Synergistic Effect of PARP Inhibitor and BRD4 Inhibitor in Multiple Models of Ovarian Cancer

2021 ◽  
Author(s):  
Han Yu Huang ◽  
Chen Liu ◽  
Xin Li You ◽  
Xi Li ◽  
Yang chao Sun ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Replication ◽  
Replication Fork ◽  
Synergistic Effects ◽  
Parp Inhibitor ◽  
Lethal Effect ◽  
Parp Inhibitors ◽  
Multiple Models ◽  
Chromosomal Breakage ◽  
Current Therapies

Abstract Background: Ovarian cancer has the highest fatality rate among patients with gynaecological tumours. Current therapies including poly-ADP ribose polymerase (PARP) inhibitors have limitations due to the frequent recurrence of ovarian cancer after treatment and resistance to therapy.Methods: In this study, we used multiple models with different genetic backgrounds to investigate the potential synergism effect and mechanism between the bromodomain-containing protein 4 (BRD4) inhibitor AZD5153 and the PARP inhibitor Olaparib. The models were two-dimensional (2D) and 3D cell lines, patient-derived organoids (PDO) and patient-derived xenografts (PDX). Results: Cotreatment with Olaparib and AZD5153 exhibited marked synergistic effects, and significantly attenuated cell viability, whereas it increased DNA replication fork instability, chromosomal breakage and apoptosis compared to treatment with either drug alone. Mechanistically, the tumor upregulates PTEN after Olaparib treatment to make its DNA and chromosome more stable and therefore induces Olaparib resistance. AZD5153 can downregulate PTEN to reverse Olaparib resistance and thus increase joint lethal effect with Olaparib.Conclusion: This study reveals that AZD5153 can downregulate PTEN to reverse Olaparib resistance and thus increase joint lethal effect on DNA replication fork instability, chromosomal breakage, and apoptosis with Olaparib.

scholarly journals First-line PARP inhibitors in ovarian cancer: summary of an ESMO Open - Cancer Horizons round-table discussion

ESMO Open ◽  
2020 ◽  
Vol 5 (6) ◽  
pp. e001110
Author(s):  
Susana Banerjee ◽  
Antonio Gonzalez-Martin ◽  
Philipp Harter ◽  
Domenica Lorusso ◽  
Kathleen N Moore ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Maintenance Therapy ◽  
Parp Inhibitor ◽  
Advanced Ovarian Cancer ◽  
Round Table ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
European Medicines Agency ◽  
First Line ◽  
Phase Iii Trials

Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is the latest breakthrough in the management of newly diagnosed advanced ovarian cancer. The results of the SOLO-1 trial in 2018 led to European Medicines Agency and Food and Drug Administration approval of olaparib as first-line maintenance therapy in patients with BRCA1/2 mutation, establishing a new standard of care. Subsequently, the results of three phase III trials (PRIMA, PAOLA-1, VELIA) evaluating the use of first-line PARP inhibitors beyond patients with BRCA1/2 mutations and as combination strategies were presented in 2019, leading to the recent approval of maintenance niraparib irrespective of biomarker status and olaparib in combination with bevacizumab in homologous recombination deficiency-positive-associated advanced ovarian cancer. An ESMO Open - Cancer Horizons round-table expert panel discussed the four phase III trials of first-line PARP inhibitor therapy and how they are changing the clinical management of advanced ovarian cancer.

scholarly journals Maintenance therapy for recurrent epithelial ovarian cancer: current therapies and future perspectives – a review

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Sudeep Gupta ◽  
Shona Nag ◽  
Shyam Aggarwal ◽  
Amit Rauthan ◽  
Narayanankutty Warrier
Keyword(s):  
Ovarian Cancer ◽  
Maintenance Therapy ◽  
Epithelial Ovarian Cancer ◽  
Maintenance Treatment ◽  
Progression Free Survival ◽  
Parp Inhibitors ◽  
Optimal Timing ◽  
Special Focus ◽  
Future Perspectives ◽  
Current Therapies

