Comparison of genomic instability test scores used for predicting PARP activity in ovarian cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1586-1586
Author(s):  
Kirsten M Timms ◽  
Gordon B. Mills ◽  
Michael Perry ◽  
Alexander Gutin ◽  
Jerry Lanchbury ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trials ◽  
Homologous Recombination ◽  
Genomic Instability ◽  
Clinical Laboratory ◽  
Parp Inhibitor ◽  
Mutation Screening ◽  
Gene Panel ◽  
Snp Analysis ◽  
Gene Panels

1586 Background: Clinical trials have explored the utility of various genomic instability (GI) scores or gene panels to assess deficiencies in the homologous recombination (HR) DNA repair pathway and support PARP inhibitor use in ovarian cancer; however, these methods of assessing homologous recombination deficiency (HRD) may not be equivalent. The myChoice HRD test is the only analytically and clinically validated, FDA-approved HRD test that includes BRCA1/2 mutation status and three measures of GI. We compared the proportion of patients identified as candidates for PARP inhibitor use by two measures of HRD [percent loss of heterozygosity (%LOH), 11-gene panel] to myChoice HRD. Methods: Whole-genome SNP analysis was used to reconstruct ovarian tumor genomic profiles to calculate the myChoice HRD score and %LOH in 2 cohorts (clinical laboratory cohort, N = 3,278; SCOTROC4 trial, N = 248). Mutation screening for a set of 11 genes in the HR pathway ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, MRE11A, NBN, PALB2, RAD51C, RAD51D) was performed for a subset of tumors from the SCOTROC trial (n = 187). Samples were considered positive if the myChoice HRD score was above the threshold (threshold scores of 42 and 33 were assessed), %LOH above the threshold (16%), or a pathogenic variant in one of the 11 HR genes. The correlation between positive results from %LOH and the 11-gene panel were compared to myChoice HRD. Percent positive agreement (PPA) was the proportion of positive test results from myChoice HRD that were also positive by %LOH or the 11-gene panel. Results: The table shows the correlation and PPA between myChoice HRD, %LOH, and the 11-gene panel. Overall, 19%-61% of patients identified as positive by myChoice HRD would have been missed by %LOH or the 11-gene panel in these two cohorts. Conclusions: These data show that HRD tests used in published and ongoing clinical trials are not equivalent, and they should not be considered interchangeable in predicting PARP inhibitor response in clinical practice. [Table: see text]

scholarly journals 53BP1 as a potential predictor of response in PARP inhibitor-treated homologous recombination-deficient ovarian cancer

2019 ◽  
Vol 153 (1) ◽  
pp. 127-134 ◽  
Author(s):  
Rachel M. Hurley ◽  
Andrea E. Wahner Hendrickson ◽  
Daniel W. Visscher ◽  
Peter Ansell ◽  
Maria I. Harrell ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Parp Inhibitor ◽  
Potential Predictor

scholarly journals Stenoparib, an Inhibitor of Cellular Poly(ADP-Ribose) Polymerase, Blocks Replication of the SARS-CoV-2 and HCoV-NL63 Human Coronaviruses In Vitro

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nathan E. Stone ◽  
Sierra A. Jaramillo ◽  
Ashley N. Jones ◽  
Adam J. Vazquez ◽  
Madison Martz ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trials ◽  
Viral Replication ◽  
Phase Ii ◽  
Parp Inhibitor ◽  
Target Range ◽  
Phase Ii Clinical Trials ◽  
Human Coronaviruses ◽  
Respiratory Coronavirus

