Perspectives on PARP Inhibitor Combinations for Ovarian Cancer

Poly (ADP-ribose) polymerase (PARP) inhibitors constitute an important treatment option for ovarian cancer nowadays. The magnitude of benefit from PARP inhibitors is influenced by the homologous recombination status, with greater benefit observed in patients with BRCA mutated or BRCA wild-type homologous recombination deficient (HRD) tumors. Although some PARP inhibitor activity has been shown in homologous recombination proficient (HRP) ovarian tumors, its clinical relevance as a single agent is unsatisfactory in this population. Furthermore, even HRD tumors present primary or secondary resistance to PARP inhibitors. Strategies to overcome treatment resistance, as well as to enhance PARP inhibitors’ efficacy in HRP tumors, are highly warranted. Diverse combinations are being studied with this aim, including combinations with antiangiogenics, immunotherapy, and other targeted therapies. This review discusses the rationale for developing therapy combinations with PARP inhibitors, the current knowledge, and the future perspectives on this issue.

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The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatin

Nature Cell Biology ◽

10.1038/s41556-021-00807-6 ◽

2022 ◽

Cited By ~ 1

Author(s):

Dragomir B. Krastev ◽

Shudong Li ◽

Yilun Sun ◽

Andrew J. Wicks ◽

Gwendoline Hoslett ◽

...

Keyword(s):

Mass Spectrometry ◽

Homologous Recombination ◽

Ubiquitin Ligase ◽

Antitumour Activity ◽

Parp Inhibitor ◽

Bound State ◽

Parp Inhibitors ◽

Tumour Cells ◽

Wild Type ◽

Endogenous Proteins

AbstractPoly (ADP-ribose) polymerase (PARP) inhibitors elicit antitumour activity in homologous recombination-defective cancers by trapping PARP1 in a chromatin-bound state. How cells process trapped PARP1 remains unclear. Using wild-type and a trapping-deficient PARP1 mutant combined with rapid immunoprecipitation mass spectrometry of endogenous proteins and Apex2 proximity labelling, we delineated mass spectrometry-based interactomes of trapped and non-trapped PARP1. These analyses identified an interaction between trapped PARP1 and the ubiquitin-regulated p97 ATPase/segregase. We found that following trapping, PARP1 is SUMOylated by PIAS4 and subsequently ubiquitylated by the SUMO-targeted E3 ubiquitin ligase RNF4, events that promote recruitment of p97 and removal of trapped PARP1 from chromatin. Small-molecule p97-complex inhibitors, including a metabolite of the clinically used drug disulfiram (CuET), prolonged PARP1 trapping and enhanced PARP inhibitor-induced cytotoxicity in homologous recombination-defective tumour cells and patient-derived tumour organoids. Together, these results suggest that p97 ATPase plays a key role in the processing of trapped PARP1 and the response of tumour cells to PARP inhibitors.

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The BET inhibitor INCB054329 reduces homologous recombination efficiency and augments PARP inhibitor activity in ovarian cancer

Gynecologic Oncology ◽

10.1016/j.ygyno.2018.03.049 ◽

2018 ◽

Vol 149 (3) ◽

pp. 575-584 ◽

Cited By ~ 35

Author(s):

Andrew J. Wilson ◽

Matthew Stubbs ◽

Phillip Liu ◽

Bruce Ruggeri ◽

Dineo Khabele

Keyword(s):

Ovarian Cancer ◽

Homologous Recombination ◽

Parp Inhibitor ◽

Inhibitor Activity ◽

Bet Inhibitor ◽

Recombination Efficiency

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

Diagnostics ◽

10.3390/diagnostics9020055 ◽

2019 ◽

Vol 9 (2) ◽

pp. 55 ◽

Cited By ~ 16

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.

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PARP inhibitors for BRCA wild type ovarian cancer; gene alterations, homologous recombination deficiency and combination therapy

Japanese Journal of Clinical Oncology ◽

10.1093/jjco/hyz090 ◽

2019 ◽

Vol 49 (8) ◽

pp. 703-707 ◽

Cited By ~ 7

Author(s):

Koji Matsumoto ◽

Meiko Nishimura ◽

Takuma Onoe ◽

Hideki Sakai ◽

Yusaku Urakawa ◽

...

