Role Of Poly (ADP-ribose) Polymerase Inhibitors Research Articles

Current Evidence and Future Perspectives about the Role of PARP Inhibitors in the Treatment of Thoracic Cancers.

In recent years, poly (ADP-ribose) polymerase (PARP) inhibition has become a promising therapeutic option for several tumors, especially for those harboring a BRCA 1-2 mutation or a deficit in the homologous recombination repair (HRR) pathway. Nevertheless, to date, PARP inhibitors are still not largely used for thoracic malignancies neither as a single agent nor in combination with other treatments. Recently, a deeper understanding of HRR mechanisms, alongside the development of new targeted and immunotherapy agents, particularly against HRR-deficient tumors, traced the path to new treatment strategies for many tumor types including lung cancer and malignant pleural mesothelioma. The aim of this review is to sum up the current knowledge about cancer-DNA damage response pathways inhibition and to update the status of recent clinical trialsinvestigating the use of PARP inhibitors, either as monotherapy or in combination with other agents for the treatment of thoracic malignancies. We will also briefly discuss available evidence on Poly(ADP-Ribose) Glycohydrolase (PARG) inhibitors, a novel promising therapeutic option in oncology.

Role of PARP Inhibitors in Cancer Immunotherapy: Potential Friends to Immune Activating Molecules and Foes to Immune Checkpoints.

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) induce cytotoxic effects as single agents in tumors characterized by defective repair of DNA double-strand breaks deriving from BRCA1/2 mutations or other abnormalities in genes associated with homologous recombination. Preclinical studies have shown that PARPi-induced DNA damage may affect the tumor immune microenvironment and immune-mediated anti-tumor response through several mechanisms. In particular, increased DNA damage has been shown to induce the activation of type I interferon pathway and up-regulation of PD-L1 expression in cancer cells, which can both enhance sensitivity to Immune Checkpoint Inhibitors (ICIs). Despite the recent approval of ICIs for a number of advanced cancer types based on their ability to reinvigorate T-cell-mediated antitumor immune responses, a consistent percentage of treated patients fail to respond, strongly encouraging the identification of combination therapies to overcome resistance. In the present review, we analyzed both established and unexplored mechanisms that may be elicited by PARPi, supporting immune reactivation and their potential synergism with currently used ICIs. This analysis may indicate novel and possibly patient-specific immune features that might represent new pharmacological targets of PARPi, potentially leading to the identification of predictive biomarkers of response to their combination with ICIs.

The Role of PARP Inhibitors in Patients with Primary Malignant Central Nervous System Tumors.

Primary malignant central nervous (CNS) tumors are a devastating group of diseases with urgent need for improved treatment options. Surgery, radiation, and cytotoxic chemotherapy remain the primary standard treatment modalities, with molecularly targeted therapies having proven efficacy in only small subsets of cases. Poly(ADP-ribose) polymerase (PARP) inhibitors, which have had immense success in the treatment of extracranial cancers with homologous recombination deficiency (HRD), are emerging as a potential targeted treatment for various CNS tumors. Although few primary CNS tumors display canonical BRCA gene defects, preclinical evidence suggests that PARP inhibitors may benefit certain CNS tumors with functional HRD or elevated replication stress. In addition, other preclinical studies indicate that PARP inhibitors may synergize with standard therapies used for CNS tumors including radiation and alkylating agents and may prevent or overcome drug resistance. Thus far, initial clinical trials with early-generation PARP inhibitors, typically as monotherapy or in the absence of selective biomarkers, have shown limited efficacy. However, the scientific rationale remains promising, and many clinical trials are ongoing, including investigations of more CNS penetrant or more potent inhibitors and of combination therapy with immune checkpoint inhibitors. Early phase trials are also critically focusing on determining active drug CNS penetration and identifying biomarkers of therapy response. In this review, we will discuss the preclinical evidence supporting use of PARP inhibitors in primary CNS tumors and clinical trial results to date, highlighting ongoing trials and future directions in the field that may yield important findings and potentially impact the treatment of these devastating malignancies in the coming years.

Poly (ADP-ribose) polymerase inhibitors (PARPi) for advanced malignancies with multiple DNA-repair genetic aberrations

ABSTRACT Introduction Poly (ADP-ribose) polymerase inhibitors (PARPi) have been approved for the treatment of advanced tumors with defects in genes involved in homologous recombination repair (HRR), including cancers of the prostate, pancreas, breast, and ovary. In these advanced tumors, PARPi afford ‘synthetic lethality’ by blocking the PARP-associated repair pathway in cancer cells with HRR genetic mutations, resulting in chromosome instability and cellular apoptosis. According to the synthetic lethality theory, patients with a greater burden of genetic alterations, in proportion (relative quantity) or category, would have more satisfactory outcomes after PARPi administration. However, this issue remains obscure based on the existing sporadic evidence. Areas covered We summarize the therapeutic effects of PARPi in advanced tumors with multiple HRR genetic mutations, and attempted to compare these results with those obtained for cancers with a single mutation. Expert opinion Limited evidence has provided a possibly encouraging response to PARPi among patients carrying multiple HRR genetic mutations compared with those with a single mutation (although the treatment effect was negative in some patients). Further research is needed to understand the role of PARPi in tumor cells with multiple HRR genetic mutations.

