scholarly journals Evaluation of the methods to identify patients who may benefit from PARP inhibitor use

2016 ◽  
Vol 23 (6) ◽  
pp. R267-R285 ◽  
Author(s):  
Diana Lim ◽  
Joanne Ngeow
Keyword(s):  
Anticancer Agents ◽  
Germ Line ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Predictive Biomarkers ◽  
Clinical Diagnostics ◽  
Gold Standard Method ◽  
Biomarker Testing ◽  
Molecular Aberrations ◽  
No Gold Standard

The effectiveness of poly (ADP-ribose) polymerase inhibitors (PARPi) in treating cancers associated withBRCA1/2mutations hinges upon the concept of synthetic lethality and exemplifies the principles of precision medicine. Currently, most clinical trials are recruiting patients based on pathological subtypes or have includedBRCAmutation analysis (germ line and/or somatic) as part of the selection criteria. Mounting evidence, however, suggests that these drugs may also be efficacious in tumors with defects in other genes involved in the homologous recombination repair pathway. Advances in molecular profiling techniques together with increased research efforts have led to a better understanding of the molecular aberrations underlying this BRCA-like phenotype and helped broaden the concept of BRCAness. Hence, it is likely that the list of predictive biomarkers for PARPi therapy will increase in future. There is currently no gold standard method of testing for PARPi response and no universal guidelines are in place on how to incorporate biomarker testing into routine clinical diagnostics. In this review, we explore the concept of BRCAness and highlight the different methods that have been used to identify patients who may benefit from the use of these anticancer agents. The identification of predictive biomarkers is crucial in improving patient selection and expanding the clinical applications of PARPi therapy.

scholarly journals Use of Circulating Tumour DNA (ctDNA) for Measurement of Therapy Predictive Biomarkers in Patients with Cancer

2022 ◽  
Vol 12 (1) ◽  
pp. 99
Author(s):  
Michael J. Duffy ◽  
John Crown
Keyword(s):  
Gold Standard ◽  
Kinase Inhibitors ◽  
Predictive Biomarkers ◽  
Lower Sensitivity ◽  
Cancer Therapies ◽  
Gold Standard Method ◽  
Biomarker Analysis ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Biomarker Testing ◽  
Circulating Tumour Dna

Biomarkers that predict likely response or resistance to specific therapies are critical in personalising treatment for cancer patients. Such biomarkers are now available for an increasing number of anti-cancer therapies, especially targeted therapy and immunotherapy. The gold-standard method for determining predictive biomarkers requires tumour tissue. Obtaining tissue, however, is not always possible and even if possible, the amount or quality of tissue obtained may be inadequate for biomarker analysis. Tumour DNA, however, can be released into the bloodstream, giving rise to what is referred to as circulating tumour DNA (ctDNA). In contrast to tissue, blood can be obtained from effectively all patients in a minimally invasive and safe manner. Other advantages of blood over tissue for biomarker testing include a shorter turn-around time and an ability to perform serial measurements. Furthermore, blood should provide a more complete profile of mutations present in heterogeneous tumours than a single-needle tissue biopsy. A limitation of blood vis-à-vis tissue, however, is lower sensitivity and, thus, the possibility of missing an actionable mutation. Despite this limitation, blood-based predictive biomarkers, such as mutant EGFR for predicting response to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer and mutant PIK3CA for predicting response to alpelisib in combination with fulvestrant in advanced breast cancer, may be used when tissue is unavailable. Although tissue remains the gold standard for detecting predictive biomarkers, it is likely that several further blood-based assays will soon be validated and used when tissue is unavailable or unsuitable for analysis.

scholarly journals PARP Inhibitors as a Therapeutic Agent for Homologous Recombination Deficiency in Breast Cancers

2019 ◽  
Vol 8 (4) ◽  
pp. 435 ◽  
Author(s):  
Man Keung ◽  
Yanyuan Wu ◽  
Jaydutt Vadgama
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Predictive Biomarkers ◽  
Parp Inhibitors ◽  
Homologous Recombination Deficiency ◽  
Repair Pathways

