Science of PARP (Parp inhibitor, Parp inhibitors)

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 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.

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]

Targeted therapy for cancer using PARP inhibitors

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]

About PARP and DNA Repair

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 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

[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