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Jeff's targeted therapy has kept his advanced lung cancer at bay.
When Fermina Hanson needed to have chemotherapy and radiation for her breast cancer,
one side effect really got her down. It wasn't the nausea or fatigue, although both were
debilitating. The thing she remembers most was the psychological impact of losing her long,
dark hair. "It was traumatic, and a real struggle," Hanson recalls.
Back on therapy for a recurrence
of her cancer, the 54-year old Hanson
is having a different experience this
time. For the last eight months, she has
been taking an experimental drug
called a PARP inhibitor. [PARP stands
for poly (ADP-ribose) polymerase.]
A PARP inhibitor is a new, targeted
therapy for breast and ovarian cancer
that is being tested at Dana-Farber.
Her treatment consists of eight pills,
twice a day. Her tumor has receded.
Her hair looks great.
Targeted therapies, such as PARP
inhibitors, are designed to zero in on
the exact genetic changes that make
cancer cells so deadly, and leave normal
cells alone. That lets the treatment
effectively kill tumors and spare
patients from the severe side effects
that often come with chemotherapy.
For Hanson, whose cancer is
caused by a mutation in one of the
two most common breast cancer genes
(BRCA1 and BRCA2), the PARP
inhibitors offer the first potential treatment
aimed at hereditary breast cancer.
That is good news for the approximately
five percent of breast and
ovarian cancer patients with BRCA mutations. For other women, new
research points to a similar defect even
in tumors without BRCA mutations,
and opens the door to the possibility
that PARP inhibitors could be effective
against a wider range of both ovarian
and breast cancers.
Research into BRCA function over
the past decade, including key work by
scientists in Dana-Farber's Women's
Cancers Program, elucidated the role
of BRCA proteins involved in DNA
repair. Researchers have identified six
different repair mechanisms (or pathways),
each made up of dozens of
proteins that work together to mend
breaks and correct genetic mistakes.
This process is critical to cell life;
without it, cells quickly accumulate a
lethal load of genetic damage.
In breast and ovarian cancers with BRCA mutations, one of the six repair
pathways loses function. To survive,
the cells compensate by increasing
the activity of an alternative repair
pathway. The PARP enzyme is a key
protein in the back-up pathway, and
the tumors soon become dependent
on PARP activity for their survival.
Once the biology of PARP in BRCA-deficient cells became clear,
clinical translation quickly followed.
PARP-inhibiting compounds were
already sitting on the shelf at several
pharmaceutical companies, the product
of earlier investigations for other
disease treatments. So far, the results
from clinical trials in cancer patients
have been encouraging.
In the Gynecologic Medical
Oncology Program, Director Ursula
Matulonis, MD, and her team have
completed a first study of the PARP
inhibitor AZD2281. All of the women
who took part had recurrent ovarian
cancer and the BRCA1 or BRCA2 mutations; they all received the PARP
inhibitor, and though the study was
small, the doctors saw some "remarkable"
responses. "PARP inhibitors are definitely active drugs in these patients," Dr. Matulonis said.
Doctors are now recruiting for a
follow-on study comparing the same
PARP inhibitor to a standard treatment
regimen in women with advanced
ovarian cancer whose cancer progressed
in spite of prior chemotherapy.
Fermina Hanson had her first bout
with breast cancer in 1997. When the
tumor reappeared in 2004, she came
to see Harold Burstein, MD, PhD, at
Dana-Farber's Breast Oncology Center.
She received a standard course of
radiation and chemotherapy for her BRCA2-positive tumor. Two years later,
after another local recurrence,
Dr. Burstein suggested a clinical trial.
The first experimental treatment she
tried had no effect, but she then
enrolled in a multi-center study of
PARP inhibitors and she's seen her
When she was undergoing
chemotherapy and radiation, Hanson
traveled to Dana-Farber at least weekly
from her home in Brookline, New
Hampshire, and had to take a leave
from her job as a medical secretary
when the side effects became too
severe. With the PARP inhibitor, she
takes her pills in the morning and
evening, feels a little tired and sometimes
nauseous, but she says, "I go
to work, I do everything I want to do.