Poly (ADP-ribose) polymerases (PARPs) play an important role in various cellular processes, such as replication, recombination, chromatin remodeling, and DNA repair. Emphasizing PARP’s role in facilitating DNA repair, the PARP pathway has been a target for cancer researchers in developing compounds which selectively target cancer cells and increase sensitivity of cancer cells to other anticancer agents, but which also leave normal cells unaffected. Since certain tumors (BRCA1/2 mutants) have deficient homologous recombination repair pathways, they depend on PARP-mediated base excision repair for survival. Thus, inhibition of PARP is a promising strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Although PARP inhibitor therapy has predominantly targeted BRCA-mutated cancers, this review also highlights the growing conversation around PARP inhibitor treatment for non-BRCA-mutant tumors, those which exhibit BRCAness and homologous recombination deficiency. We provide an update on the field’s progress by considering PARP inhibitor mechanisms, predictive biomarkers, and clinical trials of PARP inhibitors in development. Bringing light to these findings would provide a basis for expanding the use of PARP inhibitors beyond BRCA-mutant breast tumors.

Phase II open-label randomized multi-centre study of neoadjuvant olaparib in patients (pts) with platinum sensitive (PS) relapsed high grade serous ovarian cancer (OC): The NEO trial.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS5608-TPS5608 ◽  
Author(s):  
Yada Kanjanapan ◽  
Stephanie Lheureux ◽  
Taymaa May ◽  
Michelle K. Wilson ◽  
Marcus Bernardini ◽  
...  
Keyword(s):  
Synthetic Lethality ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Predictive Biomarkers ◽  
Parp Inhibition ◽  
High Grade ◽  
Open Label ◽  
Fallopian Tube Cancer ◽  
Multi Centre Study ◽  
Platinum Based Chemotherapy

TPS5608 Background: Olaparib is a PARP inhibitor with clinical benefit in relapsed OC, especially in pts with germline BRCA1/2 mutation ( gBRCA). Study 19 (NCT00753545) found a progression free survival (PFS) gain from maintenance olaparib, post chemotherapy for PS relapse. Olaparib treatment in gBRCA OC pts relapsing post ≥ 3 prior chemotherapy regimens gave a response rate (RR) of 46% in the PS subgroup (Study 42; NCT01078662). Efficacy of olaparib may extend to OC with homologous recombination DNA repair pathway deficiency (HRD); susceptible to synthetic lethality from PARP inhibition. NEO [NCT02489006] is a window of opportunity study to assess tumor heterogeneity and the pharmacodynamic effects of olaparib given prior to surgery in PS OC, analyse the tumor genomic landscape pre and post olaparib, and assess for predictive biomarkers beyond BRCA mutation. Methods: This phase 2 study enrols pts with high grade serous OC, primary peritoneal or fallopian tube cancer with a progression free interval of ≥6 months and sensitive to their last line of platinum therapy. Pts must be suitable for secondary debulking surgery and agree to pre-operative tumour biopsy. All pts receive olaparib tablets 300mg po bid for 6 ± 2 weeks pre-surgery. Post-operatively, pts are randomised 1:1 to olaparib or 6 cycles of platinum-based chemotherapy followed by maintenance olaparib. The primary endpoint is the degree of PAR and PARP-1 inhibition in the blood and tumor following pre-operative olaparib in PS relapsed OC. Clinical efficacy is assessed by RR (RECIST 1.1), CA125, PFS and PFS2. Translational studies include next generation sequencing HRD panel to assess for somatic and germline mutations including RAD51B/C/D, PPM1D, FANCM, BRIP1, PALB2 and BARD1; evaluation of gene expression change in tumor tissue pre and post olaparib; assessment for resistance mechanisms and impact of heterogeneity. Circulating tumor DNA measured weekly pre-surgery is assessed for its prognostic value, alone and compared with CA125. The study will enrol 50-70 pts with estimated accrual of 3 pts/month across multiple sites, and opened at Princess Margaret Cancer Centre in 7/2016. Clinical trial information: NCT02489006.

