PARP inhibitor

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

Contents

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

Related Research Articles

<span class="mw-page-title-main">BRCA1</span> Gene known for its role in breast cancer

Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the BRCA1 gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. BRCA1 is a human tumor suppressor gene and is responsible for repairing DNA.

The Institute of Cancer Research is a public research institute and a member institution of the University of London in London, United Kingdom, specialising in oncology. It was founded in 1909 as a research department of the Royal Marsden Hospital and joined the University of London in 2003. It has been responsible for a number of breakthrough discoveries, including that the basic cause of cancer is damage to DNA.

<span class="mw-page-title-main">DNA repair</span> Cellular mechanism

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur. This can eventually lead to malignant tumors, or cancer as per the two-hit hypothesis.

<span class="mw-page-title-main">BRCA2</span> Gene known for its role in breast cancer

BRCA2 and BRCA2 are human genes and their protein products, respectively. The official symbol and the official name are maintained by the HUGO Gene Nomenclature Committee. One alternative symbol, FANCD1, recognizes its association with the FANC protein complex. Orthologs, styled Brca2 and Brca2, are common in other vertebrate species. BRCA2 is a human tumor suppressor gene, found in all humans; its protein, also called by the synonym breast cancer type 2 susceptibility protein, is responsible for repairing DNA.

<span class="mw-page-title-main">Poly (ADP-ribose) polymerase</span> Family of proteins

Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in a number of cellular processes such as DNA repair, genomic stability, and programmed cell death.

Triple-negative breast cancer (TNBC) is any breast cancer that either lacks or shows low levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification. Triple-negative is sometimes used as a surrogate term for basal-like.

<span class="mw-page-title-main">PARP1</span> Mammalian protein found in Homo sapiens

Poly [ADP-ribose] polymerase 1 (PARP-1) also known as NAD+ ADP-ribosyltransferase 1 or poly[ADP-ribose] synthase 1 is an enzyme that in humans is encoded by the PARP1 gene. It is the most abundant of the PARP family of enzymes, accounting for 90% of the NAD+ used by the family. PARP1 is mostly present in cell nucleus, but cytosolic fraction of this protein was also reported.

<span class="mw-page-title-main">BARD1</span> Protein-coding gene in the species Homo sapiens

BRCA1-associated RING domain protein 1 is a protein that in humans is encoded by the BARD1 gene. The human BARD1 protein is 777 amino acids long and contains a RING finger domain, four ankyrin repeats, and two tandem BRCT domains.

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<span class="mw-page-title-main">Olaparib</span> Chemical compound (cancer therapy drug)

Olaparib, sold under the brand name Lynparza, is a medication for the maintenance treatment of BRCA-mutated advanced ovarian cancer in adults. It is a PARP inhibitor, inhibiting poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair. It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which include some ovarian, breast, and prostate cancers.

<span class="mw-page-title-main">Iniparib</span> Chemical compound

Iniparib was a drug candidate for cancer treatment. It was originally believed to act as an irreversible inhibitor of PARP1 and possibly other enzymes through covalent modification, but its effects against PARP were later disproven. It underwent clinical trials for treatment of some types of breast cancer, but was discontinued after disappointing phase III clinical trials.

<span class="mw-page-title-main">Veliparib</span> Chemical compound

Veliparib (ABT-888) is a potential anti-cancer drug acting as a PARP inhibitor. It kills cancer cells by blocking a protein called PARP, thereby preventing the repair of DNA or genetic damage in cancer cells and possibly making them more susceptible to anticancer treatments. Veliparib may make whole brain radiation treatment work more effectively against brain metastases from NSCLC. It has been shown to potentiate the effects of many chemotherapeutics, and as such has been part of many combination clinical trials.

<span class="mw-page-title-main">Cancer treatment</span> Overview of various treatment possibilities for cancer

Cancer treatments are a wide range of treatments available for the many different types of cancer, with each cancer type needing its own specific treatment. Treatments can include surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy including small-molecule drugs or monoclonal antibodies, and PARP inhibitors such as olaparib. Other therapies include hyperthermia, immunotherapy, photodynamic therapy, and stem-cell therapy. Most commonly cancer treatment involves a series of separate therapies such as chemotherapy before surgery. Angiogenesis inhibitors are sometimes used to enhance the effects of immunotherapies.

<i>BRCA</i> mutation Medical condition

A BRCA mutation is a mutation in either of the BRCA1 and BRCA2 genes, which are tumour suppressor genes. Hundreds of different types of mutations in these genes have been identified, some of which have been determined to be harmful, while others have no proven impact. Harmful mutations in these genes may produce a hereditary breast–ovarian cancer syndrome in affected persons. Only 5–10% of breast cancer cases in women are attributed to BRCA1 and BRCA2 mutations, but the impact on women with the gene mutation is more profound. Women with harmful mutations in either BRCA1 or BRCA2 have a risk of breast cancer that is about five times the normal risk, and a risk of ovarian cancer that is about ten to thirty times normal. The risk of breast and ovarian cancer is higher for women with a high-risk BRCA1 mutation than with a BRCA2 mutation. Having a high-risk mutation does not guarantee that the woman will develop any type of cancer, or imply that any cancer that appears was actually caused by the mutation, rather than some other factor.

<span class="mw-page-title-main">Hereditary cancer syndrome</span> Inherited genetic condition that predisposes a person to cancer

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<span class="mw-page-title-main">Talazoparib</span> Chemical compound

Talazoparib, sold under the brand name Talzenna, is an anti-cancer medication used for the treatment of breast cancer and prostate cancer. It is an orally available poly ADP ribose polymerase PARP inhibitor marketed by Pfizer for the treatment of advanced breast cancer with germline BRCA mutations. Talazoparib is similar to the first in class PARP inhibitor, olaparib.

<span class="mw-page-title-main">Niraparib</span> Anti-cancer medication

Niraparib, sold under the brand name Zejula, is an anti-cancer medication used for the treatment of epithelial ovarian, fallopian tube, or primary peritoneal cancer. It is taken by mouth. It is a PARP inhibitor.

Susan M. Domchek is an oncologist at the University of Pennsylvania, Executive Director of the Basser Center for BRCA, the Basser Professor in Oncology at the Perelman School of Medicine, and Director of the Mariann and Robert MacDonald Cancer Risk Evaluation Program at Penn Medicine. She has authored more than 250 articles in scholarly journals and serves on a number of editorial review boards. In 2018, Domchek was elected to the National Academy of Medicine.

<span class="mw-page-title-main">HRDetect</span>

HRDetect is a whole-genome sequencing (WGS)-based classifier designed to predict BRCA1 and BRCA2 deficiency based on six mutational signatures. Additionally, the classifier is able to identify similarities in mutational profiles of tumors to that of tumors with BRCA1 and BRCA2 defects, also known as BRCAness. This classifier can be applied to assess the implementation of PARP inhibitors in patients with BRCA1/BRCA2 deficiency. The final output is a probability of BRCA1/2 mutation.

<span class="mw-page-title-main">Breast and ovarian cancer</span>

Breast and ovarian cancer does not necessarily imply that both cancers occur at the same time, but rather that getting one cancer would lead to the development of the other within a few years. Women with a history of breast cancer have a higher chance of developing ovarian cancer, vice versa.

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 .
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