Abstract Epithelial ovarian cancer (EOC) is usually diagnosed late at an advanced stage. Though EOC initially responds to treatment, the recurrence rate is pretty high. The efficacy of different targeted therapies reduces with each recurrence. Hence there is need of effective maintenance therapy in recurrent EOC. Recently, polyADP-ribose polymerase (PARP) inhibitors (PARPi) have been approved both for initial treatment of EOC and as its maintenance treatment. PARPi have also been found to act regardless of BRCA status or homologous recombination (HR) deficiency. Several trials testing PARPi early in maintenance therapy are in progress and their results will shed light on the optimal timing of maintenance therapy that gives the most benefit with least toxicity. Right patient selection for maintenance treatment is also a challenge. Hence, though PARPi are emerging as a promising maintenance treatment in recurrent EOC with prolongation of progression free survival (PFS), results from further trials and overall survival (OS) data from current trials are awaited to fulfill the gaps in understanding the role of this pathway in treatment of EOC. This review discusses the current therapies for EOC, challenges in the treatment of recurrent EOC, recent developments and trials in recurrent EOC maintenance with special focus on PARPi and future perspectives.

scholarly journals Genome-scale CRISPR knockout screen identifies TIGAR as a modifier of PARP inhibitor sensitivity

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Pingping Fang ◽  
Cristabelle De Souza ◽  
Kay Minn ◽  
Jeremy Chien
Keyword(s):  
Ovarian Cancer ◽  
Metabolic Pathways ◽  
Clinical Utility ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Loss Of Function ◽  
Poor Overall Survival ◽  
Cytotoxic Effects ◽  
Cancer Types ◽  
Genome Scale

Abstract Treatment of cancer with poly (ADP-ribose) polymerase (PARP) inhibitors is currently limited to cells defective in the homologous recombination (HR) pathway. Identification of genetic targets that induce or mimic HR deficiencies will extend the clinical utility of PARP inhibitors. Here we perform a CRISPR/Cas9-based genome-scale loss-of-function screen, using the sensitivity of PARP inhibitor olaparib as a surrogate. We identify C12orf5, encoding TP53 induced glycolysis and apoptosis regulator (TIGAR), as a modifier of PARP inhibitor response. We show that TIGAR is amplified in several cancer types, and higher expression of TIGAR associates with poor overall survival in ovarian cancer. TIGAR knockdown enhances sensitivity to olaparib in cancer cells via downregulation of BRCA1 and the Fanconi anemia pathway and increases senescence of these cells by affecting metabolic pathways and increasing the cytotoxic effects of olaparib. Our results indicate TIGAR should be explored as a therapeutic target for treating cancer and extending the use of PARP inhibitors.

scholarly journals Niraparib in ovarian cancer: results to date and clinical potential

2017 ◽  
Vol 9 (9) ◽  
pp. 579-588 ◽  
Author(s):  
Davide Caruso ◽  
Anselmo Papa ◽  
Silverio Tomao ◽  
Patrizia Vici ◽  
Pierluigi Benedetti Panici ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Synthetic Lethality ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Repair System ◽  
Gynaecological Malignancy ◽  
Platinum Based Chemotherapy ◽  
Base Excision

Ovarian cancer is the first cause of death from gynaecological malignancy. Germline mutation in BRCA1 and 2, two genes involved in the mechanisms of reparation of DNA damage, are showed to be related with the incidence of breast and ovarian cancer, both sporadic and familiar. PARP is a family of enzymes involved in the base excision repair (BER) system. The introduction of inhibitors of PARP in patients with BRCA-mutated ovarian cancer is correlated with the concept of synthetic lethality. Among the PARP inhibitors introduced in clinical practice, niraparib showed interesting results in a phase III trial in the setting of maintenance treatment in ovarian cancer, after platinum-based chemotherapy. Interestingly, was niraparib showed to be efficacious not only in BRCA-mutated patients, but also in patients with other alterations of the homologous recombination (HR) system and in patients with unknown alterations. These results position niraparib as the first PARP-inhibitor with clinically and statistically significant results also in patients with no alterations in BRCA 1/2 and other genes involved in the DNA repair system. Even if the results are potentially practice-changing, the action of niraparib must be further studied and deepened.

scholarly journals Targeting the nucleotide salvage factor DNPH1 sensitizes BRCA-deficient cells to PARP inhibitors

Science ◽  
2021 ◽  
Vol 372 (6538) ◽  
pp. 156-165 ◽  
Author(s):  
Kasper Fugger ◽  
Ilirjana Bajrami ◽  
Mariana Silva Dos Santos ◽  
Sarah Jane Young ◽  
Simone Kunzelmann ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Suppressor Genes ◽  
Replication Fork ◽  
Synthetic Lethality ◽  
Acquired Resistance ◽  
Parp Inhibitors ◽  
Breast And Ovarian Cancer ◽  
Promising Strategy ◽  
Dna Break ◽  
Break Formation