To have a drug with so few side effects
and that is effective, is wonderful."
"This is a very new drug, and I
know there aren't that many people
on it worldwide. But my background
matched it, and now I'm having positive
results," Hanson said. "A big
reason I chose to go to Dana-Farber is
because they have these opportunities
for study drugs. I feel blessed to have
Only a fraction of women with
breast and ovarian cancer have BRCA mutations, but many tumors have
defects in DNA repair. In ovarian
cancer, up to 70 percent of tumors are
deficient in some part of the the BRCA DNA repair pathway, even though their BRCA genes may be normal. The problem
could lie in regulation of BRCA gene
expression or in trouble with other
proteins in the same pathway. Whatever
the cause, if the cells are relying
on the PARP pathway to take up the
slack, the inhibitor might work for
these tumors, too.
To test that idea, Dr. Matulonis is
planning a trial to evaluate the compound
AZD2281 in women with
recurrent ovarian cancer that is still
responsive to platinum, whether their
tumors have BRCA mutations or not.
In breast cancer, a similar opportunity
may exist to treat an aggressive
and stubborn class of tumors known as
triple negatives. These cancers lack
three clinical cancer markers, estrogen
receptors, progesterone receptors, and
the growth-promoting protein HER2.
Because of this, the cells do not respond
to anti-estrogen therapy, or to the
HER2-targeted therapy trastuzumab.
Dan Silver, MD, PhD, then a
research fellow with David
Livingston, MD, found that triple
negative breast cancers share features
of BRCA-mutated tumors, including
defects in DNA repair and an accompanying
sensitivity to the DNA-damaging
drug cisplatin. Could this
parallel extend to sensitivity to PARP
Dr. Silver, now an assistant
professor in the Women's Cancers
Program, believes so. He has found
that some of the tumors are very sensitive
to PARP inhibitors when grown in
the lab. This work is being translated
in a clinical trial in collaboration with
Judy Garber, MD, MPH, the director
of the Friends of Dana-Farber Cancer
Risk and Prevention Clinic. Building
on the program's recent success using
cisplatin chemotherapy to treat triple-negative breast cancers, the
researchers plan to combine a PARP inhibitor with cisplatin,
and treat women with newly
diagnosed triple-negative tumors, with
or without BRCA mutations.
Alan D'Andrea, MD, has spent
the last 15 years uncovering the genes
and proteins involved in all six DNA
repair pathways, and he thinks there
may be more tumors with the right
profile for PARP inhibitor treatment.
"Any cell that has become dependent on the PARP pathway for survival
is fair game," says Dr. D'Andrea, the
chief of the Division of Radiation and
To sort out the cancers that
qualify, Dr. D'Andrea and colleagues
are working out a series of laboratory
tests to determine, in tumor samples,
which DNA repair pathways are active.
Having that information up front will
allow doctors to figure out which
patients are the best candidates for
PARP inhibitor treatment. "This is a
really good opportunity for personalized
medicine," Dr. D'Andrea says.
"Our challenge is to find the perfect
patients for the PARP inhibitors."
Many questions remain about the
new approach. Which PARP inhibitors
of several in the pipeline will emerge
as the best? Should the inhibitors be
combined with chemotherapy? Should
they be used early in treatment, or
later? Resistance to PARP inhibitors
can emerge when cells find a way to
reactivate the BRCA-dependent repair
pathway – will that limit their use?
It will take time to get the
answers, but Dr. Matulonis sees PARP
inhibitors as just the beginning of a
whole new class of therapies. "As time
goes on we are going to see more and
more drugs targeting DNA repair," she
says. "For women with ovarian cancer
who don't have the BRCA mutation,
this is going to be an area of new drug
therapies and active research. This is an
2009 Turning Point