See ((Poly(adenosine triphosphate (ADP)-ribose) polymerizes (PARPs) ))
PARP inhibitors are pharmacological inhibitors of the enzyme poly ADP ribose polymerase (PARP).
PARP1 and PARP2 our key components of the DNA damage response mechanism.
PARP inhibitors selectively kill specific cancer cells via the so-called synthetic lethality, a mechanism whereby deficiency in function of one gene or genes product has little effect alone but is toxic in combination with deficiency in the function of the second gene or genes products.
PARP inhibitors are lethal in cells with homozygous deletions or deleterious alterations, or both, in DNA damage response genes involved either directly or indirectly in homologous recombination repair.
PARP inhibitors have multiple indications, including the treatment of heritable cancers.
Several cancers are more dependent on PARP than regular cells, making PARP an attractive target for cancer therapy.
PARP inhibitors improve progression-free survival in women with recurrent platinum-sensitive ovarian cancer.
PARP inhibitors are considered a potential treatment for acute life-threatening diseases, such as stroke and myocardial infarction, as well as for long-term neurodegenerative diseases.
PARP1 inhibits DNA repair.
BRCA1, BRCA2 and PALB2are proteins that are important for the repair of double-strand DNA breaks.
When the gene for one of these proteins is mutated, the change can lead to errors in DNA repair that can eventually cause cancer.
PARP1 is a protein vital for repairing single-strand breaks in the DNA.
If such breaks persist unrepaired until DNA is replicated it can cause double strand breaks to form.
PARP1 inhibitors cause multiple double strand breaks to reform.
In tumors with BRCA1, BRCA2 or PALB2 mutations, these double strand breaks cannot be efficiently repaired, leading to the death of the cells.
Cells which are normal and don’t replicate their DNA as often as malignant cells, and that lack any mutated BRCA1 or BRCA2 still have homologous repair operating, which allows them to survive the inhibition of PARP.
PARP inhibitors trap PARP proteins on DNA and block their catalytic action:
interfering with replication, causing cell death preferentially in cancer cells.
Cancer cells that lack the tumor suppressor PTEN may be sensitive to PARP inhibitors.
PARP inhibitors may be effective against many PTEN-defective tumors.
Low oxygen cancer cells are sensitive to PARP inhibitors.
Excessive PARP-1 activity may exacerbate stroke, myocardial infarction, neurodegeneration, and a number of other disease conditions due to excessive inflammation: reduction of inflammation by PARP-1 inhibition can mitigate these conditions.
The most common side effects with PARP inhibitors is nausea, and other side effects include fatigue, and tiredness.
Use of PARP inhibitors is associated with increased risk of development of MDS and AML,
Olaparib, Rucaparib,Niraparib, Talazoparib.
PARP inhibitors are approved for use as frontline maintenance therapy in advanced ovarian cancer in patients that have responded to other antecedent platinum-based chemotherapy: they are also approved for maintenance therapy and patients with recurrent, platinum sensitive disease.
Combining radiation therapy with PARP inhibitors lead to formation of double strand breaks from the single-strand breaks generated by the radiotherapy in tumor tissue with BRCA1/BRCA2 mutations.
In patients with BRCA positive advanced or metastatic breast cancer objective response rates are approximately 60%, with Improved median progression free survival of approximately three months o er chemotherapy but no improvement in overall survival.
In the PAOLA-1 study patients with advanced ovarian cancer received maintenance treatment wilh Bevacizumab plus olaparib:adding the PARP inhibitor improved median free survival from 16.6 months to 22.1 months.
The SOLO-1 trail of women who had advanced BRCA mutated ovarian cancers and who had undergone cytoreduction Surgery and who were in complete or partial response to platinum based chemotherapy randomize to Olaparib or placebo: follow up for 40.7 months the olaparib reduced risk of progression free survival by 70%.
Recent studies suggest the use of PARP inhibitors in relapsed patients may decrease overall survival compared to chemotherapy.
Trials have shown benefit of PARP inhibitors, an adult patients with ovarian, breast, pancreatic or prostate cancer with deleterious suspected BRCA1 or BRCA2 alterations.
Patients with early breast cancer are eligible for one year of adjuvant PARP inhibitors if they have a germline pathogenic variant in BRCA1 or BRCA2, human epidermal growth factor receptor, negativity and high risk pathological factors, following local treatment and neoadjuvant or adjuvant chemotherapy.
Patients with early triple negative breast cancer are eligible if they have either residual disease after neoadjuvant chemotherapy, or T2, tumors or tumors involving the lymph nodes if they did not receive neoadjuvant therapy.