ABSTRACT By late 2020, the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), had caused tens of millions of infections and over 1 million deaths worldwide. A protective vaccine and more effective therapeutics are urgently needed. We evaluated a new poly(ADP-ribose) polymerase (PARP) inhibitor, stenoparib, that recently advanced to phase II clinical trials for treatment of ovarian cancer, for activity against human respiratory coronaviruses, including SARS-CoV-2, in vitro. Stenoparib exhibits dose-dependent suppression of SARS-CoV-2 multiplication and spread in Vero E6 monkey kidney and Calu-3 human lung adenocarcinoma cells. Stenoparib was also strongly inhibitory to the human seasonal respiratory coronavirus HCoV-NL63. Compared to remdesivir, which inhibits viral replication downstream of cell entry, stenoparib impedes entry and postentry processes, as determined by time-of-addition (TOA) experiments. Moreover, a 10 μM dosage of stenoparib—below the approximated 25.5 μM half-maximally effective concentration (EC50)—combined with 0.5 μM remdesivir suppressed coronavirus growth by more than 90%, indicating a potentially synergistic effect for this drug combination. Stenoparib as a stand-alone or as part of combinatorial therapy with remdesivir should be a valuable addition to the arsenal against COVID-19. IMPORTANCE New therapeutics are urgently needed in the fight against COVID-19. Repurposing drugs that are either already approved for human use or are in advanced stages of the approval process can facilitate more rapid advances toward this goal. The PARP inhibitor stenoparib may be such a drug, as it is currently in phase II clinical trials for the treatment of ovarian cancer and its safety and dosage in humans have already been established. Our results indicate that stenoparib possesses strong antiviral activity against SARS-CoV-2 and other coronaviruses in vitro. This activity appears to be based on multiple modes of action, where both pre-entry and postentry viral replication processes are impeded. This may provide a therapeutic advantage over many current options that have a narrower target range. Moreover, our results suggest that stenoparib and remdesivir in combination may be especially potent against coronavirus infection.

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

2018 ◽  
Vol 149 (3) ◽  
pp. 575-584 ◽  
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

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.

scholarly journals Alternate therapeutic pathways for PARP inhibitors and potential mechanisms of resistance

2021 ◽  
Vol 53 (1) ◽  
pp. 42-51
Author(s):  
Dae-Seok Kim ◽  
Cristel V. Camacho ◽  
W. Lee Kraus
Keyword(s):  
Clinical Trials ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Cancer Therapeutics ◽  
Progression Free Survival ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Combination Strategies

AbstractHomologous recombination (HR) repair deficiency impairs the proper maintenance of genomic stability, thus rendering cancer cells vulnerable to loss or inhibition of DNA repair proteins, such as poly(ADP-ribose) polymerase-1 (PARP-1). Inhibitors of nuclear PARPs are effective therapeutics for a number of different types of cancers. Here we review key concepts and current progress on the therapeutic use of PARP inhibitors (PARPi). PARPi selectively induce synthetic lethality in cancer cells with homologous recombination deficiencies (HRDs), the most notable being cancer cells harboring mutations in the BRCA1 and BRCA2 genes. Recent clinical evidence, however, shows that PARPi can be effective as cancer therapeutics regardless of BRCA1/2 or HRD status, suggesting that a broader population of patients might benefit from PARPi therapy. Currently, four PARPi have been approved by the Food and Drug Administration (FDA) for the treatment of advanced ovarian and breast cancer with deleterious BRCA mutations. Although PARPi have been shown to improve progression-free survival, cancer cells inevitably develop resistance, which poses a significant obstacle to the prolonged use of PARP inhibitors. For example, somatic BRCA1/2 reversion mutations are often identified in patients with BRCA1/2-mutated cancers after treatment with platinum-based therapy, causing restoration of HR capacity and thus conferring PARPi resistance. Accordingly, PARPi have been studied in combination with other targeted therapies to overcome PARPi resistance, enhance PARPi efficacy, and sensitize tumors to PARP inhibition. Moreover, multiple clinical trials are now actively underway to evaluate novel combinations of PARPi with other anticancer therapies for the treatment of PARPi-resistant cancer. In this review, we highlight the mechanisms of action of PARP inhibitors with or without BRCA1/2 defects and provide an overview of the ongoing clinical trials of PARPi. We also review the current progress on PARPi-based combination strategies and PARP inhibitor resistance.

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