INTRODUCTION:

Ovarian cancer is a type of cancer that develops in or on the ovary. It causes abnormal cells to form that can invade or spread to other sections of the body. There may be no or just sporadic symptoms when this process begins. As the cancer advances, the symptoms become more evident. Bloating, pelvic pain, abdominal swelling, constipation, and loss of appetite are some of the symptoms^1-3.

Women who have ovulated more frequently throughout their lives have a higher risk of ovarian cancer. Those who have never had children, those who begin ovulation at a younger age, and those who reach menopause at a later age all fall under this category.

Hormone therapy after menopause, reproductive medicine, and obesity are all risk factors. Hormonal birth control, tubal ligation, and breastfeeding are all risk-reducing measures. Inherited genetic risk accounts for roughly 10% of cases; women with mutations in the BRCA1 or BRCA2 genes have a 50% probability of acquiring the disease. The most frequent type of ovarian cancer is ovarian carcinoma, which accounts for more than 95% of all occurrences. Ovarian carcinoma is divided into five subtypes, the most frequent of which is high-grade serous carcinoma (HGSC). The cells that surround the ovaries are thought to be the source of these ovarian tumours, while some may grow in the Fallopian tubes. Germ cell tumours and sex cord stromal tumours are two less prevalent kinds of ovarian cancer. A sample of tissue, which is normally removed after surgery, confirms the diagnosis of ovarian cancer^4-6.

Introduction to PARP:

PARPs (poly (ADP-ribose) polymerases) are a newly discovered family of enzymes that catalyse the transfer of ADP-ribose to target proteins (poly ADP-ribosylation). There are at least 18 members of the PARP family, each of which is encoded by a distinct gene and has a conserved catalytic domain. Although some PARP isoforms, such as PARP1 and PARP2, are well recognised for their roles in DNA repair, it is now obvious that these and other PARPs are involved in a variety of cellular activities, including cell proliferation and death. A variety of cellular PARP substrates have been identified, the bulk of which are nuclear proteins involved in nucleic acid metabolism, chromatin structure regulation, DNA synthesis, and DNA repair. PARP also automodifies itself in the presence of DNA strand breaks, and it is one of the primary poly ADP ribose acceptors in the body. PARP1 is the most well-known and studied member of the PARP family. PARP2 is the most closely linked to PARP1 in terms of its catalytic domain, with 69 percent similarity, and was discovered due to the persistence of PARP activity in PARP1-deficient cells^7-9.

PARP1:

One of the most promising molecular targets for the identification of anticancer medicines is the poly (ADP-ribose) polymerase 1 (PARP1) enzyme. PARP1 is a common nuclear protein that acts as a "sensor" for DNA strand breaks (1-2 million molecules per cell). Melanomas, breast cancer, lung cancer, and other neoplastic disorders can all have elevated PARP1 expression. The level of PARP1 expression is a prognostic indication and is linked to a bad prognosis. There is evidence that increased PARP1 expression is linked to tumor treatment resistance. Because they operate as chemo- and radiosensitizers in the traditional treatment of malignant tumours, PARP1 inhibitors are promising anticancer medicines⁹. PARP1 inhibitors can also be utilized as a stand-alone treatment for cancers with faulty DNA repair processes¹⁰.

Mechanism of Action of PARP1 Inhibitors:

PARP1 is a protein that aids in the repair of single-strand breaks in DNA (nicks). If such nicks go unrepaired until DNA is duplicated (which must happen before cell division), double strand breaks can develop during replication¹¹. Multiple double strand breaks arise as a result of PARP1 inhibitors, and these double strand breaks cannot be repaired efficiently in tumours with BRCA1, BRCA2, or PALB2 mutations, resulting in cell death. Normal cells that don't duplicate their DNA as frequently as cancer cells and don't have any mutant BRCA1 or BRCA2 genes nevertheless have homologous repair, which allows them to withstand PARP inhibition. PARP inhibitors trap PARP proteins on DNA while also inhibiting their catalytic activity¹². This disrupts cell replication, resulting in cell death in cancer cells, which grow at a greater rate than non-cancerous ones^13-15.

Functions of PARP:

PARP is a crucial enzyme involved in DNA repair as well as a variety of other cellular functions such as transcription and chromatin shape modification. PARP is a key component of NER and BER, allowing DNA damage produced by alkylating chemicals and chemotherapeutic medicines to be repaired. PARP is increased in several malignancies, including TNBC and those with BRCA1 mutations, according to research. Because some tumour types (such as BRCA1 mutations) are more dependent on PARP, they are more susceptible to "synthetic lethality" from PARP inhibitors¹⁶. PARP inhibition could possibly be used in conjunction with chemotherapy to sensitise cancer cells to DNA damaging chemicals and accelerate tumour cell death.

