Copy number deletion of RAD50 as predictive marker of BRCAness and PARP inhibitor response in BRCA wild type ovarian cancer

e13125 Background: Epithelial ovarian cancer (EOC) is the second most common gynecologic cancer in the United States, and carries the highest mortality in this category in the West. The progression free survival and overall survival depend greatly on tumor sensitivity to a platinum chemotherapy. Once platinum resistance is encountered, response rates of only 6–30% are achieved. A relatively new modality in EOC that would allow targeted treatments is a PARP inhibitor, a drug that inhibits the enzyme poly (ADP-ribose) polymerase (PARP), which is showing promise for the treatment of EOC with mutations in the BRCA1 or BRCA2 tumor suppressors. Triapine, a novel small-molecule drug developed in our laboratory, potently inhibits the activity of ribonucleotide reductase involved in the key step of DNA synthesis and replication. Methods: 1. Cell sensitivity to varying ratios of treating drug combinations (Triapine with cisplatin; PARP inhibitor, olaparib) was carried out by clonogenic survival assays using multiple EOC cell lines (A2780, Caov-3, EFO, IGROV-1, BG-1, PEO1, SKOV3). 2. AKT level was measured in the cell lines before and after treatment. 3. BRCA1 wild-type and BRCA1-knockdown EOC cells were treated with cisplatin or PARP alone and in combination with Triapine. Drug-induced DNA damage was assessed by the levels of g-H2AX, the marker of double stranded breaks (DSBs), and of Rad51 foci, a marker of HR repair of DSBs. Results: Treatment with Triapine leads to synergistic sensitization of BRCA1 wild-type EOC cells to platinum drugs and to olaparib. Both platinum drugs and olaparib induce DNA damage that is repaired by HR. This suggests that Triapine inhibits HR and sensitizes EOC cells to these drugs. Triapine attenuates olaparib-induced Rad51 foci in BRCA1-wild type cells, which resembles the impairment of such foci formation in BRCA1-knockdown cells. Triapine causes down-regulation of AKT activity in EOC cells. Conclusions: Triapine produces synthetic lethality by inhibiting both DNA repair and pro-survival pathways. Combination of Triapine and platinum drugs/PARP inhibitors represents a rational and innovative therapy that targets EOC with a high level of AKT activity.

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Combination of triapine, olaparib, and cediranib suppresses progression of BRCA-wild type and PARP inhibitor-resistant epithelial ovarian cancer

PLoS ONE ◽

10.1371/journal.pone.0207399 ◽

2018 ◽

Vol 13 (11) ◽

pp. e0207399 ◽

Cited By ~ 9

Author(s):

Z. Ping Lin ◽

Yong-Lian Zhu ◽

Ying-Chun Lo ◽

Jake Moscarelli ◽

Amy Xiong ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Parp Inhibitor ◽

Wild Type

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Role of BRCA Mutation and HE4 in Predicting Chemotherapy Response in Ovarian Cancer: A Retrospective Pilot Study

Biomedicines ◽

10.3390/biomedicines9010055 ◽

2021 ◽

Vol 9 (1) ◽

pp. 55

Author(s):

Francesco Plotti ◽

Corrado Terranova ◽

Federica Guzzo ◽

Carlo De Cicco Nardone ◽

Daniela Luvero ◽

...

Keyword(s):

Ovarian Cancer ◽

Brca Mutation ◽

Predictive Marker ◽

Chemotherapy Response ◽

High Grade ◽

Serous Ovarian Cancer ◽

Wild Type ◽

Platinum Sensitive ◽

Platinum Resistant

Even though 80% of patients with High-Grade Serous Ovarian Cancer respond to standard first-line chemotherapy, a majority of them could relapse in the following five years due to a resistance to platinum. Human Epididymis protein 4 (HE4) is one of the most promising markers in predicting platinum therapy response. This pilot study aims to evaluate the potential role of HE4 value in predicting chemotherapy response in BRCA mutated patients and in BRCA wild-type (non-mutated) ones. We selected 69 patients, affected by High-Grade Serous Ovarian Cancer, and optimally debulked and submitted to standard chemotherapy protocols. HE4 was dosed during every chemotherapy course. Patients were classified as platinum-resistant and platinum-sensitive. According to BRCA mutation test, patients were further divided into BRCA wild-type (53 patients), and BRCA mutated (16 patients). 35 patients out of 69 (52%) were platinum-sensitive (recurrence > 12 months), while 33 patients (48%) were platinum-resistant (recurrence < 12 months). Thus, in the total population, HE4 performed as a marker of chemosensitivity with a sensibility of 79% and a specificity of 97%. In the BRCA WT group, 23 patients out of 53 (43%) were platinum-sensitive, while 30 patients out of 53 (57%) were platinum-resistant. In the BRCA WT group, HE4 performed as a predictive marker of chemosensitivity with a sensibility of 80% and a specificity of 100%. In the BRCA mutated group, 13 patients out of 16 (82%) were platinum-sensitive, while 3 patients (18%) were platinum-resistant. In the BRCA mutated group, HE4 performed as a predictive marker of chemosensitivity in all patients. The ability to detect platinum-resistant patients before tumor relapse probably could open new therapeutic scenarios.

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Abstract 4817: EP-100 sensitizes BRCA wild-type ovarian cancer cells to PARP inhibitor

10.1158/1538-7445.am2018-4817 ◽

2018 ◽

Author(s):

Shaolin Ma ◽

Sunila Pradeep ◽

Sherry Wu ◽

Mark Seungwook Kim ◽

Wei Hu ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Parp Inhibitor ◽

Ovarian Cancer Cells ◽

Wild Type

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EP887 A synergistic anticancer effect of combination treatment with a cell cycle checkpoint kinase 1 inhibitor and PARP inhibitor in BRCA wild type epithelial ovarian cancer

10.1136/ijgc-2019-esgo.935 ◽

2019 ◽

Author(s):

YB Kim ◽

H-Y Cho ◽

WH Park ◽

DH Suh ◽

JH No

Keyword(s):

Cell Cycle ◽

Ovarian Cancer ◽

Combination Treatment ◽

Parp Inhibitor ◽

Cell Cycle Checkpoint ◽

Wild Type ◽

Anticancer Effect ◽

Checkpoint Kinase 1 ◽

Cycle Checkpoint ◽

A Cell

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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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Perspectives on PARP Inhibitor Combinations for Ovarian Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.754524 ◽

2021 ◽

Vol 11 ◽

Author(s):

Renata Colombo Bonadio ◽

Maria del Pilar Estevez-Diz

Keyword(s):

Ovarian Cancer ◽

Homologous Recombination ◽

Current Knowledge ◽

Parp Inhibitor ◽

Single Agent ◽

Treatment Resistance ◽

Parp Inhibitors ◽

Wild Type ◽

Inhibitor Activity ◽

Secondary Resistance

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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