Cancer treatment

Treatment with Exelixis' experimental
drug cabozantinib helps patients with a
form of thyroid cancer significantly
extend the time before their disease
worsens, according to results from a
late-stage study announced in
October 2011.

The phase III study enrolled 315
patients with advanced medullary
thyroid cancer and randomized them
to treatment with cabozantinib or a
placebo. Patients treated with
cabozantinib had a 72% reduction in
the risk of disease progression
compared to placebo patients. At the
median, cabozantinib delayed tumor
progression by 11.2 months compared
to 4 months for placebo -- a 7.2-month
difference which was statistically
significant and met the primary
endpoint of the study.


The cocktail comprises Chinese
peonies, Chinese liquorice, the fruit of
the Chinese date tree and flowers of
the Chinese skullcap plant. In China,
they call it 'Huang Qin Tang' and have
used it to treat gastrointestinal
problems for about 1,800 years.

A start-up pharmaceutical company
called PhytoCeutica has dubbed its
proprietary pill of the blend 'PHY906',
and shown in early clinical trials that
the mix can combat the severe
diarrhoea caused by many
chemotherapy drugs, which destroy
fast-dividing gut cells in addition to
tumor cells.

Now, researchers at PhytoCeutica and
Yale University School of Medicine,
both in New Haven, Connecticut, have
some early leads on how PHY906
does this, despite the fact that most of
its individual chemical components
remain unknown.

PHY906 still needs to prove itself in
larger clinical trials. In 2004, the US
Food and Drug Administration (FDA)
eased regulations on herbal mixtures,
allowing the approval of medicines that
have been proved to be safe and
effective, even if their individual
components aren't known.



Cancer is like trying to weed the
garden. It's no good just chopping off
the leaves, we need to target the roots
to stop the weeds coming back.

Radiotherapy and chemotherapy work
against all rapidly dividing cells.
But there is increasing evidence that
cancer stem cells are more resistant
than other cells to this treatment.
Cancer stem cells that have not been
eradicated can lead to later
recurrence of cancer.

They are called cancer stem cells
because, like stem cells present in
normal tissues of the body, they can
produce further cells like themselves
and also differentiate to provide
various different cell types.
People have assumed that cancer
stem cells made up a small proportion
of the cells in a tumor, but it is
becoming increasingly clear that this is
not correct. The most aggressive
tumors can have a majority of cells
that are cancer stem cells.

But much about cancer stem cells—
where they come from, how they affect
development of disease and whether
they can be effectively attacked with
treatment—is unclear.

One way cancer cells are believed to
turn aggressive is by reactivating
cellular-growth programs involved in
embryonic development that usually
are dormant in adult cells. The cancer
cells exploit those programs to
become invasive, metastatic and thus

Cancer Stem Cell research has
accelerated in the last two years and
considerable efforts are now being
made to identify drug molecules that
selectively target and destroy them.
Today, 50 developmental molecules
are being evaluated in the hope of
targeting this subset of cancer cells.
More than 40 companies and
commercial groups are progressing
these activities and around 20 drug-
targeting strategies are being

A company called Verastem was
launched to use the approach to
identify promising drug candidates
based on ideas of researcher Piyush

Dr. Gupta screened  some 16,000
compounds for toxicity specifically
against breast-cancer stem cells.

He came up with four hits, including an
antibiotic called salinomycin that is
given to animals such as chickens. In
tests against breast-cancer cells in
mice, salinomycin had little effect on
conventional tumor cells. But it was
100 times as effective as the widely
used breast-cancer treatment
paclitaxel in killing cancer stem cells.

Metformin is an oral diabetes medicine
that helps control blood sugar levels  
for people with type 2 (non-insulin-
dependent) diabetes. It is not for
treating type 1 diabetes.

Estimated that  more than 40 million
metformin prescriptions have been
filled in the United States.

Metformin helps stabilize blood sugar
by decreasing the liver's glucose
output and increasing the sugar's use
by muscle tissue.  

According to a new studies, it would
appear that metformin can be
successfully used to prevent the
development of tobacco-induced lung

Clinicians had noticed that Type 2
diabetics taking metformin seemed to
have lower cancer rates and improved
cancer survival than diabetics taking
other diabetes drugs. This suggests
that metformin and insulin signaling
possibly play roles in controlling
and/or killing cancer.

In recent experiments,it was found that
when four different types of breast
cancer cell cultures were treated with
metformin, the drug specifically killed
the stem cells in the culture.

When combined metformin with the
chemotherapy drug doxorubicin to
treat the cultured cancer cells, the
cocktail killed more cells than either
drug alone, suggesting that they were
working in complementary pathways.
If you treat with metformin and
chemotherapy, the chemotherapy is
nailing the traditional cancer cells and
the metformin is killing the cancer stem

GDC-0449 is being studied in more
than 15 trials in cancers of the breast,
stomach, pancreas, ovaries, skin and
Treatment with GDC-0449 will inhibit
the sonic hedgehog pathway signaling
in cancer stem cells.