Mutations in the BRCA1 or BRCA2 tumor suppressor genes predispose individuals to breast and ovarian cancer. In the clinic, these cancers are treated with inhibitors that target poly(ADP-ribose) polymerase (PARP). We show that inhibition of DNPH1, a protein that eliminates cytotoxic nucleotide 5-hydroxymethyl-deoxyuridine (hmdU) monophosphate, potentiates the sensitivity of BRCA-deficient cells to PARP inhibitors (PARPi). Synthetic lethality was mediated by the action of SMUG1 glycosylase on genomic hmdU, leading to PARP trapping, replication fork collapse, DNA break formation, and apoptosis. BRCA1-deficient cells that acquired resistance to PARPi were resensitized by treatment with hmdU and DNPH1 inhibition. Because genomic hmdU is a key determinant of PARPi sensitivity, targeting DNPH1 provides a promising strategy for the hypersensitization of BRCA-deficient cancers to PARPi therapy.

scholarly journals Efficacy and Safety of PARP Inhibitor Combination Therapy in Recurrent Ovarian Cancer: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Ning Ren ◽  
Leyin Zhang ◽  
Jieru Yu ◽  
Siqi Guan ◽  
Xinyang Dai ◽  
...  
Keyword(s):  
Systematic Review ◽  
Ovarian Cancer ◽  
Combination Therapy ◽  
Data Extraction ◽  
Meta Analysis ◽  
Parp Inhibitor ◽  
Recurrent Ovarian Cancer ◽  
Parp Inhibitors ◽  
High Grade ◽  
Efficacy And Safety

ObjectivesThough it is known to all that PARP inhibitors (PARPis) are effective when used as maintenance alone for women with recurrent ovarian cancer (ROC), little is known about whether using them in combination with other drugs would contribute to a better efficacy. We performed a systematic review and meta-analysis to explore the efficacy and safety of PARPi combination therapy compared with monotherapy.Materials and MethodsWe searched for randomized controlled trials (RCTs) that offered the date we needed in PubMed, Embase, Cochrane, and major conference. Data extraction and processing were completed by three investigators to compare OS, PFS, and ORR both in intervention and in control subset. Then, we calculated the pooled RR and 95% CI of all-grade and high-grade adverse effects to study its safety. And we evaluated the within-study heterogeneity by using subgroup and sensitivity analysis.Results and ConclusionA total of three eligible RCTs covering 343 women were included. In PFS analysis, PARP inhibitor (PARPi) combination therapy can significantly improve PFS for women with ROC when compared with the controls (HR: 0.46, 95% CI: 0.35 to 0.59), especially for those with mutated BRCA (HR: 0.29, 95% CI: 0.19 to 0.45). And in OS analysis, combination therapy is not inferior to monotherapy (HR: 0.90, 95% CI: 0.50 to 1.61). As for ORR, the effectiveness of combination therapy and monotherapy was almost the same (RR: 1.04, 95% CI: 0.82 to 1.31). Additionally, combination therapy seldom causes more adverse events, both in all-grade and in high grade.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, International Prospective Register of Systematic Reviews (PROSPERO) (identifier, CRD42018109933).

scholarly journals PARP Inhibitors in Ovarian Cancer: The Route to “Ithaca”

Diagnostics ◽  
2019 ◽  
Vol 9 (2) ◽  
pp. 55 ◽  
Author(s):  
Boussios ◽  
Karathanasi ◽  
Cooke ◽  
Neille ◽  
Sadauskaite ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Current Evidence ◽  
Repair Pathway ◽  
Significant Efficacy

Poly (ADP-ribose) polymerase (PARP) inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Genomic instability characterizes high-grade serous ovarian cancer (HGSOC), with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Early studies have shown significant efficacy for PARP inhibitors in patients with germline breast related cancer antigens 1 and 2 (BRCA1/2) mutations. It has also become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this treatment. Companion homologous recombination deficiency (HRD) scores are being developed to guide the selection of patients that are most likely to benefit from PARP inhibition. The choice of which PARP inhibitor is mainly based upon the number of prior therapies and the presence of a BRCA mutation or HRD. The identification of patients most likely to benefit from PARP inhibitor therapy in view of HRD and other biomarker assessments is still challenging. The aim of this review is to describe the current evidence for PARP inhibitors in ovarian cancer, their mechanism of action, and the outstanding issues, including the rate of long-term toxicities and the evolution of resistance.