The effect of PARP inhibition on androgen receptor localization and activity in castration resistant prostate cancer.

e17037 Background: The poly(ADP-ribose) polymerase inhibitors (PARPi) olaparib and rucaparib have been approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) in the setting of homologous recombination deficiency (HRD). Additionally, PARPi have been shown to modulate androgen receptor (AR) signaling, with a recent report demonstrating mono-ADP-ribosylation of cysteine residues in AR by Parp7. Here, we further evaluated the effect of PARPi on AR activity and localization. Methods: The effect of PARPi on cell growth and survival of CRPC cell lines was evaluated in vitro and in vivo. AR ribosylation was assessed in CRPC cell lines by immunoprecipitation (IP) assays and proximity ligation assays (PLA). The subcellular localization of AR was determined by quantitative immunofluorescence microscopy in CRPC cell lines and xenograft models. Changes in AR activity with PARPi treatment were evaluated by a luciferase reporter assay and AR target gene expression in a PDX model. Finally, PARPi mediated alteration in the AR protein interactome was evaluated by liquid chromatography tandem mass spectrometry (LC-MS/MS) proteomics. Results: The PARPi olaparib and talazoparib, and to a lesser extent veliparib, inhibited CRPC cell growth. Evidence of AR ribosylation was seen by IP and PLA. PARPi treatment of multiple in vitro and in vivo prostate cancer models resulted in a shift of AR subcellular localization, from predominantly nuclear to cytoplasmic compartments. In luciferase reporter assays, AR transactivation activity was decreased after PARPi treatment in a dose dependent manner. In vivo, in prostate cancer xenograft models, decreased AR target gene expression was seen upon PARPi treatment. LC-MS/MS proteomic studies revealed that PARP inhibition resulted in significant changes in the composition of AR interaction partners, in particular of proteins related to intracellular trafficking and nuclear transport. This suggests a potential link between altered AR complex assembly and the observed changes in AR subcellular localization in the context of PARPi treatment. Conclusions: We describe a novel sequela of PARPi therapy to alter AR localization and activity in CRPC. Single agent PARP inhibition can alter prostate cancer cell growth in vitro and in vivo. With PARPi treatment, AR localization is shifted to the cytoplasm, the AR interactome is altered, and AR transcriptional activity decreased. These findings implicate a collateral mechanism of PARPi in preventing prostate cancer cell growth/survival that may augment previously described mechanisms related to HDR and synthetic lethality. It is essential to understand the role of PARPi beyond synthetic lethality in the context of HRD in order to better define the spectrum of response to PARPi across patients, and for development of biology-informed combination therapies.

The Poly(ADP-ribose) polymerase inhibitors in pancreatic cancer

Genome instability and mutations are the hallmarks of cancer. Mutations within BRCA genes increase the risk of pancreatic cancer (PC) development. Poly(ADP-ribose) polymerase inhibitors (PARPi) show the synthetic lethality phenomenon in tumoral cells with BRCA mutation and improve outcomes in patients with breast, prostate and ovarian cancer. Olaparib was the first PARPi registered for the patient with metastatic PC with a deleterious or suspected deleterious germline BRCA - mutation. The POLO phase III clinical trial shows that olaparib in PC increases progression-free survival, however it does not prolong the overall survival. Currently, many clinical trials are ongoing to determine the clinical utility of PARPi in monotherapy or polytherapy of PC. The role of PARPi in PC has not been well established and many questions remain unanswered. This review aims to summarise the rationales behind the use of PARPi and current clinical data.

