PARP inhibitor

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Model of the inhibitor olaparib (dark gray) occupying the NAD+-binding site of PARP1. From PDB: 5DS3​.

PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase (PARP).

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 stroke and myocardial infarction, as well as for long-term neurodegenerative diseases.[7]

Medical uses[edit]

Approved for marketing[edit]

Combination with radiotherapy[edit]

The main function of radiotherapy is to produce DNA strand breaks, causing severe DNA damage and leading to cell death. Radiotherapy has the potential to kill 100% of any targeted cells, but the dose required to do so would cause unacceptable side effects to healthy tissue. Radiotherapy therefore can only be given up to a certain level of radiation exposure. Combining radiation therapy with PARP inhibitors offers promise, since the inhibitors would lead to formation of double strand breaks from the single-strand breaks generated by the radiotherapy in tumor tissue with BRCA1/BRCA2 mutations. This combination could therefore lead to either more powerful therapy with the same radiation dose or similarly powerful therapy with a lower radiation dose.[13]

Mechanism of action[edit]

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 PTEN may be sensitive to PARP inhibitors because of downregulation of Rad51, a critical homologous recombination component, although other data suggest PTEN may not regulate Rad51.[3][20] Hence PARP inhibitors may be effective against many PTEN-defective tumours[4] (e.g. some aggressive prostate cancers).

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[edit]

Examples of clinical trials[edit]

Started Phase III:

Started Phase II:

Currently Discontinued:

Experimental:

Studies of PARP inhibitor resistance[edit]

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[edit]

References[edit]

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  2. ^ Pam Stephan. "PARP Inhibitor and DNA Polymerase Repair - PARP Inhibitor". About.com Health.
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  9. ^ Zejula FDA Professional Drug Information.
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  12. ^ Lisa M. Jarvis (2 January 2019). "FDA drug approvals hit all-time high". c&en.
  13. ^ "PARP inhibitors. ESTRO 2010. ecancer - Conference highlights and events calendar". ecancer.org. Archived from the original on 2012-07-07.
  14. ^ "Today's anti-cancer tools are ever better wielded". The Economist. Retrieved 2017-09-30.
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  19. ^ Pettitt SJ, Krastev DB, Brandsma I, Dréan A, Song F, Aleksandrov R, et al. (May 2018). "Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance". Nature Communications. 9 (1): 1849. Bibcode:2018NatCo...9.1849P. doi:10.1038/s41467-018-03917-2. PMC 5945626. PMID 29748565.
  20. ^ Gupta A, Yang Q, Pandita RK, Hunt CR, Xiang T, Misri S, et al. (July 2009). "Cell cycle checkpoint defects contribute to genomic instability in PTEN deficient cells independent of DNA DSB repair". Cell Cycle. 8 (14): 2198–210. doi:10.4161/cc.8.14.8947. PMID 19502790.
  21. ^ "Experimental Drug May Work in Many Cancers | Discuss Cancer". Archived from the original on 2011-07-10.
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  23. ^ Ramos KS, Brundel BJJM. DNA Damage, an Innocent Bystander in Atrial Fibrillation and Other Cardiovascular Diseases? Front Cardiovasc Med. 2020 Apr 28;7:67. doi: 10.3389/fcvm.2020.00067. PMID 32411727; PMCID: PMC7198718
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  31. ^ "AZD2281 Plus Carboplatin to Treat Breast and Ovarian Cancer". Clinicaltrials.gov. 19 October 2019.
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  40. ^ Kanev, Petar-Bogomil; Atemin, Aleksandar; Stoynov, Stoyno; Aleksandrov, Radoslav (September 2023). "PARP1 roles in DNA repair and DNA replication: The basi(c)s of PARP inhibitor efficacy and resistance". Seminars in Oncology. doi:10.1053/j.seminoncol.2023.08.001.

External links[edit]