The Hedgehog pathway is normally
active during embryonic development
and plays a central role in cell
differentiation and proliferation.
Inappropriate activation or
dysregulation of the Hedgehog
pathway is believed to play a critical
role in the proliferation and survival of
certain cancer cells, including in basal
cell carcinoma and medulloblastoma
as well as in colorectal, ovarian,
pancreatic, small cell lung and breast
cancers, among others.

GDC-0449 was discovered  under the
ongoing collaboration agreement
between Curis and partner
Genentech, a member of the Roche

Through this collaboration, Genentech
and Roche are responsible for clinical
development, and Genentech (U.S.),
Roche (Ex-U.S. excluding Japan) and
Chugai Pharmaceuticals (Japan) are
responsible for commercialization of

Treatment with GDC-0449 to target
the stem cell compartment will be
combined with gemcitabine to target
the remaining tumor cell compartment.

Roche is examining the drug in
advanced basal cell carcinoma in a
study it expects to complete in 2011.
The company will also begin research  
in skin cancer patients whose disease
is in earlier, operable stages.
In a study reported in the New England
Journal of Medicine in September, 18
of 33 adults with an advanced basal
cell carcinoma had their tumors shrink
while taking the drug.

Basal- cell carcinoma is the most
common form of skin cancer, afflicting
about 1 million people in the U.S.
each year. It is curable for 85 to 99
percent of patients. The Roche study
focused on patients whose cancer had
defied treatment.

MK-0752 is developed by Merck.

MK-0752 is targeting the Notch

Breast cancer stem cells are
dependent on the Notch pathway for
survival. Merck's drug MK-0752, a
compound called a gamma-secretase
inhibitor, blocks that pathway.

Studies in animals and women with
advanced breast cancer showed MK-
0752 was able to kill off cancer stem
cells that linger in the breast after

New and better therapies for locally
advanced and metastatic breast
cancer are needed because, even if
standard treatment is successful in
shrinking the cancer, there is still a
high chance that the cancer will recur.

It is  thought that the reason that many
patients cannot be cured of their
breast cancers is that the stem cells
are unable to be killed and remain in
the body after standard treatment.

MK-0752, can target stem cells and
prevent tumor recurrences when the
drug is combined with docetaxel, a
chemotherapy drug commonly used to
treat breast cancer.

At OncoMed, based in Redwood City,
Calif., scientists are using a different
method to attack cancer stem cells:
disrupting the cells' ability to self-
renew and establish a blood supply.

The company's first drug, a
monoclonal antibody known as OMP-
21M18, is in phase 1 clinical trials in
patients whose solid tumors have
proven resistant to previous therapies.

OncoMed is backed by pharmaceutical
giants Genentech and
GlaxoSmithKline, among other

In a trial OMP-21M18  is  given in
combination with FOLFIRI, a standard
drug treatment for advanced
colorectal cancer. Participants must
not have had more than one
chemotherapy regimen for their
metastatic disease.

OMP 21M18 is a humanized
monoclonal antibody (a protein made
in the  laboratory) developed to target
cancer stem cells.

Up to 32 participants, 21 years or
older, at up to 6 centres in Australia
and New Zealand, will receive
intravenous infusions of OMP-21M18
followed by FOLFIRI every two weeks,
until disease progression or limited by
drug toxicity. After 8 weeks,
participants will undergo assessments
to determine their disease status. If
there is no evidence of disease
progression participants will continue
to receive infusions of OMP-21M18
and FOLFIRI every second week, until
disease progression.

OMP 21M18 is targeting the Wnt

The Wnt pathway is believed to be a
key target in halting cancer stem cell
activity. But only a few other firms -
Avalon Pharmaceuticals Inc. (now part
of Clinical Data Inc.) and 2008 start-up
Wintherix LLC, for example - have
entered that space, largely because
Wnt is not an easily druggable target.
Lead drug OMP-18R5, for instance, is
an antibody candidate targeting the
Frizzled, or FZD, receptor.

That compound is set to enter Phase I
testing in 2011.


Cancer patients fare better if they are
diagnosed and treated based on their
tumor's genetic abnormality rather
than its location.
In this vision of the future, a tumor will
not be treated as a breast cancer or a
colorectal cancer; the tumor will be
treated according to the driver
mutations that are found, and these
will be targeted with mutation-specific

This approach requires  molecular

A trial led by University of Texas M.D.
Anderson Cancer Center doctors
suggests so-called targeted drugs,
both experimental ones and existing
ones in new combinations, are more
effective than the one-size-fits-all
drugs routinely given for tumors found
in common parts of the body.

"This study shows the future is here,"
said Dr. Razelle Kurzrock, chair of M.
D. Anderson's department of
investigational cancer therapeutics
and the study's senior author. "In more
and more patients, matching drugs to
the genetic abnormality yields
significantly better responses."

