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

Approved for marketing

Combination with radiotherapy

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

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

Examples of clinical trials

Started Phase III:

Started Phase II:

Currently Discontinued:

Experimental:

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

References

  1. ↑ Blankenhorn D (2009-06-25). "PARP inhibitors working against inherited cancers | ZDNet Healthcare | ZDNet.com". ZDNet Healthcare owned by CBS Interactive Inc. ZDNet. Archived from the original on 2009-06-28. Retrieved 2019-12-05.
  2. ↑ Pam Stephan. "PARP Inhibitor and DNA Polymerase Repair - PARP Inhibitor". About.com Health.
  3. 1 2 "Development of PARP Inhibitors: An Unfinished Story". cancernetwork.com. ONCOLOGY Vol 24 No 1. 24 (1). 15 January 2010.
  4. 1 2 "PARP Inhibitors – More Widely Effective than First Thought". drugdiscoveryopinion.com.
  5. ↑ "PARP inhibitors: Halting cancer by halting DNA repair". Cancer Research UK. 24 September 2020.
  6. ↑ Tattersall, Abigail; Ryan, Neil; Wiggans, Alison J.; Rogozińska, Ewelina; Morrison, Jo (2022-02-16). "Poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer". The Cochrane Database of Systematic Reviews. 2022 (2): CD007929. doi:10.1002/14651858.CD007929.pub4. ISSN 1469-493X. PMC 8848772. PMID 35170751.
  7. ↑ Graziani G, Szabó C (July 2005). "Clinical perspectives of PARP inhibitors". Pharmacological Research. 52 (1): 109–18. doi:10.1016/j.phrs.2005.02.013. PMID 15911339.
  8. ↑ "PARP Inhibitor Gets FDA Nod for Ovarian Cancer". medpagetoday.com. 19 December 2016.
  9. ↑ Zejula FDA Professional Drug Information.
  10. ↑ "Tesaro earns CHMP thumbs-up for Zejula as three-way PARP race heats up | FiercePharma". Fierce Pharma. 15 September 2017. Retrieved 2018-03-28.
  11. ↑ "PARP inhibitor, MK-4827, shows anti-tumor activity in first trial in humans". 17 Nov 2010.
  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.
  15. ↑ Rajman L, Chwalek K, Sinclair DA (March 2018). "Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence". Cell Metabolism. 27 (3): 529–547. doi:10.1016/j.cmet.2018.02.011. PMC 6342515. PMID 29514064.
  16. 1 2 Buisson R, Dion-Côté AM, Coulombe Y, Launay H, Cai H, Stasiak AZ, et al. (October 2010). "Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination". Nature Structural & Molecular Biology. 17 (10): 1247–54. doi:10.1038/nsmb.1915. PMC 4094107. PMID 20871615.
  17. ↑ McGlynn, P. and Lloyd, B. "Recombinational Repair and Restart of Damaged Replication Forks." Nature Reviews, 2002, pp.859-870
  18. ↑ Lord CJ, Ashworth A (March 2017). "PARP inhibitors: Synthetic lethality in the clinic". Science. 355 (6330): 1152–1158. Bibcode:2017Sci...355.1152L. doi:10.1126/science.aam7344. PMC 6175050. PMID 28302823.
  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.
  22. ↑ Banasik M, Stedeford T, Strosznajder RP (August 2012). "Natural inhibitors of poly(ADP-ribose) polymerase-1". Molecular Neurobiology. 46 (1): 55–63. doi:10.1007/s12035-012-8257-x. PMID 22476980. S2CID 8439334.
  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
  24. ↑ BioMarin Pharmaceutical Inc. (28 July 2011). "BioMarin Announces Second Quarter 2011 Financial Results". prnewswire.com.
  25. ↑ "BioMarin Initiates Phase 3 BMN 673 Trial for Metastatic gBRCA Breast Cancer. Oct 2013". Benzinga. 2013-10-31.
  26. 1 2 "AbbVie takes PARP inhibitor into third phase III trial". PMLive. 27 June 2014.
  27. ↑ "BeiGene Initiates Phase 3 Trial of Pamiparib as Maintenance Therapy in Chinese Patients with Ovarian Cancer". 17 May 2018.
  28. ↑ BeiGene application accepted in China for pamiparib for ovarian cancer July 2020
  29. ↑ "BeiGene Announces Acceptance of a New Drug Application of Pamiparib in Ovarian Cancer in China | Seeking Alpha".
  30. ↑ "Study to Assess the Safety and Tolerability of a PARP Inhibitor in Combination With Carboplatin and/or Paclitaxel". Clinicaltrials.gov. 2 March 2022.
  31. ↑ "AZD2281 Plus Carboplatin to Treat Breast and Ovarian Cancer". Clinicaltrials.gov. 19 October 2019.
  32. ↑ "Trial shows benefit of 'BRCA-targeting' drug in prostate cancer". icr.ac.uk.
  33. ↑ "Study of CEP-9722 as Single-Agent Therapy and as Combination Therapy With Temozolomide in Patients With Advanced Solid Tumors". 14 August 2012.
  34. 1 2 Guha M (May 2011). "PARP inhibitors stumble in breast cancer". Nature Biotechnology. 29 (5): 373–4. doi:10.1038/nbt0511-373. PMID 21552220. S2CID 205267931.
  35. ↑ Liu X, Shi Y, Maag DX, Palma JP, Patterson MJ, Ellis PA, et al. (January 2012). "Iniparib nonselectively modifies cysteine-containing proteins in tumor cells and is not a bona fide PARP inhibitor". Clinical Cancer Research. 18 (2): 510–23. doi:10.1158/1078-0432.CCR-11-1973. PMID 22128301.
  36. ↑ Patel AG, De Lorenzo SB, Flatten KS, Poirier GG, Kaufmann SH (March 2012). "Failure of iniparib to inhibit poly(ADP-Ribose) polymerase in vitro". Clinical Cancer Research. 18 (6): 1655–62. doi:10.1158/1078-0432.CCR-11-2890. PMC 3306513. PMID 22291137.
  37. ↑ "Sanofi breast cancer drug flunks Phase III trial". Fierce Biotech. 28 January 2011.
  38. ↑ "Sanofi Ends Iniparib Research". Bloomberg News. 3 June 2013.
  39. ↑ Karlberg T, Hammarström M, Schütz P, Svensson L, Schüler H (February 2010). "Crystal structure of the catalytic domain of human PARP2 in complex with PARP inhibitor ABT-888". Biochemistry. 49 (6): 1056–8. doi:10.1021/bi902079y. PMID 20092359.
  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.
Wikimedia Commons has media related to PARP inhibitors.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.