A randomized phase 2 trial comparing efficacy of the combination of the PARP inhibitor olaparib and the antiangiogenic cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer.

2014 ◽  
Vol 32 (18_suppl) ◽  
pp. LBA5500-LBA5500 ◽  
Author(s):  
Joyce Liu ◽  
William Thomas Barry ◽  
Michael J. Birrer ◽  
Jung-min Lee ◽  
Ronald J. Buckanovich ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase 1 ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Progression Free Survival ◽  
Recurrent Ovarian Cancer ◽  
Parp Inhibitors ◽  
Open Label ◽  
Angiogenic Therapy ◽  
Platinum Sensitive

LBA5500 Background: PARP inhibitors and anti-angiogenics are clinically active in recurrent ovarian cancer (OvCa). Preclinical studies suggest these agents can synergize, and a phase 1 study showed that the combination of cediranib (ced) and olaparib (olap) is well-tolerated. We therefore compared the activity of olap alone (Olap) to combined ced and olap (Ced/Olap) in treatment of recurrent platinum-sensitive (plat-sens) high-grade serous (HGS) or BRCA-related OvCa (NCT 01116648). Methods: Patients (pts) across 9 centers were randomized 1:1 in this Ph 2 open label study to Olap (olap 400 mg capsules BID) or Ced/Olap (olap 200 mg capsules BID; ced 30 mg daily), stratified by BRCA status and prior anti-angiogenic therapy. Eligibility included pts with recurrent plat-sens HGS or BRCA-related OvCa. Pts had measurable disease by RECIST 1.1, PS 0 or 1, and the ability to take POs. No prior anti-angiogenics in the recurrent setting or prior PARP inhibitor was allowed. Progression-free survival (PFS) was defined as time from randomization to radiographic progression or death. With a target N=90 pts, the study was powered to detect a hazard ratio (HR) of 1.75 (median PFS 6 vs 10.5 mo). Results: Pts were enrolled from Oct 2011 to Jun 2013: 46 to Olap, 44 to Ced/Olap. 48 pts were known BRCA carriers (25 Olap; 23 Ced/Olap). At a planned interim analysis the DSMB recommended release of data. As of Jan 7, 2014, 41 pts had a PFS event. Median PFS was 9.0 mos for Olap and 17.7 mos for Ced/Olap (HR 2.9, 95% CI 1.5-5.6, p = 0.001). There were 2 complete responses (CR) and 21 partial responses (PR) in pts on Olap (56% objective response rate, ORR) and 3 CRs and 33 PRs in pts on Ced/Olap (84% ORR, p = 0.008). The overall rate of Gr3/4 toxicity was higher for pts on Ced/Olap (70%) than on Olap (7%). Differentially occurring toxicities included fatigue (27% Ced/Olap vs 7% Olap), diarrhea (23% vs 0%), and hypertension (39% vs 0%). Updated efficacy and exploratory subgroup analyses will be presented. Conclusions: Combined Ced/Olap significantly extended PFS and ORR compared to Olap in plat-sens OvCa. Further studies of this oral combination in plat-sens OvCa are warranted. Clinical trial information: NCT01116648.

Real-world clinical practice: Toxicities of maintenance PARP inhibitors in recurrent ovarian cancer—The Royal Marsden experience.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18770-e18770
Author(s):  
Zohra Ali ◽  
Laura Appadu ◽  
Ellen Kitetere ◽  
Julian Wampfler ◽  
Dorothy Yang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Practice ◽  
Maintenance Therapy ◽  
Real World ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Routine Clinical Practice ◽  
Phase Iii ◽  
Low Grade ◽  
Starting Dose