Keyword(s):

Ovarian Cancer ◽

Homologous Recombination ◽

Cancer Susceptibility ◽

Checkpoint Inhibitors ◽

Parp Inhibitors ◽

Current Status ◽

Wild Type ◽

Homologous Recombination Deficiency ◽

Cancer Susceptibility Genes ◽

Gene Alterations

Abstract After a brief summary of the current status of poly-ADP ribose polymerase (PARP) inhibitors for ovarian cancer, we summarize the current status of PARP inhibitors for BRCA wild type ovarian cancer, especially regarding gene alterations other than BRCA, homologous recombination deficiency (HRD), and combinations. Discussion of gene alterations other than BRCA include the results of multiple gene panels studying homologous recombination repair deficiency genes and cancer susceptibility genes, and influences of these alterations on efficacy of PARP inhibitors and cancer susceptibility. Discussions of HRD include the results of phase three trials using HRD assay, the definition of HRD assays, and the latest assays. Discussions of combinations include early phase trial results and ongoing trials combining PARP inhibitors with immune checkpoint inhibitors, anti-angiogenic agents, and triplets.

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Efficacy of PARP Inhibitors in the Treatment of Ovarian Cancer: A Literature-Based Review

Asian Journal of Oncology ◽

10.1055/s-0039-1700619 ◽

2019 ◽

Vol 05 (01) ◽

pp. 01-18

Author(s):

Vikas Goswami ◽

Venkata Pradeep Babu Koyyala ◽

Sumit Goyal ◽

Manish Sharma ◽

Varun Goel ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Repair ◽

Homologous Recombination ◽

Germ Line ◽

Brca Mutation ◽

Parp Inhibitor ◽

Parp Inhibitors ◽

Parp Inhibition ◽

Repair Mechanism ◽

Selection Of

AbstractPoly (ADP-ribose) polymerase (PARP) inhibitors are a unique class of therapeutic agents that focus on tumors with deficiencies in the homologous recombination DNA repair mechanism. Genomic instability outlines high-grade serous ovarian cancer, with 50% of all tumors displaying defects in the important DNA repair mechanism of homologous recombination. Earlier research studies have demonstrated considerable efficiency for PARP inhibitors in patients with germ line breast-related cancer antigens 1 and 2 (BRCA-1/BRCA-2) mutations. It has also been observed that BRCA wild-type patients with other defects in the homologous recombination repair mechanism get benefited from this therapy. 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 selection of PARP inhibitor is mainly dependent upon the number of prior therapies and the presence of a BRCA mutation or HRD. The identification of cases which are most likely to get benefited from PARP inhibitor therapy in view of HRD and other biomarker assessments is still challenging. The purpose of this review is to focus and describe the current evidences for PARP inhibitors in ovarian malignancy, their mechanism of action, and the outstanding issues, including the rate of long-term toxicities and the evolving resistance.

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Meta-analysis on the PARP-inhibitor olaparib reveals therapeutic efficacy in ovarian cancer independent of BRCA1/2 mutation status

Advances in Modern Oncology Research ◽

10.18282/amor.v2.i2.54 ◽

2016 ◽

Vol 2 (2) ◽

pp. 91 ◽

Cited By ~ 1

Author(s):

Ines Vasconcelos ◽

Oscar Gaspar

Keyword(s):

Ovarian Cancer ◽

Clinical Trials ◽

Cancer Patients ◽

Fallopian Tube ◽

Parp Inhibitor ◽

Parp Inhibitors ◽

High Grade ◽

Wild Type ◽

Mutation Status ◽

Platinum Sensitive

<div>Poly(ADP-ribose) polymerase (PARP) inhibitors are one of the most promising drugs for ovarian cancer treatment. This study investigated clinical trials of PARP inhibitors, in order to obtain a more complete prognosis of ovarian cancer patients, which is usually dependent on their BRCA1/2 mutation status. The PubMed database was searched using the key terms “PARP inhibitor OR olaparib OR veliparib OR niraparib OR rucaparib OR (BMN 673) AND (ovarian cancer OR solid tumors)”, while narrowing the selection of the article type to “clinical trial” only. Women included in the study had been histologically diagnosed with recurrent high-grade serous ovarian-, fallopian tube- or primary peritoneal-carcinoma, regardless of the presence of BRCA germline mutation or platinum-sensitive disease recurrence. Data from three Phase I and eight Phase II clinical trials were obtained, two of which evaluated veliparib, eight olaparib and one niraparib. A total of 1042 patients with either high-grade serous ovarian-, fallopian tube- or primary peritoneal cancer were enrolled, of which 587 had a BRCA1/2 germline mutation and at least 370 were platinum-sensitive. The overall response rate (ORR) for patients who underwent treatment with olaparib was 44.5% (95% confidence interval = 0.396–0.496). Patients with BRCA1/2 mutation and those with wild-type BRCA1/2 showed no significant difference in ORR (p = 0.35), even when considering solely Phase II trials (p = 0.13). PARP inhibitors, particularly olaparib, proved effective in the management of ovarian cancer patients. This study identified the existence of patients who presented wild-type BRCA1/2 and possibly BRCA-independent homologous-recombination deficient tumors, or patients with wild-type BRCA1/2 and tumors presenting other forms of BRCAness, who benefit from treatment with olaparib.</div>

