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What is PARP?
PARP, or poly (ADP-ribose) polymerase, is a ubiquitous nuclear enzyme whose function in the
human body includes repairing damage to our DNA. PARP regulates the nuclear machinery
used for repairing damaged DNA. If left unrepaired, DNA damage can stall the cell cycle and
lead to cell death.
In normal, noncancerous cells, DNA repair is beneficial, promoting healthy cell growth and
proliferation. However, studies have suggested that cancer cells may use the PARP-dependent
DNA repair pathway to their advantage. For example, PARP1 expression and activity are
significantly upregulated in many cancers, implying an important role for this enzyme in survival
and proliferation of cancer cells.[1]
PARP inhibitor AZD2281
A small molecule inhibitor of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) with
potential chemosensitizing, radiosensitizing, and antineoplastic activities. PARP inhibitor
AZD2281 selectively binds to and inhibits PARP, inhibiting PARP-mediated repair of single
strand DNA breaks; PARP inhibition may enhance the cytotoxicity of DNA-damaging agents
and may reverse tumor cell chemoresistance and radioresistance. PARP catalyzes
post-translational ADP-ribosylation of nuclear proteins and can be activated by single-stranded
DNA breaks. Check for active clinical trials or closed clinical trials using this agent. (NCI
Thesaurus) [2]
What makes PARP a promising target?
While inhibition of PARP has demonstrated significant anti-tumor effects in several cancers, its
activity does not appear to be critical for normal, non-cancerous cells.3 Thus, PARP inhibition
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has the potential to impair a fundamental mechanism of tumor growth without rendering
damage to normal cells, implying a lower risk for side effects in patients who receive
PARP-inhibitor-based therapies.
PARP inhibition and chemotherapy - disrupting mechanisms of chemotherapy-resistance in
cancer cells
Chemotherapy regimens used in the treatment of cancer, including alkylating agents,
topoisomerase inhibitors, and platinum drugs, are designed to damage DNA in order to prevent
cancer cells from reproducing. DNA repair enzymes such as PARP, whose activity and
expression are upregulated in tumor cells, function to dampen the intended effect of
chemotherapy and generate resistance. PARP inhibitors, such as BSI-201, prevent cancer cells
from repairing their own DNA, thus enhancing the potential of chemotherapy and radiation
radiation therapy to -induce cell death.
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BiPar Double Helix
PARP inhibition and BRCA - targeting the Achilles Heel of Cancer
BRCA1 and BRCA2 are tumor suppressor genes that help control normal cell growth and cell
death by regulating the repair of double strand breaks in DNA. Mutations in the BRCA1 and
BRCA2 genes can impair this function, leaving cells unable to repair their own DNA, as well as
causing the uncontrolled growth that is characteristic of cancer cells. Women who inherit
mutations in the BRCA1 or BRCA2 genes have significantly higher risks for breast and ovarian
cancer.
PARP inhibitors represent a new, targeted approach to treating BRCA-associated cancers.
PARP inhibition has the potential to overwhelm cancer cells with lethal DNA damage by
exploiting the impaired DNA repair function inherent in BRCA-associated cancers. Inhibition of
PARP leads to failure to repair DNA single strand breaks, which in turn, result in DNA double
strand breaks via collapse of the replication fork. These effects are particularly detrimental to
BRCA-associated cancer cells, which fail to repair both DNA single strand breaks (via PARP
inhibition) and double strand breaks (via BRCA defects), ultimately leading to cancer cell
death.[1]
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Targeted therapy for cancer using PARP inhibitors
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The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, Fulham
Road, London, UK.
Poly (ADP-ribose) Polymerase (PARP) has a well-established role in DNA repair processes,
and small molecule inhibitors of PARP have been developed as chemotherapy sensitisers for
the treatment of cancer. The subsequent demonstration that PARP inhibition is selective for
BRCA1 or BRCA2 deficiency suggests that PARP inhibitors may be particularly useful for the
treatment of cancer with BRCA mutations. This would represent one of the first clinically
implemented examples of a synthetic lethal approach for cancer treatment. However, there are
still unanswered questions surrounding PARP inhibitors, namely the levels of specificity and
potency that are required to elicit BRCA selectivity. The recent identification of mechanisms of
cellular resistance to PARP inhibitors may provide indications as to how these drugs may be
best used in the clinic.[3]
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About PARP and DNA Repair
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PARP is an acronym for poly (ADP-ribose) polymerase. PARP is a protein that has several
roles in cellular processes, most notably in DNA repair and programmed cell death. Healthy
cells can use PARP to repair themselves and live out their normal life cycle. But cancer cells
may also use PARP to repair DNA damage, thus extending their uncontrolled growth. Such
cancers can become resistant to treatment. There are several different PARP proteins, and they
each have their own role in functions within cells.