PARP-remmers bij gemetastaseerde prostaatkanker: een systematische review

PARP inhibitors in metastatic prostate cancer: a systematic review Background. Poly ADP-ribose polymerase (PARP) inhibitors provide a novel therapeutic approach for the treatment of metastatic prostate cancer. They act on the homologous recombination DNA repair mechanism. In metastatic prostate cancer, 20-25% of the patients harbour a homologous recombination repair deficiency. This review investigates the current evidence for the use of PARP inhibitors in clinical practice. Methods. The databases MEDLINE, CENTRAL and EMBASE were searched, as well as the clinical trial registries EudraCT and Clinicaltrials.gov. Randomised controlled trials with PARP inhibitors were included. The outcomes of interest were: overall survival (OS), progression-free survival (PFS), objective response rate (ORR), adverse events and quality of life. The data were analysed according to Cochrane methodology. Results. Three controlled trials were included, all in a castration-resistant setting. Five phase 2 trials were excluded; these data are presented in a narrative form. One study of olaparib in monotherapy versus enzalutamide or abiraterone found a benefit in OS and PFS in patients with a BRCA1, BRCA2 or ATM mutation, though not in patients with other HRD (‘homologous recombination deficiency’) mutations. Two studies investigated a PARP inhibitor in combination with abiraterone versus abiraterone in monotherapy. The combination with olaparib showed a modest PFS benefit, whereas the veliparib combination showed no OS or PFS benefit. Conclusion. At present, the role of PARP inhibitors is limited to BRCA1, BRCA2 and ATM mutation carriers. Combination therapy with other agents could provide a synergistic advantage and is being researched. Fourteen ongoing trials meet the inclusion criteria and will clarify the role of PARP inhibitors in the treatment of prostate cancer.

PARP Inhibitors and Myeloid Neoplasms: A Double-Edged Sword.

Simple SummaryPoly(ADP-ribose) polymerase (PARP) inhibitors, which are medications approved to treat various solid tumors, including breast, prostate, ovarian, and prostate cancers, are being examined in hematological malignancies. This review summarizes the potential role of PARP inhibitors in the treatment of myeloid diseases, particularly acute myeloid leukemia (AML). We review ongoing clinical studies investigating the safety and efficacy of PARP inhibitors in the treatment of AML, focusing on specific molecular and genetic AML subgroups that could be particularly sensitive to PARP inhibitor treatment. We also discuss reports describing an increased risk of treatment-related myeloid neoplasms in patients receiving PARP inhibitors for solid tumors.Despite recent discoveries and therapeutic advances in aggressive myeloid neoplasms, there remains a pressing need for improved therapies. For instance, in acute myeloid leukemia (AML), while most patients achieve a complete remission with conventional chemotherapy or the combination of a hypomethylating agent and venetoclax, de novo or acquired drug resistance often presents an insurmountable challenge, especially in older patients. Poly(ADP-ribose) polymerase (PARP) enzymes, PARP1 and PARP2, are involved in detecting DNA damage and repairing it through multiple pathways, including base excision repair, single-strand break repair, and double-strand break repair. In the context of AML, PARP inhibitors (PARPi) could potentially exploit the frequently dysfunctional DNA repair pathways that, similar to deficiencies in homologous recombination in BRCA-mutant disease, set the stage for cell killing. PARPi appear to be especially effective in AML with certain gene rearrangements and molecular characteristics (RUNX1-RUNX1T1 and PML-RARA fusions, FLT3- and IDH1-mutated). In addition, PARPi can enhance the efficacy of other agents, particularly alkylating agents, TOP1 poisons, and hypomethylating agents, that induce lesions ordinarily repaired via PARP1-dependent mechanisms. Conversely, emerging reports suggest that long-term treatment with PARPi for solid tumors is associated with an increased incidence of myelodysplastic syndrome (MDS) and AML. Here, we (i) review the pre-clinical and clinical data on the role of PARPi, specifically olaparib, talazoparib, and veliparib, in aggressive myeloid neoplasms and (ii) discuss the reported risk of MDS/AML with PARPi, especially as the indications for PARPi use expand to include patients with potentially curable cancer.

Niraparib Suppresses Cholangiocarcinoma Tumor Growth by Inducing Oxidative and Replication Stress.