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In silico screening identifies a novel small molecule inhibitor that counteracts PARP inhibitor resistance in ovarian cancer

Scientific Reports ◽

10.1038/s41598-021-87325-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Z. Ping Lin ◽

Nour N. Al Zouabi ◽

Mark L. Xu ◽

Nicole E. Bowen ◽

Terence L. Wu ◽

...

Keyword(s):

Ovarian Cancer ◽

Small Molecule ◽

In Silico ◽

Parp Inhibitor ◽

Parp Inhibitors ◽

Small Molecule Inhibitor ◽

Wild Type ◽

In Silico Screening ◽

Molecule Inhibitor ◽

Inhibitor Resistance

AbstractPoly ADP-ribose polymerase (PARP) inhibitors are promising targeted therapy for epithelial ovarian cancer (EOC) with BRCA mutations or defective homologous recombination (HR) repair. However, reversion of BRCA mutation and restoration of HR repair in EOC lead to PARP inhibitor resistance and reduced clinical efficacy of PARP inhibitors. We have previously shown that triapine, a small molecule inhibitor of ribonucleotide reductase (RNR), impaired HR repair and sensitized HR repair-proficient EOC to PARP inhibitors. In this study, we performed in silico screening of small molecule libraries to identify novel compounds that bind to the triapine-binding pocket on the R2 subunit of RNR and inhibit RNR in EOC cells. Following experimental validation of selected top-ranking in silico hits for inhibition of dNTP and DNA synthesis, we identified, DB4, a putative RNR pocket-binding inhibitor markedly abrogated HR repair and sensitized BRCA-wild-type EOC cells to the PARP inhibitor olaparib. Furthermore, we demonstrated that the combination of DB4 and olaparib deterred the progression of BRCA-wild type EOC xenografts and significantly prolonged the survival time of tumor-bearing mice. Herein we report the discovery of a putative small molecule inhibitor of RNR and HR repair for combination with PARP inhibitors to treat PARP inhibitor-resistant and HR repair-proficient EOC.

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PARP inhibitors in ovarian cancer: evidence, experience and clinical potential

Therapeutic Advances in Medical Oncology ◽

10.1177/1758834016687254 ◽

2017 ◽

Vol 9 (4) ◽

pp. 253-267 ◽

Cited By ~ 51

Author(s):

Tarra Evans ◽

Ursula Matulonis

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Parp Inhibitor ◽

Single Agent ◽

Parp Inhibitors ◽

Phase Iii ◽

Biologic Agent ◽

Ovarian Cancer Cells ◽

Antiangiogenic Agents ◽

Brca Mutations

Inhibitors of poly(ADP-ribose) polymerase (PARP) are considered one of the most active and exciting new therapies for the treatment of ovarian cancer. The anticancer activity of PARP inhibitors is based on the DNA repair vulnerability of many ovarian cancer cells, and multiple mechanisms of action of PARP inhibitors have been identified. As single agents, PARP inhibitors have demonstrated their greatest activity in ovarian cancer cells that harbor mutations in BRCA genes. Additionally, recent phase III studies have shown that single-agent PARP inhibitor activity extends beyond BRCA-related cancers and can benefit patients with ovarian cancers that do not have known BRCA mutations, especially when clinical characteristics such as platinum sensitivity and high-grade serous histology are present. PARP inhibitors have also been combined with chemotherapy, however, overlapping myelosuppression observed with PARP inhibitor and chemotherapy combinations has hampered development of these combinations. Contrariwise, PARP inhibitor and biologic agent combinations, specifically antiangiogenic agents, appear well tolerated and show promising activity in both BRCA mutated ( BRCAm) and BRCA wild-type ( BRCAwt) cancers. Currently, multiple clinical trials are underway examining the antitumor activity of PARP inhibitor combination therapy.

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Translational Highlights in Breast and Ovarian Cancer 2019 – Immunotherapy, DNA Repair, PI3K Inhibition and CDK4/6 Therapy

Geburtshilfe und Frauenheilkunde ◽

10.1055/a-1039-4458 ◽

2019 ◽

Vol 79 (12) ◽

pp. 1309-1319 ◽

Cited By ~ 2

Author(s):

Andreas D. Hartkopf ◽

Volkmar Müller ◽

Achim Wöckel ◽

Michael P. Lux ◽

Wolfgang Janni ◽

...

