative Medicine, and his
then post-doc, Mohamed Al-Hajj, claimed to find cancer stem cells in
breast tumors. The cells had two markers that are now synonymous with
cancer stem cells: high expression of the antigen CD44 and low
expression of antigen CD24. Isolated on the basis of these markers, the
human cells were cultured and introduced into immunocompromised mice.
Clarke and Al-Hajj found that only a few of the cells could spawn
aggressive, metastatic tumors in the animals. Those findings bolstered
a theory that solid tumors arise from a small population of cancer stem
cells that, like normal stem cells, have the capacity for self-renewal.
Clarke and his colleague Max Wicha, the director of the University of
Michigan Comprehensive Cancer Center, founded OncoMed to pursue
clinical opportunities in cancer stem cells in 2004. They now sit on
the company's scientific advisory board.
Findings in other
laboratories have since suggested cancer stem cells exist in various
tumors, including those of the brain, head and neck, prostate, and
colon. Scientists further postulate that cancer stem cells resist
current drug therapies and repair DNA after radiation treatment more
efficiently than their differentiated, daughter cells. That explains
why solid tumors often recur after treatment, Schreiner explains. "What
happens is the stem cells survive and repopulate to form a new tumor,"
he says. "And because they transmit their resistance to daughter cells,
the new tumors are much harder to treat." Some researchers now believe
the only way to cure cancer is by killing the stem cells that give rise
OncoMed is one of a handful of companies preparing to
test compounds against cancer stem cells in the clinic. In the GSK
deal, OncoMed receives an undisclosed, up-front payment in cash and
equity investment, with $1.4 billion more tied to achieving milestones.
Royalties on product sales would follow. OncoMed's lead candidate, a
humanized monoclonal antibody (mAb) OMP-21M18, targets "a cancer stem
cell pathway with broad applicability across multiple solid tumors,"
says Paul Hastings, the company's CEO.
Other companies preparing
for clinical trials this year include Arius Research in Toronto, whose
lead humanized IgG1 mAb targets a variant form of CD44 found in
leukemia, breast, colon and prostate cancer cells. Also, Raven
Biotechnologies has two mAbs in preclinical development: RAV17 (which
targets the pancreatic assigned tumor marker PAN), which Schreiner says
targets prostate as well as pancreatic cancer cells, and RAV18 (which
targets ADAM-9), for colon and lung cancer. Raven is now preparing to
merge with VaxGen, a San Francisco-based vaccine manufacturer, picking
up needed cash reserves from a company with a depleted pipeline but
plenty of manufacturing assets. Reflecting a broader trend in cancer
drug development, most compounds targeting cancer stem cells are
monoclonal antibodies, Bates says (see Table 1
MAbs predominate because they target antigens on the cell surface
rather than processes inside the cell as small molecules do.
chief safety concern with targeting cancer stem cells, Clarke warns, is
that these mAbs might also attack normal stem cells that replenish
damaged tissues. "The main thing is to ensure that we eliminate the
malignant cancer stem cells only without affecting the normal stem
cells," he says. "Whether we'll be able to do this is the billion
dollar question that everyone wants to answer."
commercial entities grow up around it, skeptics question the validity
of targeting cancer stem cells. Current thinking holds that a tiny
population of stem cells can explain why cancers recur even when
existing treatments kill off up to 99% of a given tumor. According to
Bert Volgestein, a professor of oncology at Johns Hopkins University in
Baltimore, tumors can be completely eradicated only if those small—and
presumably drug-resistant—stem cell fractions are destroyed.
tumor fraction contributed by stem cells ranges from a low of 0.1% to a
high of 40%, and some reports have described tumors made entirely of
stem cells. But Vogelstein also admits that if a tumor containing a
large fraction of stem cells were almost completely eliminated by
treatment, this would undermine the logic of targeting stem cells as
the last, drug-resistant holdouts from which aggressive metastatic
tumors would likely emerge refractive to treatment.
in OncoMed comes from a desperation "to tap into oncology space, an
area in which it is particularly weak," says Sho Matsubara, an analyst
with London-based Standard and Poor's Equity Research Division. Also,
GSK's sales are assumed to decline in coming years, due to generic
competition (Matsubara estimates a 7% drop annually for the next five
years). It does have a compound of its own that may have shrunk breast
tumors by attacking cancer stem cells. According to evidence described
at the San Antonio Breast Cancer Symposium on December 17, six weeks'
treatment with GSK's Tyverb (lapatinib), a small molecule used in
conjunction with Xeloda (capecitabine) for late-stage breast cancer,
slashed the number of stem cells by more than half among 30 women
studied. Two-thirds of the women were reportedly cancer-free after
But others remain cautious as, in some
instances, claims pointing to the existence of cancer stem cells have
turned out to be wrong upon closer inspection. "More studies are needed
to confirm that cancer stem cells were in fact targeted by Tyverb,"
Bates notes. "We need further evidence to show that cancer stem cells
in humans have been fully characterized. And we need ways to
demonstrate that a particular subpopulation of cells has been reduced
by treatment," he notes.
Ultimately, the best evidence will come from more studies that show killing cancer stem cells improves patient
survival, Bates says. For fast-moving cancers such as pancreatic
tumors, the evidence may come sooner. In the case of slow-moving
cancers, such as prostate, accumulating the necessary evidence could
take more time, he points out.