Simple SummaryCholangiocarcinoma (CCA) is a rare and highly aggressive tumor with limited therapeutic options, thus underscoring the need to develop novel therapeutic approaches. We analyzed a publicly available CCA patient database to identify mutations in DNA damage response (DDR) genes. Mutations in DDR genes were prevalent, thus rendering these tumors potentially susceptible to poly-ADP-ribose polymerase (PARP) inhibition. PARP genes are critical to DNA repair and genomic stability. The role of PARP inhibitors in CCA was investigated by employing a series of in vitro functional assays and in vivo patient-derived xenograft models. This study highlights the therapeutic potential of PARP inhibitors alone or in combination with the chemotherapeutic agent gemcitabine for the treatment of CCA.Cholangiocarcinoma (CCA) is the second most common hepatobiliary cancer, an aggressive malignancy with limited therapeutic options. PARP (poly (ADP-ribose) polymerase) 1 and 2 are important for deoxyribonucleotide acid (DNA) repair and maintenance of genomic stability. PARP inhibitors (PARPi) such as niraparib have been approved for different malignancies with genomic alteration in germline BRCA and DNA damage response (DDR) pathway genes. Genomic alterations were analyzed in DDR genes in CCA samples employing The Cancer Genome Atlas (TCGA) database. Mutations were observed in various DDR genes, and 35.8% cases had alterations in at least one of three genes (ARID1A, BAP1 and ATM), suggesting their susceptibility to PARPi. Niraparib treatment suppressed cancer cell viability and survival, and also caused G2/M cell cycle arrest in patient-derived xenograft cells lines (PDXC) and established CCA cells harboring DDR gene mutations. PARPi treatment also induced apoptosis and caspase3/7 activity in PDXC and CCA cell lines, and substantially reduced expression of BCL2, BCL-XL and MCL1 proteins. Niraparib caused a significant increase in oxidative stress, and induced activation of DNA damage markers, phosphorylation of CHK2 and replication fork stalling. Importantly, niraparib, in combination with gemcitabine, produced sustained and robust inhibition of tumor growth in vivo in a patient-derived xenograft (PDX) model more effectively than either treatment alone. Furthermore, tissue samples from mice treated with niraparib and gemcitabine display significantly lower expression levels of pHH3 and Ki-67, which are a mitotic and proliferative marker, respectively. Taken together, our results indicate niraparib as a novel therapeutic agent alone or in combination with gemcitabine for CCA.

PARP (Poly ADP-Ribose Polymerase) inhibitors for locally advanced or metastatic breast cancer.

Locally advanced and metastatic breast cancer remains a challenge to treat. With emerging study results, it is important to interpret the available clinical data and apply the evidence offering the most effective treatment to the right patient. Poly(ADP Ribose) Polymerase (PARP) inhibitors are a new class of drug and their role in the treatment of locally advanced and metastatic breast cancer is being established. To determine the efficacy, safety profile, and potential harms of Poly(ADP-Ribose) Polymerase (PARP) inhibitors in the treatment of patients with locally advanced or metastatic breast cancer. The primary outcome of interest was overall survival; secondary outcomes included progression-free survival, tumour response rate, quality of life, and adverse events. On 8 June 2020, we searched the Cochrane Breast Cancer Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via OvidSP, Embase via OvidSP, World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) search portal and ClinicalTrials.gov. We also searched proceedings from the major oncology conferences as well as scanned reference lists from eligible publications and contacted corresponding authors of trials for further information, where needed. We included randomised controlled trials on participants with locally advanced or metastatic breast cancer comparing 1) chemotherapy in combination with PARP inhibitors, compared to the same chemotherapy without PARP inhibitors or 2) treatment with PARP inhibitors, compared to treatment with other chemotherapy. We included studies that reported on our primary outcome of overall survival and secondary outcomes including progression-free survival, tumour response rate, quality of life, and adverse events. We used standard methodological procedures defined by Cochrane. Summary statistics for the endpoints used hazard ratios (HR) with 95% confidence intervals (CI) for overall survival and progression-free survival, and odds ratios (OR) for response rate (RR) and toxicity. We identified 49 articles for qualitative synthesis, describing five randomised controlled trials that were included in the quantitative synthesis (meta-analysis). A sixth trial was assessed as eligible but had ended prematurely and no data were available for inclusion in our meta-analysis. Risk of bias was predominately low to unclear across all studies except in regards to performance bias (3/5 high risk) and detection bias for the outcomes of quality of life (2/2 high risk) and reporting of adverse events (3/5 high risk). High-certainty evidence shows there may be a small advantage in overall survival (HR 0.87, 95% CI 0.76 to 1.00; 4 studies; 1435 patients). High-certainty evidence shows that PARP inhibitors offer an improvement in PFS in locally advanced/metastatic HER2-negative, BRCA germline mutated breast cancer patients (HR 0.63, 95% CI 0.56 to 0.71; 5 studies; 1474 patients). There was no statistical heterogeneity for these outcomes. Subgroup analyses for PFS outcomes based on trial level data were performed for triple-negative breast cancer, hormone-positive and/or HER2-positive breast cancer, BRCA1 and BRCA2 germline mutations, and patients who had received prior chemotherapy for advanced breast cancer or not. The subgroup analyses showed a persistent PFS benefit regardless of the subgroup chosen. Pooled analysis shows PARP inhibitors likely result in a moderate improvement in tumour response rate compared to other treatment arms (66.9% vs 48.9%; RR 1.39, 95% CI 1.24 to 1.54; 5 studies; 1185 participants; moderate-certainty evidence). The most common adverse events reported across all five studies included neutropenia, anaemia and fatigue. Grade 3 or higher adverse events probably occur no less frequently in patients receiving PARP inhibitors (59.4% for PARP arm versus 64.5% for non-PARP arm, RR 0.98, 95% CI 0.91 to 1.04; 5 studies; 1443 participants; moderate-certainty evidence). Only two studies reported quality of life outcomes so this was not amenable to meta-analysis. However, both studies that did assess quality of life showed PARP inhibitors were superior compared to physician's choice of chemotherapy in terms of participant-reported outcomes. In people with locally advanced or metastatic HER2-negative, BRCA germline mutated breast cancer, PARP inhibitors offer an improvement in progression-free survival, and likely improve overall survival and tumour response rates. This systematic review provides evidence supporting the use of PARP inhibitors as part of the therapeutic strategy for breast cancer patients in this subgroup. The toxicity profile for PARP inhibitors is probably no worse than chemotherapy but more information is required regarding quality of life outcomes, highlighting the importance of collecting such data in future studies. Future studies should also be powered to detect clinically important differences in overall survival and could focus on the role of PARP inhibitors in other relevant breast cancer populations, including HER2-positive, BRCA-negative/homologous recombination repair-deficient and Programmed Death-Ligand 1 (PDL1) positive.