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Homologous Recombination ◽

Parp Inhibitor ◽

Complete Response ◽

Parp Inhibitors ◽

Breast And Ovarian Cancer ◽

First Line Therapy ◽

Recent Developments ◽

Patient Groups

AbstractIn the near future, important translational questions of clinical relevance will be adressed by studies currently in progress. On the one hand, the role of PD-L1 expression must be further understood, after it was found to be relevant in the use of atezolizumab in first-line therapy of patients with metastatic triple-negative breast cancer (TNBC). No association between efficacy and PD-L1 expression was found in a neoadjuvant study that included pembrolizumab in TNBC. The pathological complete response rate (pCR) was higher in both patient groups with and without PD-L1 expression when pembrolizumab was added to chemotherapy. Another future question is the identification of further patient groups in which efficacy of PARP inhibitors is seen, which are licensed for the pBRCA1/2 germline mutation. These include, for example, patients with mutations in other genes, which are involved in homologous recombination, or patients with tumours that show an abnormality in global tests of homologous recombination deficiencies (HRD tests). The question of whether a PARP inhibitor can be given and with which chemotherapy combination partners is currently being investigated in both breast and ovarian cancer. While the data on improved overall survival are being consolidated for the CDK4/6 inhibitors, knowledge of molecular changes during the therapy and during progression on the therapy is growing. Both the accumulation of PI3K mutations and also PTEN changes might play a part in planning subsequent therapies. This review article summarises these recent developments in breast cancer and in part also in ovarian cancer.

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An optimized homologous recombination deficiency (HRD) algorithm ASGAD for predicting PARP inhibitor response in ovarian cancer patient.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e17077 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e17077-e17077

Author(s):

Yang Jiao ◽

Dong Ju Chen ◽

Bo Liu ◽

Pei Meng ◽

Lei Sun ◽

...

Keyword(s):

Ovarian Cancer ◽

Homologous Recombination ◽

Cancer Patient ◽

Large Scale ◽

Clustering Algorithm ◽

Ovarian Cancer Patient ◽

Parp Inhibitor ◽

Gynecologic Cancer ◽

Parp Inhibitors ◽

Homologous Recombination Deficiency

e17077 Background: Homologous recombination deficiency (HRD) results less efficient and error-prone DNA double strand break (DSB) repair, thus causes genomic in stability and impacts on cancer susceptibility to Poly‐(ADP‐Ribose)‐Polymerase (PARP) inhibitors. Evaluating HRD level in gynecologic cancer patients is becoming far more important and influential, so far, there is no standard method to be used in clinical. Methods: Here, we optimized an HRD score algorithm, termed as ASGAD, which combines three classic factors, including loss of heterozygosity score (LOH), telomeric allelic imbalance score (TAI), large-scale state transition score (LST), along with tumor ploidy to predict PARP inhibitor response in ovarian cancer patient. Results: Traditional global optimization strategy for purity and ploidy calculation is usually sensitive to initial values and may lead to incorrect convergences. Here we designed a two-step optimization manner to avoid this problem. Firstly, a density-based clustering algorithm was applied on BAF and CN, and the genotype was assigned to the most legible cluster. Then the rectified BAF and CN was calculated and used to find the maximum likelihood genotype of each segment. The segmentation processed was also improved by applying a series of statistical test to merge similar adjacent segments. The accuracy of allele-specific copy-number detection is significantly improved vie this algorithm, deriving stable and reliable HRD scores especially on aneuploid and hyperploid tumor cases. In this study, we assessed ASGAD algorithm in almost 150 ovarian cancer patient samples, who had treated with platinum effectively. BRCA1/2 deficient was defined as either one deleterious mutation in BRCA1/2, with LOH in the wild type copy or two deleterious mutations in the same gene. The results showed that the 19/23 BRCA1/2 deficient samples are also HRD-high, giving the sensitivity of 82.61%. Besides, we identify 58 HRD-high samples with intact BRCA1/2, who might benefit from PARP inhibitors, by the ASGAD algorithm. Interestingly, we analyzed 4 HRD-high samples by using whole-exome sequencing (WES), and found other HR genes mutations in these samples, including PARP4, FANCM, MSH2, MSH6, ATR, POLD1. Conclusions: The expanded use of PARP inhibitors in HRD tumors using the ASGAD algorithm requires more validation.

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