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Poly(adenosine triphosphate (ADP)-ribose) polymerase (PARPs)

A family of multifunctional enzymes that play important role in the repair of DNA single strand breaks through the repair of base excisions.

PARP1 is the most abundant enzyme in this family of proteins.

PARP proteins our family of nuclear enzymes involved in multiple DNA damage pathways.

PARP1 is the most involved in DNA repair.

PARP binds to DNA brakes, recruits DNA damage repair components that cooperate to stabilize the replication fork, and allows for DNA repair.

they have a role in the sequence of events after DNA damage come and act as a scaffold to assemble components of the homologous recombination repair at the site of double stranded breaks.

PARP inhibitors can lead to the accumulation of DNA single strand breaks which can lead to DNA double strand breaks at replication forks.

Inhibition of PARP  enzyme may diminish self-repair mechanisms, make cancer cells more sensitive to treatment, and promote cancer cell death.

An enzyme involved in the recognition of DNA damage.

Lymphoblastoid cell lines established from blood samples of centenarians have significantly higher activity of the DNA repair protein Poly ADP ribose polymerase (PARP) than cell lines from younger individuals.

After ribosylation PARP recruit’s a DNA repair complex.

When blocked in normal cells, cells can repair that damage by recombination.

In BRCA deficient states such as with mutations or with deletion of BRCA genes PARP inhibition prevents DNA repair by the accumulation of genetic damage that cells cannot be tolerated.

BRCA and PARP pathways are critically relevant to DNA repair and inhibition of PARP produces cell kill in cells genetically deficient in BRCA.

Agents available are Olaparib, Rucaparib, talazoparib, Niraparib.

During transformation of cancer cells in BRCA1 or BRCA 2 mutations, the second functional allele of these genes are lost, inhibiting the ability to repair double-strnd breaks in DNA through homologous recombination: therefore cancer cells are selectively sensitized to inhibitors of other DNA pathways, including base excision repair, a process that requires PARP.

Women with germline mutations of BRCA1 and BRCA2 have objective response rates of 40%-60% to PARP inhibitors in breast and ovarian cancers (Yap TA, Fong PC).

Patients with triple negative breast cancers had greater benefit treated with the PARP1 inhibitor BSI-201 plus gemcitabine/carboplatin compared to gemcitabine/carboplatinum alone resulted in a clinical benefit rate of 62% vs. 21%, respectively and an objective response rate of 48% vs. 16%, respectively, and there was a significant survival benefit both the median progression free survival and median overall survival (O’Shaughnessy).

Other studies showed an initial high rate of response, but the duration of response in metastatic breast cancer was from 5.4-6.4 months with no improvement in survival compared to chemotherapy.

In a phase 2 study comparing the efficacy and safety of gemcitabine and carboplatin with or without iniparib, a small molecule with PARP inhibitory activity, in patients with metastatic TNBC: the addition of iniparib to gemcitabine and carboplatin improved the rate of clinical benefit from 34%-56%, and the overall response from 32%-52%, and also prolonged the median progression free survival from 3.6 months to 5.9 months and the median overall survival from 7.7 months to 12.3 months (O’Shaughnessy J et al).

All PARP inhibitors enhance disease-free survival when used in serious ovarian cancers after primary treatment, including surgery and platinum – taxane doublets.

PARP inhibitors are associated with long delays in recurrence in patients with germline BRCA 1/2 mutation ovarian cancers.

While PARP inhibitors have become the standard of care IN maintenance treatment of ovarian cancer, recent studies suggest benefits as front line treatment.
The PAOLA-1: PRIMA, and VELIA trials all found increases in median progression free survival of significant degree.

PARP inhibitors come with increased risk of bone marrow and gastrointestinal toxicity, along with severe hematologic toxicity.

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