Understanding structural characteristics of PARP-1 inhibitors through combined 3D-QSAR and molecular docking studies and discovery of new inhibitors by multistage virtual screening

Poly(ADP-ribose) polymerase (PARP) belongs to family of nuclear proteins having a critical role in base excision DNA repair system by catalysing the process of poly(ADP-ribosyl)ation leading to cell proliferation. The role of PARP inhibitors as anticancer agents was accepted after the approval of olaparib for the treatment of BRCA mutation-induced ovarian cancer. A combined ligand-based and receptor-based approach has been reported here for identification of PARP-1 inhibitors. Seventy one analogues of phthalazinone and 4-carboxamide benzimidazole showing activities against PARP-1 were used to develop ligand-based pharmacophore hypothesis using PHASE. The five-point pharmacophore hypothesis ADHRR.1031 was developed, and atom-based 3D-QSAR studies were carried. The developed 3D QSAR model has good correlation coefficient value (R2 = 0.952) and cross validated with correlation coefficient value (Q2 = 0.764). To further ascertain the structural requirement for PARP-1 inhibition, molecular interaction studies of inhibitors with PARP-1 were carried out by performing docking studies using Glide 5.6. Hydrogen bond interaction with Gly202 and Ser243 is an important interaction observed by the carboxyl amide group. The pharmacophore model depicts the importance of the hydrogen bond donor and acceptor nature of the carboxyl amide group. Further multistage virtual screening was performed to screen molecules with possible PARP-1 inhibition. Initial screening was performed based on pharmacophoric features followed by docking that consisted of HTVS, SP, and XP docking and final optimisation by Prime MM-GBSA calculation. The screened molecules were further scrutinised for their ADME-toxicity properties.

DNA methyltransferase inhibitors induce a BRCAness phenotype that sensitizes NSCLC to PARP inhibitor and ionizing radiation

A minority of cancers have breast cancer gene (BRCA) mutations that confer sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis), but the role for PARPis in BRCA-proficient cancers is not well established. This suggests the need for novel combination therapies to expand the use of these drugs. Recent reports that low doses of DNA methyltransferase inhibitors (DNMTis) plus PARPis enhance PARPi efficacy in BRCA-proficient AML subtypes, breast, and ovarian cancer open up the possibility that this strategy may apply to other sporadic cancers. We identify a key mechanistic aspect of this combination therapy in nonsmall cell lung cancer (NSCLC): that the DNMTi component creates a BRCAness phenotype through downregulating expression of key homologous recombination and nonhomologous end-joining (NHEJ) genes. Importantly, from a translational perspective, the above changes in DNA repair processes allow our combinatorial PARPi and DNMTi therapy to robustly sensitize NSCLC cells to ionizing radiation in vitro and in vivo. Our combinatorial approach introduces a biomarker strategy and a potential therapy paradigm for treating BRCA-proficient cancers like NSCLC.

