PARP inhibitor

PARP inhibitors are a group of

They are developed for multiple indications, including the treatment of heritable cancers.^[1] Several forms of cancer are more dependent on PARP than regular cells, making PARP (PARP1, PARP2 etc) an attractive target for cancer therapy.^[2][3][4][5] PARP inhibitors appear to improve progression-free survival in women with recurrent platinum-sensitive ovarian cancer, as evidenced mainly by olaparib added to conventional treatment.^[6]

In addition to their use in cancer therapy, PARP inhibitors are considered a potential treatment for acute life-threatening diseases, such as

• US FDA approved olaparib as monotherapy (at 400 mg taken twice per day) for patients with germline BRCA mutated (gBRCAm) advanced ovarian cancer
  who have been treated with three or more prior lines of chemotherapy.
• accelerated approval for previously treated BRCA-mutant ovarian cancer.^[8]
  In April 2018 it was granted FDA approval.
• primary peritoneal cancer.^[9][10] Inhibitor of PARP1 and PARP2.^[11]
• Talazoparib was approved in 2018 by US FDA for breast cancer with germline BRCA mutations.^[12]

Combination with radiotherapy

The main function of

DNA is damaged thousands of times during each cell cycle, and that damage must be repaired, including in cancer cells. Otherwise the cells may die due to this damage.[14] Chemotherapy and radiation therapy attempt to kill cancer cells by inducing high levels of DNA damage. By inhibiting PARP1 DNA repair, the effectiveness of these therapies can be increased.^[15]

BRCA1, BRCA2 and PALB2^[16] are proteins that are important for the repair of double-strand DNA breaks by the error-free homologous recombinational repair, or HRR, pathway. When the gene for one of these proteins is mutated, the change can lead to errors in DNA repair that can eventually cause breast cancer. When subjected to enough damage at one time, the altered gene can cause the death of the cells.

PARP1 is a protein that is important for repairing single-strand breaks ('nicks' in the DNA). If such nicks persist unrepaired until DNA is replicated (which must precede cell division), then the replication itself can cause double strand breaks to form.^[17]

Drugs that inhibit PARP1 cause multiple double strand breaks to form in this way, and in tumours with BRCA1, BRCA2 or PALB2^[16] mutations, these double strand breaks cannot be efficiently repaired, leading to the death of the cells. Normal cells that don't replicate their DNA as often as cancer cells, and that lack any mutated BRCA1 or BRCA2 still have homologous repair operating, which allows them to survive the inhibition of PARP.^[18]

PARP inhibitors lead to trapping of PARP proteins on DNA in addition to blocking their catalytic action.^[19] This interferes with replication, causing cell death preferentially in cancer cells, which grow faster than non-cancerous cells.

Some cancer cells that lack the tumor suppressor

Cancer cells that are low in oxygen (e.g. in fast growing tumors) are sensitive to PARP inhibitors.[21]

Excessive PARP-1 activity may exacerbate the pathogenesis of stroke, myocardial infarction, neurodegeneration, and a number of other disease conditions due to excessive inflammation. Thus, reduction of inflammation by PARP-1 inhibition can mitigate these conditions.^[22] PARP inhibitors such as olaparib, under experimental conditions, appear to be beneficial in limiting atrial fibrillation and other DNA damage associated cardiovascular diseases.^[23]

Research

Examples of clinical trials

Started Phase III:

• Talazoparib after trials for advanced hematological malignancies and for advanced or recurrent solid tumors.^[24] it started in 2013 a phase III for metastatic germline BRCA mutated breast cancer.^[25]
• non-small cell lung cancer (NSCLC).^[26]
• Pamiparib (BGB-290) For ovarian cancer, 1st patient enrolled May 2018.^[27] It is a PARP1 and PARP2 inhibitor.^[28][29]

Started Phase II:

• Olaparib (developed by AstraZeneca) for breast, ovarian and colorectal cancer.^[30][31]
• Olaparib TOPARP-A trial for use in advanced prostate cancer (published c. April 21, 2015).^[32]
• Rucaparib for metastatic breast and ovarian cancer.
• Veliparib for metastatic melanoma.
• CEP 9722^[33] for non-small-cell lung cancer (NSCLC)^[34]
• E7016 (developed by Eisai): underwent phase II trial in melanoma.^[26]

Currently Discontinued:

• squamous cell lung cancer patients in a phase III trial, prompting the company to end research into the once-promising compound.^[37][38]

• 3-Aminobenzamide, a prototypical PARP inhibitor.^[39]

Studies of PARP inhibitor resistance

Despite the clinical success of PARP inhibitors, their efficacy is limited by the development of resistance. Overcoming resistance has thus become a major focus within the PARP inhibitor research field, prompting comprehensive studies into resistance mechanisms. At present, reversion-driven HR restoration has been established as the most common resistance mechanism. Reversion-driven HR restoration is the result of secondary mutation events within BRCA1, BRCA2, or other HR-related factors, which restore protein function and, thus, HR proficiency. HR can also be re-established without reversion events. For example, loss of end-protection (e.g. via 53BP1 loss), has been shown to restore HR. Other resistance mechanisms include enhanced drug efflux, restoration of DNA replication fork protection, mutations in PARP1, and PARG downregulation.^[40]

See also

• PARP1
• Parthanatos – PARP-1 dependent cell death

References

External links

Wikimedia Commons has media related to PARP inhibitors.

• Parp Inhibitors information site
• PARP structure