scholarly journals XRCC1 deficient triple negative breast cancers are sensitive to ATR, ATM and Wee1 inhibitor either alone or in combination with olaparib

2020 ◽  
Vol 12 ◽  
pp. 175883592097420
Author(s):  
Reem Ali ◽  
Adel Alblihy ◽  
Michael S. Toss ◽  
Mashael Algethami ◽  
Rabab Al Sunni ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Triple Negative ◽  
Germ Line ◽  
Synthetic Lethality ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Strand Break ◽  
Breast Cancers ◽  
Single Strand Break

Background: PARP inhibitor (PARPi) monotherapy is a new strategy in BRCA germ-line deficient triple negative breast cancer (TNBC). However, not all patients respond, and the development of resistance limits the use of PARPi monotherapy. Therefore, the development of alternative synthetic lethality strategy, including in sporadic TNBC, is a priority. XRCC1, a key player in base excision repair, single strand break repair, nucleotide excision repair and alternative non-homologous end joining, interacts with PARP1 and coordinates DNA repair. ATR, ATM and Wee1 have essential roles in DNA repair and cell cycle regulation. Methods: Highly selective inhibitors of ATR (AZD6738), ATM (AZ31) and Wee1 (AZD1775) either alone or in combination with olaparib were tested for synthetic lethality in XRCC1 deficient TNBC or HeLa cells. Clinicopathological significance of ATR, ATM or Wee1 co-expression in XRCC1 proficient or deficient tumours was evaluated in a large cohort of 1650 human breast cancers. Results: ATR (AZD6738), ATM (AZ31) or Wee1 (AZD1775) monotherapy was selectively toxic in XRCC1 deficient cells. Selective synergistic toxicity was evident when olaparib was combined with AZD6738, AZ31 or AZD1775. The most potent synergistic interaction was evident with the AZD6738 and olaparib combination therapy. In clinical cohorts, ATR, ATM or Wee1 overexpression in XRCC1 deficient breast cancer was associated with poor outcomes. Conclusion: XRCC1 stratified DNA repair targeted combinatorial approach is feasible and warrants further clinical evaluation in breast cancer.

In silico discovery of novel flavonoids as poly ADP ribose polymerase (PARP) inhibitors

2020 ◽  
Vol 16 ◽  
Author(s):  
Ashish Shah ◽  
Ghanshyam Parmar ◽  
Avinash Kumar Seth
Keyword(s):  
Virtual Screening ◽  
In Silico ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Docking Studies ◽  
Docking Score ◽  
Docking Method ◽  
Anti Cancer ◽  
In Silico Toxicity

Background: The concept of synthetic lethality is emerging field in the treatment of cancer and can be applied for new drug development of cancer as it has been already represented by Poly (ADP-ribose) polymerase (PARPs) inhibitors. Objectives: In this study we performed virtual screening of 329 flavonoids obtained from Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target (NPACT) database to identify novel PARP inhibitors. Materials and methods: Virtual screening carried out using different In Silico methods which includes molecular docking studies, prediction of druglikeness and In Silico toxicity studies. Results: Fifteen out of 329 flavonoids achieved better docking score as compared to rucaparib which is an FDA approved PARP inhibitor. These 15 hits were again rescored using accurate docking mode and drug-likeliness properties were evaluated. Accuracy of docking method was checked using re-docking. Finally NPACT00183 and NPACT00280 were identified as potential PARP inhibitors with docking score of -139.237 and -129.36 respectively. These two flavonoids were also showed no AMES toxicity and no carcinogenicity which was predicted using admetSAR. Conclusion: Our finding suggests that NPACT00183 and NPACT00280 have promising potential to be further explored as PARP inhibitors.