The Role of PARP Inhibitors in Ovarian Cancer: An Emerging Picture

Dr Oaknin welcomed the delegates to the symposium and presented the objectives and agenda for the meeting as well as a case study presentation. Dr Birrer presented on the current landscape of platinum-sensitive recurrent ovarian cancer (PSR OC), including USA and European treatment guidelines. He highlighted data from three landmark Phase III studies that demonstrated the efficacy of platinum-based doublet therapy for patients with PSR OC. The role of cytoreductive surgery is still being debated but bevacizumab and a newer anti-angiogenic agent, cediranib, may both extend progression-free survival (PFS) in these patients. He predicted that new combinations of therapies will be tested. Prof Ledermann followed with a presentation on the role of poly(ADP-ribose) polymerase (PARP) inhibitors, olaparib, niraparib, and rucaparib, in the treatment of PSR OC. The largest increase in PFS is seen in patients with platinum-sensitive BRCA-mutant tumours but there is also significant benefit over placebo in groups of patients with platinum-sensitive BRCA wild-type tumours. Prof McNeish discussed the challenge of identifying the 30% of women with high-grade serous OC who would respond to treatment with a PARP inhibitor even though their tumour does not carry a BRCA mutation. Loss of heterozygosity (LOH) is a key indicator of homologous recombination deficiency (HRD) but current tests miss some women who would benefit from treatment. Dr Lorusso concluded the meeting by exploring future directions for research into PARP inhibitors, such as whether they should be used in the front-line setting and as single agents rather than in combination with chemotherapy. New combinations with anti-angiogenic and immune-oncology agents show promise, as does the potential for retreatment with a different PARP inhibitor.

Poly(ADP-ribose) Polymerase (PARP) and PARP Inhibitors: Mechanisms of Action and Role in Cardiovascular Disorders.

Poly(ADP-ribosyl)ation is an immediate cellular repair response to DNA damage and is catalyzed primarily by poly(ADP-ribose)polymerase-1 (PARP1), which is the most abundant of the 18 different PARP isoforms and accounts for more than 90% of the catalytic activity of PARP in the cell nucleus. Upon detection of a DNA strand break, PARP1 binds to the DNA, cleaves nicotinamide adenine dinucleotide between nicotinamide and ribose and then modifies the DNA nuclear acceptor proteins by formation of a bond between the protein and the ADP-ribose residue. This generates ribosyl-ribosyl linkages that act as a signal for other DNA-repairing enzymes and DNA base repair. Extensive DNA breakage in cells results in excessive activation of PARP with resultant depletion of the cellular stores of nicotinamide adenine dinucleotide (NAD+) which slows the rate of glycolysis, mitochondrial electron transport, and ultimately ATP formation in these cells. This paper focuses on PARP in DNA repair in atherosclerosis, acute myocardial infarction/reperfusion injury, and congestive heart failure and the role of PARP inhibitors in combating the effects of excessive PARP activation in these diseases. Free oxygen radicals and nitrogen radicals in arteries contribute to disruption of the vascular endothelial glycocalyx, which increase the permeability of the endothelium to inflammatory cells and also low-density lipoproteins and the accumulation of lipid in the vascular intima. Mild inflammation and DNA damage within vascular cells promote PARP1 activation and DNA repair. Moderate DNA damage induces caspase-dependent PARP cleavage and vascular cell apoptosis. Severe DNA damage due to vascular inflammation causes excessive activation of PARP1. This causes endothelial cell depletion of NAD+ and ATP, downregulation of atheroprotective SIRT1, necrotic cell death, and ultimately atherosclerotic plaque disruption. Inhibition of PARP decreases vascular endothelial cell adhesion P-selectin and ICAM-1 molecules, inflammatory cells, pro-death caspase-3, and c-Jun N-terminal kinase (JNK) activation and upregulates prosurvival extracellular signal-regulated kinases and AKT, which decrease vascular cell apoptosis and necrosis and limit atherosclerosis and plaque disruption. In myocardial infarction with coronary occlusion then reperfusion, which occurs with coronary angioplasty or thrombolytic therapy, reperfusion injury occurs in as many as 31% of patients and is caused by inflammatory cells, free oxygen and nitrogen radicals, the rapid transcriptional activation of inflammatory cytokines, and the activation of PARP1. Inhibition of PARP attenuates neutrophil infiltration and inflammatory cytokine expression in the reperfused myocardium and preserves myocardial NAD+ and ATP. In addition, PARP inhibition increases the activation of myocyte survival enzymes protein kinase B (Akt) and protein kinase C epsilon (PKCε), and decreases the activity of myocardial ventricular remodeling enzymes PKCα/β, PKCζ/λ, and PKCδ. As a consequence, cardiomyocyte and vascular endothelial cell necrosis is decreased and myocardial contractility is preserved. In heart failure and circulatory shock in animal models, PARP inhibition significantly attenuates decreases in left ventricular systolic pressure, ventricular contractility and relaxation, stroke volume, and increases survival by limiting or preventing upregulation of adhesion molecules, proinflammatory cytokines, myocardial mononuclear cell infiltration, and PKCα/β and PKC λ/ζ. In this manner, PARP inhibition partially restores the myocardial concentrations of NAD+, limits ventricular remodeling and fibrosis, and prevents significant decreases in myocardial contractility. Based primarily on investigations in preclinical models of atherosclerosis, myocardial infarction, and heart failure, PARP inhibition appears to be beneficial in limiting or inhibiting cardiovascular dysfunction. These studies indicate that investigations of acute and chronic PARP inhibition are warranted in patients with atherosclerotic coronary artery disease.

