PARP inhibitor
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 an attractive target for cancer therapy.[2][3][4] 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.[5]
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.[6]
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.[7]
BRCA1, BRCA2 and PALB2[8] 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.[9]
Drugs that inhibit PARP1 cause multiple double strand breaks to form in this way, and in tumours with BRCA1, BRCA2 or PALB2 [8] 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.[10]
PARP inhibitors lead to trapping of PARP proteins on DNA in addition to blocking their catalytic action.[11] 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][12] 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.[13]
Approved for marketing
- Olaparib: In December, 2014, the EMA and 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.
- Rucaparib: On December 19, 2016 the US FDA granted accelerated approval for previously treated BRCA-mutant ovarian cancer.[14] In April 2018 it was granted FDA approval.
- Niraparib: In March 2017 approved by US FDA for epithelial ovarian, fallopian tube, and primary peritoneal cancer.[15][16] Inhibitor of PARP1 and PARP2.[17]
- Talazoparib was approved in 2018 by US FDA for breast cancer with germline BRCA mutations.[18]
Examples in clinical trials
Started Phase III:
- Talazoparib after trials for advanced hematological malignancies and for advanced or recurrent solid tumors.[19] it started in 2013 a phase III for metastatic germline BRCA mutated breast cancer.[20]
- Veliparib June 2014 in phase III trials, for advanced ovarian cancer, triple-negative breast cancer and in non-small cell lung cancer (NSCLC).[21]
- BGB-290 (Pamiparib) 1st patient enrolled May 2018.[22]
Started Phase II:
- Olaparib for breast, ovarian and colorectal cancer.[23][24] AZ
- Olaparib TOPARP-A trial for use in advanced prostate cancer (published c. April 21, 2015).[25]
- Rucaparib for metastatic breast and ovarian cancer.
- Veliparib for metastatic melanoma.
- CEP 9722[26] for non–small-cell lung cancer (NSCLC)[27]
- E7016 (developed by Eisai): underwent phase II trial in melanoma.[21]
Currently Discontinued:
- Iniparib (BSI 201, developed by Sanofi) was determined in 2012 not to be a true PARP inhibitor[28][29] and failed trial for triple negative breast cancer.[27] In 2013 Sanofi disclosed that iniparib failed to help squamous cell lung cancer patients in a phase III trial, prompting the company to end research into the once-promising compound.[30][31]
Experimental:
- 3-aminobenzamide, a prototypical PARP inhibitor
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.[32]
See also
References
- ^ Blankenhorn, Dana (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 2009-06-29. Retrieved 2019-12-05.
{{cite web}}:|archive-date=/|archive-url=timestamp mismatch; 2009-06-28 suggested (help) - ^ Pam Stephan. "PARP Inhibitor and DNA Polymerase Repair - PARP Inhibitor". About.com Health.
- ^ a b "Development of PARP Inhibitors: An Unfinished Story". cancernetwork.com.
- ^ a b "PARP Inhibitors – More Widely Effective than First Thought". drugdiscoveryopinion.com.
- ^ Wiggans, Alison J; Cass, Gemma KS; Bryant, Andrew; Lawrie, Theresa A; Morrison, Jo; Morrison, Jo (2015). "Poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer". Reviews (5): CD007929. doi:10.1002/14651858.CD007929.pub3. PMC 6457589. PMID 25991068.
- ^ Graziani G, Szabó C (July 2005). "Clinical perspectives of PARP inhibitors". Pharmacol. Res. 52 (1): 109–18. doi:10.1016/j.phrs.2005.02.013. PMID 15911339.
- ^ "Today's anti-cancer tools are ever better wielded". The Economist. Retrieved 2017-09-30.
- ^ a b Buisson R; Dion-Côté A.M; et al. (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.
- ^ McGlynn, P. and Lloyd, B. "Recombinational Repair and Restart of Damaged Replication Forks." Nature Reviews, 2002, pp.859-870
- ^ Lord, Christopher J.; Ashworth, Alan (17 March 2017). "PARP inhibitors: Synthetic lethality in the clinic". Science. 355 (6330): 1152–1158. doi:10.1126/science.aam7344. ISSN 1095-9203. PMC 6175050. PMID 28302823.