Kinase Phosphorylation-based Mechanisms of PARP Inhibitor Resistance During Synthetic Lethal Oncotherapy

2020 ◽  
Vol 15 (1) ◽  
pp. 12-23
Author(s):  
Eriko Osaki ◽  
Shinya Mizuno
Keyword(s):  
Cancer Progression ◽  
Catalytic Domain ◽  
Synthetic Lethality ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Clinical Importance ◽  
Parp Inhibition ◽  
Special Focus ◽  
Driver Genes ◽  
Kinase Phosphorylation

Background: Poly-(ADP-Ribose) Polymerase (PARP) plays a central role in recovery from single-strand DNA (ssDNA) damage via base excision repair. When PARP activity is inhibited by a NAD+ mimetic analog, ssDNA is converted into a Double-Strand Break (DSB) during the S-phase in a cell cycle. However, the DSB site is repaired in a process of Homologous Recombination (HR) that is derived by genes such as BRCA1/2, PALB2, and RAD51. Under conditions of HR dysfunction, including mutations of BRCA1/2 (called BRCAness), PARP inhibitor (PARPi) induces “synthetic lethality” in BRCAness-specific cancer cells. Indeed, clinical trials using forms of PARPi that include olaparib, veliparib and rucaparib, have revealed that PARP inhibition produces a dramatic effect that actually arrests cancer progression. Its clinical efficiency is limited, however, due to the acquisition of PARPi resistance during long-term use of this inhibitor. Thus, it is important to elucidate the mechanisms of PARPi resistance. Methods: We searched the scientific literature published in PubMed, with a special focus on kinase phosphorylation that is involved in acquiring PARPi resistance. We also summarized the possible molecular events for recovering HR system, a key event for acquiring PARPi resistance. Results: CDK1 is a critical kinase for 5’-3’ DNA end resection, which is important for generating ssDNA for recruiting HR-priming factors. CDK12 is necessary for the transcription of HR-driver genes, such as BRCA1, BRCA2, RAD51 and ATR via the phosphorylation of RNA Pol-II. PLK-1 participates in driving HR via the phosphorylation of RAD51. The PI3K-AKT-mTOR signaling cascade is involved in BRCA1 induction via an ETS1 transcriptional pathway. Even under ATMdeficient conditions, the ATR-CHK1 axis compensates for loss in the DNA damage response, which results in HR recovery. The HGF receptor Met tyrosine kinase is responsible for promoting DNA repair by activating the PARP catalytic domain. Conclusion: These kinase-based signaling pathways are biologically important for understanding the compensatory system of HR, whereas inactivation of these kinases has shown promise for the release of PARPi resistance. Several lines of preclinical studies have demonstrated the potential use of kinase inhibitors to enhance PARPi sensitivity. We emphasize the clinical importance of chemical inhibitors as adjuvant drugs to block critical kinase activities and prevent the possible PARPi resistance.

scholarly journals HIV-1 Drug Resistance Genotyping in Resource Limited Settings: Current and Future Perspectives in Sequencing Technologies

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1125
Author(s):  
Sontaga Manyana ◽  
Lilishia Gounder ◽  
Melendhran Pillay ◽  
Justen Manasa ◽  
Kogieleum Naidoo ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Sanger Sequencing ◽  
Clinical Diagnostics ◽  
Treatment Programs ◽  
People Living With Hiv ◽  
Resource Limited Settings ◽  
Gold Standard Method ◽  
Sequencing Technologies ◽  
Resource Limited ◽  
Hiv 1

Affordable, sensitive, and scalable technologies are needed for monitoring antiretroviral treatment (ART) success with the goal of eradicating HIV-1 infection. This review discusses use of Sanger sequencing and next generation sequencing (NGS) methods for HIV-1 drug resistance (HIVDR) genotyping, focusing on their use in resource limited settings (RLS). Sanger sequencing remains the gold-standard method for detecting HIVDR mutations of clinical relevance but is mainly limited by high sequencing costs and low-throughput. NGS is becoming a more common sequencing method, with the ability to detect low-abundance drug-resistant variants and reduce per sample costs through sample pooling and massive parallel sequencing. However, use of NGS in RLS is mainly limited by infrastructure costs. Given these shortcomings, our review discusses sequencing technologies for HIVDR genotyping, focusing on common in-house and commercial assays, challenges with Sanger sequencing in keeping up with changes in HIV-1 treatment programs, as well as challenges with NGS that limit its implementation in RLS and in clinical diagnostics. We further discuss knowledge gaps and offer recommendations on how to overcome existing barriers for implementing HIVDR genotyping in RLS, to make informed clinical decisions that improve quality of life for people living with HIV.