Abstract 3852: Validation of synthetic lethality of PARP and NAMPT dual inhibition in a small cell lung cancer PDX model

Abstract Small cell lung cancer (SCLC) is a highly malignant cancer type with a 5-year survival rate of less than 10%. Different from non-small cell lung cancer (NSCLC), no effective target therapies have been approved to treat SCLC. Poly (ADP) ribose polymerase (PARP) overexpression in SCLC has prompted great efforts to evaluate the role of PARP inhibitors in clinic. To maximize their therapeutic value it is urgent in need to explore the best combination strategies between PARP inhibitors and other pathway modulators. In this study we identified a SCLC patient-derived xenograft (PDX) model with high PARP level and low nicotinamide phosphoribosyltransferase (NAMPT) level. Furthermore, synergistic effect of PARP and NAMPT dual inhibition was demonstrated, supporting translational research of PARP inhibitors and NAMPT inhibitors in this model. The mRNA expression of PARP as well as its 30 most-studied synthetic lethality genes was compared between SCLC and NSCLC in both PDXs and cancer cell lines. We found that NAMPT levels decreased most significantly in SCLC compared with NSCLC across the 30 synthetic lethality genes of PARP. As NAMPT is the rate-limiting enzyme for the synthesis of the PARP substrate β-NAD+, we hypothesized that low β-NAD+ level due to low NAMPT level might render SCLC sensitive to PARP inhibition. LU-01-0547, a SCLC PDX model with high PARP and low NAMPT expression, was identified here. To test our hypothesis, we investigated the preclinical efficacy of ABT888, a PARP inhibitor, with or without FK866, a NAMPT inhibitor, in this subcutaneous xenograft model. The single-agent efficacy of ABT888 was demonstrated (TGI=96%@100 mg/kg, BID). At a sub-optimal dose (50 mg/kg, BID), treatment of ABT888 alone produced little activity in the same model, while its combination with a NAMPT inhibitor, FK866, significantly boosted the antitumor response indicating the synergistic effect (TGI=117%, ORR=6/6, CR=4/6). When nicotinic acid (NA) was administered to promote β-NAD+ biosynthesis via the de novo pathway other than the NAMPT-mediated transformation, the PARP inhibitor’s effectiveness was greatly antagonized (TGI=70% vs. 13%), suggesting β-NAD+ level might correlate with PARP inhibitor sensitivity. In conclusion, this study identified a SCLC PDX model with high PARP and low NAMPT expression. Synergistic inhibition of PARP and NAMPT in this model was demonstrated superior to either treatment alone in efficacy, which warranted its future application in drug discovery. To our knowledge, this was the first in vivo evidence of synthetic lethality in SCLC PDX, supporting future clinical test of combination of PARP and NAMPT inhibitors in SCLC patients. Citation Format: Zhixiang Zhang, Dongfang Li, Chen Chen, Bo Zhang, Xuzhen Tang, Hao Ye, Qingyang Gu, Qunsheng Ji. Validation of synthetic lethality of PARP and NAMPT dual inhibition in a small cell lung cancer PDX model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3852. doi:10.1158/1538-7445.AM2017-3852

New Targeted Agents in Gynecologic Cancers: Synthetic Lethality, Homologous Recombination Deficiency, and PARP Inhibitors.

Inhibitors of poly (ADP-ribose) polymerase (PARP) have emerged as a new class of anti-cancer drugs, specifically for malignancies bearing aberrations of the homologous recombination pathway, like those with mutations in the BRCA 1 and BRCA 2 genes. Olaparib, a potent PARP1 and PARP2 inhibitor, has been shown to significantly increase progression-free survival (PFS) in women with recurrent ovarian cancer related to a germline BRCA mutation and is currently approved fourth-line treatment in these patients. PARP inhibitors (PARPi) target the genetic phenomenon known as synthetic lethality to exploit faulty DNA repair mechanisms. While ovarian cancer is enriched with a population of tumors with known homologous recombination defects, investigations are underway to help identify pathways in other gynecologic cancers that may demonstrate susceptibility to PARPi through synthetically lethal mechanisms. The ARIEL2 trial prospectively determined a predictive assay to identify patients with HRD. The future of cancer therapeutics will likely incorporate these HRD assays to determine the best treatment plan for patients. While the role of PARPi is less clear in non-ovarian gynecologic cancers, the discovery of a predictive assay for HRD may open the door for clinical trials in these other gynecologic cancers enriched with patients with HRD. Identification of patients with tumors deficient in homologous repair or have HRD-like behavior moves cancer treatment towards individualized therapies in order to maximize treatment effect and quality of life for women living with gynecologic cancers.