Rapid mitochondrial malfunction with membrane permeability transition, NAD+ depletion, and AIF translocation from the mitochondria to the nucleus are other methods by which PARP exerts its effects. Inhibition/manipulation of additional PARP pathway components, such as PAR and PARG, may thus be valuable therapeutic approaches not only for cancer but also for other disease conditions^17-18. With drugs like -LAP, hyperactivation of PARP1 can be used to selectively destroy cancer cells, and the combination of this medication with novel delivery vehicles could offer patients exciting new therapy choices. Finally, additional members of the PARP family, such as telomeric PARPs (tankyrases), may provide another path for therapeutic intervention in cancer and possibly other diseases. The selectivity of the various PARP inhibitors now in research and/or during clinical trials may help to expand PARP's and its inhibition's utility¹⁹.

BRCA1 and BRCA2 Genes:

BRCA1 (Breast Cancer gene 1) and BRCA2 (Breast Cancer gene 2) are proteins that aid in the repair of damaged DNA. Each of these genes is passed down in two copies, one from each parent. BRCA1 and BRCA2 are referred to as tumour suppressor genes because they can cause cancer when they have damaging (or pathogenic) variants (or mutations). BRCA1 is a protein that aids in the repair of damaged DNA. The BRCA1 protein interacts with multiple other proteins in the nucleus of many types of normal cells to repair DNA breaks. Natural and medicinal radiation, as well as other environmental exposures, can trigger these fractures, which also happen when chromosomes exchange genetic material in preparation for cell division²⁰. The BRCA protein is important for maintaining the stability of a cell's genetic information because it aids in DNA repair. BRCA2 has been found to play an important role in protecting reversed forks from MRE11-dependent nucleolytic destruction during DNA replication fork stalling (caused by obstacles such as mutations, intercalating agents etc.)²¹.

Biomarkers of PARP Inhibition:

Determining predictive biomarkers of response to PARP inhibition is an area of significant interest and continued investigation. The presence of a BRCA mutation or a “BRCA-like” gene expression profile both correlate with PARP1 response. Among patients with a germline BRCA mutation, platinum sensitivity and fewer prior lines of therapy were associated with higher response rates and longer durations of response to PARP1. The measurement of HR (homologous recombination) deficiency, based on genomic characteristics, such as loss of heterozygosity or telomeric allelic imbalance, are utilized in commercial assays, such as the Myriad my Choice HRD assay, and also appear to correlate with PARP1 response. Whether level of PARP1 expression correlates with response to PARP1 remains under investigation. One study evaluating primary ovarian cancer samples found no correlation, whereas a radiotracer-PARP1 study found a significant correlation with response to two PARP1²².

Mechanisms of PARP Inhibitor Resistance in HR Deficient Tumor:

The BRCA1/2 proteins are involved in two different cellular processes: HR repair and the protection of a halted replication fork. As a result, tumour cells can grow resistant to PARP1 in one of two ways. Tumor cells may be able to re-establish HR repair by inducing somatic reversion in a mutant BRCA1/2 allele. Alternatively, the tumour cell can devise another method of safeguarding its replication fork. In this case, the PARP1 resistant tumour may still have an HR deficiency, but it will not be cytotoxic when exposed to PARP1. In this situation, the ATR/CHK1 pathway is frequently activated, resulting in the phosphorylation of several proteins that contribute to fork stability. Secondary intragenic mutations that restore BRCA1 or BRCA2 protein functionality are the most common acquired cause of resistance to PARP1s in BRCA1/2-mutated cancers. Reversing BRCA1 promoter methylation can also restore HR repair. Patients with BRCA-mutated malignancies who are treated with platinum-based therapy should be aware of this route of resistance; 46 percent of platinum-resistant BRCAmutated HGSOCs have tumor-specific secondary mutations that restore the ORF of either BRCA1 or BRCA2. In a recent study of whole-genome analysis of chemoresistant ovarian cancer, numerous reversion events in BRCA1/2 genes were also described as a mechanism of platinum resistance. Furthermore, by evaluating circulating free DNA (cfDNA) generated from patients receiving PARP1 or platinum therapy, the somatically-reverted BRCA1/2 alleles can be discovered^23-26.

Figure 3: The use of PARP inhibitor combinations for the treatment of homologous recombination proficient tumors²⁵

PARP1 Mutations:

PARP1 mutations can reduce PARP1 binding or allow PARP1 to keep its natural functions. In-frame mutations in PARP1's DNA-binding zinc-finger domain were discovered in a large-scale Crispr-cas9 mutagenesis screen with in vitro clonal selection after PARP1 selection pressure. The residues K119 and S120, as well as the surrounding area, were often mutated, affecting PARP1's ability to bind DNA damage sites. This shows that the clones' resistance to PARP1 is due to the removal of PARP1 trapping. PARP1 trapping was removed by a mutation in a location believed to contribute to the DNA-binding interface, as well as a separate unique mutation in the PARP1 regulatory region. A mutation in the catalytic domain resulted in a mutant PARP1 with reduced recruitment to DNA damage sites, PARylation, and DNA binding capacity. There was only temporary PARP entrapment in response to PARP1. These preliminary findings suggest that PARP1 mutations that modify PARP trapping could be a mechanism of PARP1 resistance. A reported case of a patient with EOC with de novo olaparib resistance who was later shown to have a PARP1 mutation affecting a region important for communication between the DNA-binding and catalytic domains supports this notion. The PARP1 protein that resulted had the ability to bind DNA but was unable to become trapped in response to PARP1^27-28.