- ^ Pettitt, Stephen J.; Krastev, Dragomir B.; Brandsma, Inger; Dréan, Amy; Song, Feifei; Aleksandrov, Radoslav; Harrell, Maria I.; Menon, Malini; Brough, Rachel (10 May 2018). "Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance". Nature Communications. 9 (1): 1849. doi:10.1038/s41467-018-03917-2. ISSN 2041-1723. PMC 5945626. PMID 29748565.
- ^ Gupta A, Yang Q, Pandita RK, 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.
- ^ "Experimental Drug May Work in Many Cancers | Discuss Cancer".
- ^ "PARP Inhibitor Gets FDA Nod for Ovarian Cancer". medpagetoday.com. 19 December 2016.
- ^ Zejula FDA Professional Drug Information.
- ^ "Tesaro earns CHMP thumbs-up for Zejula as three-way PARP race heats up | FiercePharma". www.fiercepharma.com. Retrieved 2018-03-28.
- ^ "PARP inhibitor, MK-4827, shows anti-tumor activity in first trial in humans". 17 Nov 2010.
- ^ Lisa M. Jarvis (2 January 2019). "FDA drug approvals hit all-time high". c&en.
- ^ BioMarin Pharmaceutical Inc. (28 July 2011). "BioMarin Announces Second Quarter 2011 Financial Results". prnewswire.com.
- ^ "BioMarin Initiates Phase 3 BMN 673 Trial for Metastatic gBRCA Breast Cancer. Oct 2013". Benzinga. 2013-10-31.
- ^ a b "AbbVie takes PARP inhibitor into third phase III trial". PMLive. 27 June 2014.
- ^ "BeiGene Initiates Phase 3 Trial of Pamiparib as Maintenance Therapy in Chinese Patients with Ovarian Cancer".
- ^ "Study to Assess the Safety and Tolerability of a PARP Inhibitor in Combination With Carboplatin and/or Paclitaxel". clinicaltrials.gov.
- ^ "AZD2281 Plus Carboplatin to Treat Breast and Ovarian Cancer". clinicaltrials.gov.
- ^ "Trial shows benefit of 'BRCA-targeting' drug in prostate cancer". icr.ac.uk.
- ^ "Study of CEP-9722 as Single-Agent Therapy and as Combination Therapy With Temozolomide in Patients With Advanced Solid Tumors".
- ^ a b Guha, Malini (6 May 2011). "PARP inhibitors stumble in breast cancer". Nature Biotechnology. 29 (5): 373–374. doi:10.1038/nbt0511-373. PMID 21552220.
- ^ Liu, X; Shi, Y; Maag, DX; Palma, JP; Patterson, MJ; Ellis, PA; Surber, BW; Ready, DB; Soni, NB; Ladror, US; Xu, AJ; Iyer, R; Harlan, JE; Solomon, LR; Donawho, CK; Penning, TD; Johnson, EF; Shoemaker, AR (Jan 2012). "Iniparib nonselectively modifies cysteine-containing proteins in tumor cells and is not a bona fide PARP inhibitor". Clin Cancer Res. 18 (2): 510–23. doi:10.1158/1078-0432.CCR-11-1973. PMID 22128301.
- ^ Patel, Anand G.; De Lorenzo, Silvana B.; Flatten, Karen S.; Poirier, Guy G.; Kaufmann, Scott H. (2012). "Failure of Iniparib to Inhibit Poly(ADP-Ribose) Polymerase In Vitro". Clin Cancer Res. 18 (6): 1655–62. doi:10.1158/1078-0432.CCR-11-2890. PMC 3306513. PMID 22291137.
- ^ "Sanofi breast cancer drug flunks Phase III trial".
- ^ "Sanofi Ends Iniparib Research".
- ^ "PARP inhibitors. ESTRO 2010. ecancer - Conference highlights and events calendar". ecancer.org.
External links
- Parp Inhibitors information site
- PARP structure