The Role of PARP Inhibitors in the Treatment of Gynecologic Malignancies

Gynecologic malignancies annually account for over 91,000 new cancer cases and approximately 28,000 deaths in the United States. Although there have been advancements in cytotoxic chemotherapies, there has not been significant improvement in overall survival in these patients. While targeted therapies have shown some benefit in many solid tumors, further development of these agents is needed for the treatment of gynecologic malignancies. Poly(ADP-ribose) polymerase (PARP) catalyzes the polyADP-ribosylation of proteins involved in DNA repair. Inhibitors of PARP were originally developed for cancers with homologous recombination deficiencies, such as those harboring mutations in BRCA1 or BRCA2 genes. However, pre-clinical research and clinical trials have suggested that the activity of PARP inhibitors is not limited to those with BRCA mutations. PARP inhibitors may have activity in cancers deficient in other DNA repair genes, signaling pathways that mitigate DNA repair, or in combination with DNA-damaging agents independent of DNA repair dysfunction. Currently there are seven different PARP inhibitors in clinical development for cancer. While there has been promising clinical activity for some of these agents, there are still significant unanswered questions regarding their use. Going forward, specific questions that must be answered include timing of therapy, use in combination with cytotoxic agents or as single-agent maintenance therapy, and whether there is a predictive biomarker that can be used with PARP inhibition. Even with large strides in the treatment of many gynecologic malignancies in recent years, it is imperative that we develop newer agents and methods to identify patients that may benefit from these compounds. The focus of this review will be on pre-clinical data, current clinical trials, and the future of PARP inhibitors in the treatment of ovarian, endometrial, and cervical cancer.

The Role of PARP Inhibitors in the Treatment of Ovarian Carcinomas

Homologous recombination (HR), a key mechanism of DNA double strand break (DSB) repair, is commonly defective in high grade serous carcinomas (HGSC) of the ovary. BRCA1/2 mutations, as well as many other molecular and genetic defects, can lead to impaired HR. Treatment of HR-defective tumours with poly-ADP ribose polymerase (PARP) inhibitors, which block the key mechanism of single strand DNA breaks (SSB), exploits a therapeutic concept called "synthetic lethality". Early experiences with PARP inhibitors in germline BRCA mutation carriers and sporadic HGSCs of the ovary have been promising. The development of PARP inhibitors for ovarian cancer is an area of active research. This article provides an overview of the molecular rationale for the use of PARP inhibitors and summarizes some of the key early clinical data of their use in ovarian cancer.

Role of PARP inhibitors in cancer biology and therapy.

Deeper understanding of DNA repair mechanisms and their potential value as therapeutic targets in oncology heralded the clinical development of poly(ADP-ribose) polymerase (PARP) inhibitors. Although initially developed to exploit synthetic lethality in models of cancer associated with defective DNA repair, our burgeoning knowledge of PARP biology has resulted in these agents being exploited both in cancer with select chemotherapeutic agents and in non-malignant diseases. In this review article, we briefly review the mechanisms of DNA repair and pre-clinical development of PARP inhibitors before discussing the clinical development of the various PARP inhibitors in depth.

Targeted Therapy for Brain Tumours: Role of PARP Inhibitors

The prognosis of malignant glioma and metastatic brain tumours is still extremely poor, despite recent advances in therapeutic strategies with molecular-targeted agents. Poly(ADP-ribose) polymerase (PARP) inhibitors are a promising, novel class of anticancer drugs to be used either as single agents or in combination with chemotherapy and radiotherapy. PARP-1 and PARP-2 are the only PARP proteins that bind to DNA single strand breaks (SSBs), facilitating the repair process by the base excision repair. For this reason, PARPs have been extensively investigated as targets of novel drugs that may be used to enhance the antitumour activity of SSBs inducing agents, such as the methylating compound temozolomide, which is the drug of choice for glioblastoma, or ionizing radiations. Moreover, PARP inhibitors exert cytotoxic effects in monotherapy in BRCA mutated tumours, which are defective in the homologous recombination (HR) repair. Finally, recent studies have shown that inhibition of PARP function might also induce anti-angiogenic effects which might contribute to impair tumour growth. Many clinical trials with PARP inhibitors are ongoing for the treatment of a variety of advanced solid tumours, including primary or secondary brain tumours. This review discusses the implications of targeting PARP on the design of new treatment regimens.