PARP Inhibitors in Ovarian Cancer:

The usage of PARP1 in the treatment of EOC has increased considerably in recent years. Olaparib, rucaparib, and niraparib were first licenced for use as monotherapy in the recurrent context, regardless of platinum sensitivity, and then as post-chemotherapy maintenance for platinum sensitive illness. PARP1 has been authorised by the FDA for frontline maintenance. Olaparib was approved by the FDA in 2018 as a maintenance treatment for individuals with germline or somatic BRCA mutations who had responded to frontline platinum-based therapy. Niraparib was approved by the FDA in April 2020 as maintenance after a response to frontline platinum, regardless of HR status, while olaparib/bevacizumab was approved by the FDA in May 2020 as maintenance for patients with HRD EOC²⁹.

Because this population is the least influenced by prior lines of treatment, analysis of frontline PARP1 maintenance trials may offer the best indicators of baseline rates and kinetics of de novo and acquired PARP1 resistance. In patients with germline or somatic BRCA-mutated advanced HGSOC or high grade endometrioid EOC, the randomised placebo-controlled phase III SOLO-1 study looked at maintenance olaparib after partial or complete responses to platinum-based frontline treatment. Because median PFS has not yet been attained at the time of data reporting, olaparib maintenance was predicted to improve median PFS by about 36 months. However, despite PARP1 treatment, the Kaplan–Meier survival curve for patients taking olaparib continues to be negative, indicating disease recurrence. Similarly, niraparib was evaluated in the frontline maintenance setting in the randomised placebo-controlled phase III PRIMA/ENGOT-Ov26 trial in patients with or without a confirmed BRCA mutation or evidence of HRD by the Myriad my Choice assay. In the entire population, median PFS improved from 8.2 to 13.8 months with niraparib maintenance, and prespecified molecular subgroup analysis revealed that those with BRCA mutations benefited the most (median PFS 22.1 versus 10.9 months), followed by those with non-BRCA HR insufficiency (19.6 versus 8.2 months). However, disease recurrence confirms the development of PARP1 resistance, regardless of susceptibility²⁹.

Figure 4: Structure of Olaparib (a) and Niraparib (b)

PARP Role in the Immune System:

The formation of T cells in mice has been found to be dependent on PARP efficiency at all stages; PARP2 impairment reduces the number of thymocytes, resulting in a higher rate of apoptosis during the maturation process. Both the CD4+ and CD8+ populations in the periphery are reduced when PARP1 and 2 are deficient. PARP also plays a role in cell activation; PARP1 depletion appears to steer T cells toward the Th1 and Treg phenotypes rather than the Th2 phenotype. B lymphocytes are also harmed, however the reasons for this are unknown; dual deficiency affects the periphery population in the same way as it impacts T cells, indicating that PARP prevents the buildup of DNA damage that is required for cell proliferation. PARP is implicated in neutrophil activation and recruitment, macrophage expression of pro-inflammatory cytokines including IL-6 and TNF, and dendritic cell recruitment (in which PARP1 is involved, but PARP2's role is unknown). As a result, the effects of PARP inhibition are multifaceted and overlap^30-38.

CONCLUSION:

The PARP protein family has been postulated to have numerous functions in biological processes, including transcription, cell death, and DNA repair, since their discovery half a century ago. Knowledge of PARP1's fundamental biology and participation in DNA repair pathways, in particular, led to the invention of PARP1, a targeted treatment for BRCA-mutated malignancies. A large number of preclinical studies and clinical trials have demonstrated PARP1 therapy's improved efficacy over standard chemotherapies in a variety of cancer subtypes, highlighting its potential in a variety of cancer subtypes. PARP1 has also been shown to offer considerable anti-tumor advantages when used in combination with other anti-cancer drugs to generate significant tumour regression in studies. However, while the therapeutic significance of PARP1 is obvious, the underlying mechanisms of PARP1 action remain unknown, limiting our knowledge of potential PARP1 tumour biomarkers and therapy resistance pathways. To guarantee that PARP1 therapy is used to provide maximum patient benefit, more research into the mechanism of action of PARP1 is needed, as well as the validation and approval of additional biomarkers.

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Received on 23.07.2022 Modified on 13.11.2022

Asian J. Pharm. Tech. 2023; 13(3):223-228.

DOI: 10.52711/2231-5713.2023.00040