PARP Inhibitors And Breast Cancer Treatment:
A PARP inhibitor is a drug that blocks PARP proteins from performing their roles in repairing
damaged cancer cells. Chemotherapy and radiation work by breaking the DNA of cells so that
they may not reproduce. Some types of cancer cells use PARP enzymes to repair their DNA
damage and recover from the assault of cancer treatments. Clinical trials are being done to see
if PARP inhibitors, in combination with other cancer treatments, can block PARP protein from
damaged cancer cells.
Effects On Breast Cancer Treatment:
If a PARP inhibitor is added to chemotherapy treatments for breast cancer, researchers hope
cancer cells that have resisted anticancer drugs will be become vulnerable to fatal DNA
damage. In some cases, a PARP inhibitor may be used alone, rather than in conjunction with
chemo and radiation. Even better news is that PARP inhibitors do not appear to affect normal,
non-cancerous cells. That means fewer side effects for patients and faster recovery from
treatments.
Hope for Hereditary Breast Cancers:
PARP inhibitors may be especially helpful for patients with hereditary breast cancer. People
who have BRCA1 and BRCA2 genetic mutations are at very high risk for developing breast
cancer. Healthy BRCA genes can suppress tumor formation, but mutated BRCA genes are
powerless against cancer cells. PARP inhibitors may exploit the weakness inherent in cancer
cells with mutated BRCA. One possible use for PARP inhibitors may be prevention of hereditary
breast cancer. Perhaps PARP inhibitors will become a preventative treatment for high-risk
women and would make prophylactic mastectomies obsolete.
Encouraging News for Triple-Negative Breast Cancers:
A phase 2 clinical trial of a PARP inhibitor, BSI-201, was done with patients who were
diagnosed with metastatic triple negative breast cancer. The 89 patients enrolled in this trial had
already been treated with no more than two chemotherapy regimens. Half of the patients were
treated with Gemcitabine and Carboplatin, the other half had the same chemotherapy with the
addition of BSI-201. Side effects for both groups were about the same, suggesting that the
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PARP inhibitor was well tolerated. Preliminary data suggests clinical benefits may include
slower tumor growth or tumor regression.
Other Uses For PARP Inhibitors:
Drugs developed with PARP inhibitors are being tested on several kinds of cancer: breast and
ovarian, uterine, brain, and pancreatic.
Potential Importance of PARP Inhibitors:
The addition of PARP inhibitors to the current arsenal of weapons against breast cancer looks
very promising. PARP inhibitors increase the effectiveness of chemotherapy against aggressive
hereditary and triple-negative breast cancers, potentially without adding many serious side
effects. These drugs appear to improve quality of life as well as extend survival for patients.
Fighting breast cancer at the level of its DNA looks like the wave of the future.[4]
ASCO hightlights Herceptin, PARP inhibitors
There's no shortage of cancer news this morning, thanks to the annual ASCO meeting. One
drug that's getting a lot of press is Roche's blockbuster breast cancer biologic Herceptin. In
patients with the HER-2 gene, Herceptin plus chemotherapy increased survival to 13.8 months,
compared with 11.1 month with chemo alone. A stomach cancer approval for Herceptin would
mark the first new indication for the drug, which brought in $4.74 billion in sales last year. Roche
will seek ex-U.S. approval for the drug, while Genentech will pursue the additional indication in
the U.S.
Another hot topic today is a new class of drug called PARP inhibitors. The compounds work by
"obstructing the ability of cells damaged by chemotherapy or through genetic mutations to repair
themselves, causing tumor cells to die as a result," explains the WSJ. In one trial, Sanofi
Aventis reported that BSI-201 plus chemotherapy extended average survival times by three and
a half months, to 9.2 months. Sanofi acquired BSI-201 in its recent $500 million buyout of BiPar
Sciences--a deal that's now looking like a bargain for Sanofi. And in a study of 52 women with
BRCA1 and BRCA2 mutations, AstraZeneca's olaparib spurred tumor shrinkage that reached
up to 41 percent. Merck and Abbott are also developing PARP inhibitors.
- here's the WSJ summary
- read more on Herceptin
- see this analysis of PARP inhibitors[5]
Sources
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[1] www.biparsciences.com/000010.html
[2] www.nci.nih.gov/Templates/drugdictionary.aspx?CdrID=560191
[3] www.ncbi.nlm.nih.gov/pubmed/18644251
[4] breastcancer.about.com/od/targetedbiologictherapies/p/parp_basics.htm
[5] www.fiercepharma.com/story/asco-hightlights-herceptin-parp-inhibitors/2009-06-01
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