e18770 Background: Maintenance therapy with PARP inhibitors (PARPi) in recurrent high grade ovarian cancer is standard of care for patients who have responded to second or subsequent lines of platinum-based chemotherapy. The increased access to PARP inhibitors (Olaparib, Niraparib and Rucaparib) has provided the opportunity to explore the real-world toxicities in routine clinical practice, toxicity management and the consequent impact on maintenance therapy outcomes. Methods: Patients with relapsed ovarian cancer that received maintenance PARP inhibitor therapy in routine clinical practice between April 2015 and April 2020 were identified. Electronic patient records were reviewed retrospectively to retrieve details of any reported toxicities (occurring at any time during therapy) and their management. Data was entered into and analysed in a Microsoft Excel spreadsheet. Results: 99 patients who received second or subsequent line maintenance PARPi therapy were included (median age 63.6 years). 36% had a germline BRCA1/2 mutation, 6% had a somatic BRCA1/2 mutation and 58% were BRCA wild-type. 69% received 2nd line maintenance therapy; 22% and 9% received a maintenance PARP inhibitor following 3rd or 4+ line therapy respectively. 56% had not received previous maintenance therapy; 43% had received Bevacizumab. 48% patients commenced maintenance therapy at full dose. 13% of patients experienced no toxicities. 60% of patients experienced G1-2 toxicities, with 42% experiencing >2 episodes; most common toxicities were fatigue, nausea/vomiting and thrombocytopenia. 26% of patients experienced >G3 toxicity, with 9% experiencing >2 episodes, 4% of which were recurring toxicities; most common toxicities were hypertension, neutropenia and anaemia. 64% of patients developed toxicity within the first cycle of treatment; 39% had a dose interruption, 56% of which were < 2 weeks duration. 59% patients required a dose reduction from their starting dose due to toxicities. There was no significant difference in median PFS between patients who had been dose reduced compared to those who received full starting dose (p > 0.05). Conclusions: In keeping with phase III clinical trials, our real-world experience is that most PARPi toxicities are low grade and occur early in treatment. Toxicities can be effectively managed with brief dose interruptions and dose reductions, without adverse impact on survival outcomes.

Retrospective analysis of ovarian cancer patients treated with PARP inhibitors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17555-e17555
Author(s):  
Connie Liang ◽  
Ashley Leung ◽  
Chung-Shien Lee ◽  
Jennifer Hernandez ◽  
Kit Cheng ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Retrospective Study ◽  
Adverse Events ◽  
Parp Inhibitor ◽  
Time Frame ◽  
Parp Inhibitors ◽  
Primary Objective ◽  
Hematologic Toxicity ◽  
Single Institution ◽  
Cancer Data

e17555 Background: Over the last few years, targeted therapy has become the mainstay maintenance treatment of patients with ovarian cancer including patients with BRCA1 or BRCA2 mutations. Poly ADP ribose polymerase (PARP) inhibitors are effective in the treatment of patients who are in complete or partial remission. PARP inhibitors are known to cause hematological adverse events (AEs), but have not been compared directly to each other. Methods: We conducted a single institution, IRB approved, retrospective study on patients who were treated with PARP inhibitors from December 2016 to October 2020. Patients were stratified according to which PARP inhibitor they received. Our primary objective was to assess the incidence of hematological and non-hematological adverse events associated with the use of PARP inhibitor therapy used in patients with ovarian cancer. Data from absolute neutrophil count, hemoglobin and platelet count during the first 2 cycles were graded for hematologic toxicity according to CTCAE v 5.0. Results: A total of 126 patients received a PARP inhibitor during the study time frame. 34 were excluded and 92 patients were included for analysis. Median age of patients were 64.3 (range, 33.8 to 92.3) years, 66 (71.7%) white, and 84 (91.3%) had an ECOG PS of 0/1. Thirty-one (33.7%) of patients received niraparib and 61 (66.3%) of patients received olaparib. Patients in the niraparib group experienced more hematologic AEs, with 11 (35.5%) (95% CI 19.2-54.6), 20 (64.5%) (95% CI 45.4-80.8), and 18 (58.1%) (95% CI 39.1-75.5) experiencing neutropenia, anemia, thrombocytopenia, respectively. Eight (13.1%) (95% CI 5.8-24.2), 24 (39.3%) (95% CI 27.1-52.7), 16 (26.2%) (95% CI 15.8-39.1) patients in the olaparib group experienced neutropenia, anemia, thrombocytopenia, respectively. Conclusions: This single institution retrospective study outlines the hematological toxicities observed between two PARP inhibitors. Although there are four PARP inhibitors approved by FDA, our data compared only two of the four (as they were the most commonly prescribed PARP inhibitors in our institution). Our results suggested that niraparib tended to be associated with a higher risk for hematologic toxicities than olaparib. Our data showed anemia as the most common hematologic toxicity which was consistent with what has been widely documented in the literature.

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