The concept, known as personalized
cancer care, has been touted for at
least a decade, since Herceptin and
Gleevec dramatically improved the
outlook for certain breast cancer and
leukemia patients.
The promised bonanza of targeted
drugs was perceived as slow to follow,
however, and most cancers are still
treated based on which chemotherapy
drug historically has benefitted the
most patients, even though it's often
ineffective with many of them.

The study involved more than 1,000 M.
D. Anderson patients whose
metastatic or inoperable cancer failed
to respond to numerous conventional

DNA testing found one or more of 12
molecular aberrations in 460 of the
patients, whose tumors originated in
wide-ranging areas of the body.
The study found that 27 percent of
patients with a gene defect who were
matched to a targeted drug had
significant tumor shrinkage, more than
five times the rate of patients treated
with "non-matched" therapy. The
average survival of patients treated
with a matched drug was 15.8 months,
compared to 9.7 months for those
patients not matched to a targeted


DNA testing of tumors is mostly done
at academic cancer centers, but its
availability is picking up. For example
at Memorial Sloan- Kettering Cancer
Center in New York, everyone with
metastatic lung or colon cancer
undergoes tests for dozens of
variations that may influence how they
respond to treatment.

Tyrosine kinases are signaling
molecules that are frequently
mutated.  One of their responsibilities
is regulating a cell's growth based on
the extracellular signals they receive.
The presence of extracellular growth
factors tells them to induce the cell to
grow more rapidly, while a lack of
oxygen or nutrients tells them to grow
more slowly. When these kinases are
mutated they make the cell grow
uncontrollably, divorcing growth from
the conditions outside the cell. In some
cases, this mutation is what makes a
cell cancerous.

In the 1980s, a mutated kinase was
identified that caused white blood cells
to grow in this uncontrolled manner
and caused chronic myeloid leukemia
(CML). The mutated kinase is a hybrid
formed from two halves of different
proteins that is created when pieces of
chromosome 9 and 12 switch
segments in white blood cells.

The drug imatinib (Gleevec)  was
developed in the 1990s by Brian
Druker of Oregon Health and Science
University and Charles Sawyers of
Memorial Sloan Kettering to block this
mutant kinase, called BCR-ABL.

In the years that it has been on the
market, Gleevec has transformed CML
from a death sentence to a
manageable condition, with a five year
survival rate exceeding 90%.

Similar fusion genes (and proteins)
have since been found in other blood
cancers but had not been detected in
solid tumors, such as those affecting
the breast, prostate, colon, lung, and
pancreas, thyroid, kidney and brain.
Such solid tumors account for 80% of
cancer deaths in the U.S. In 2005 Arul
Chinnaiyan at the University of
Michigan found the first gene fusions
in a solid tumor, in prostate tumors.

In Texas polymerase chain reaction
(PCR)-based sequencing,
immunohistochemistry, and
fluorescence in situ hybridization
(FISH) were used to analyze the tumor
tissue for specific genetic/molecular

Initially, the researchers looked for
CKIT, and PTEN, but then added to
the profile a few more, including
GNAQ, cMET, p53, and ALK.

Molecular aberrations are found in
40% of the tumors; the majority of
these (33%) had 1 aberration. When
considered by cancer type, the most
aberrations were found in melanoma
(73%), followed by thyroid (53%),
colorectal (51%), endometrial (43%)
and lung (41%) cancers.


While the approach may benefit more
patients who enter cancer studies and
speed drug development, it narrows
the number of people who qualify for
experimental treatment -- and the
potential size of the market.
Historically it has been difficult to get
drug companies to be interested in
this type of approach because it
potentially limits their market. If you
have a drug that works in 10 percent
of the population but you can sell it to
everybody, that has been a widely
successful business model.

On the other hand the targeted
approach may save an experimental
drug from failure.
As an example, initial studies of Pfizer
Inc.'s crizotinib included patients with
any kind of cancer. Researchers
quickly realized that the three patients
who responded to treatment, out of
37, had a defect in a gene known as
ALK that is key to the growth and
survival of tumor cells.

The company decided in 2009 to
focus solely on lung cancer patients
with the ALK mutation, a group that
makes up just 5 percent of the lung
cancer population. The bet paid off.
The company filed for regulatory
approval in the U.S. based on its early
trials, with data showing dramatic
response to treatment in the properly
targeted patients.

The executive in charge was
concerned that a drug that could only
benefit 5 percent of patients might not
be commercially viable.
"Fortunately, my colleagues in
commercial development immediately
recognized that, given the high
incidence of non- small-cell lung
cancer, it still accounted for a
considerable number of patients," he

Matching tumors to treatment isn't a
magic bullet. The treatment stopped
working in the M.D. Anderson trials
after 5.2 months for those getting
targeted care, compared with 2.2
months for patients treated with
unmatched drug therapy.
Which means that a lot more work is