Folate receptor: a potential target in ovarian cancer

Pteridines ◽  
2015 ◽  
Vol 26 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Marie Bartouskova ◽  
Bohuslav Melichar ◽  
Beatrice Mohelnikova-Duchonova
Keyword(s):  
Ovarian Cancer ◽  
Anticancer Agents ◽  
Poor Prognosis ◽  
Current Knowledge ◽  
Folate Receptor ◽  
Gynecological Cancer ◽  
Predictive Biomarkers ◽  
Receptor Expression ◽  
Advanced Stage ◽  
Potential Therapeutic Target

AbstractOvarian cancer is the most frequent cause of gynecological cancer-related death. Unfortunately, many patients are diagnosed at an advanced stage and have a poor prognosis. The standard treatment for advanced disease involves maximal cytoreductive surgery and chemotherapy based on platinum compounds and taxanes. Patients presenting at an advanced stage have a higher risk of recurrence. The development of drug resistance currently represents a major obstacle in the systematic treatment and, therefore, the discovery of new anticancer agents and approaches should improve the poor prognosis of these patients. Folate receptor α is overexpressed in epithelial ovarian cancer (EOC), but has limited expression in nonmalignant human tissues. The degree of folate receptor expression corresponds with the stage and grade of the disease. Because of this, folate receptor α seems to be a potential therapeutic target for the treatment of ovarian cancer. Currently, several approaches have been studied to target this protein in ovarian cancer treatment. This review summarizes current knowledge about the potential usage of folate receptors as prognostic and predictive biomarkers as well as their role in the management and targeted therapy of ovarian cancer.

scholarly journals Predictors and Modulators of Synthetic Lethality: An Update on PARP Inhibitors and Personalized Medicine

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Stephen Murata ◽  
Catherine Zhang ◽  
Nathan Finch ◽  
Kevin Zhang ◽  
Loredana Campo ◽  
...  
Keyword(s):  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Advanced Ovarian Cancer ◽  
Parp Inhibitors ◽  
Damage Repair ◽  
Trial Testing ◽  
United States Food ◽  
States Food ◽  
And Personalized Medicine ◽  
Inhibitor Treatment

Poly(ADP-ribose) polymerase (PARP) inhibitors have proven to be successful agents in inducing synthetic lethality in several malignancies. Several PARP inhibitors have reached clinical trial testing for treatment in different cancers, and, recently, Olaparib (AZD2281) has gained both United States Food and Drug Administration (USFDA) and the European Commission (EC) approval for use inBRCA-mutated advanced ovarian cancer treatment. The need to identify biomarkers, their interactions in DNA damage repair pathways, and their potential utility in identifying patients who are candidates for PARP inhibitor treatment is well recognized. In this review, we detail many of the biomarkers that have been investigated for their ability to predict both PARP inhibitor sensitivity and resistance in preclinical studies as well as the results of several clinical trials that have tested the safety and efficacy of different PARP inhibitor agents inBRCAand non-BRCA-mutated cancers.

scholarly journals Tissue Microarray from Cell Block Material (cbTMA)—An Additional Shot for Cytology in the Predictive Pathology Era: The PD-L1 Experience

2022 ◽  
Vol 3 (1) ◽  
pp. 15-23
Author(s):  
Antonino Iaccarino ◽  
Gennaro Acanfora ◽  
Pasquale Pisapia ◽  
Umberto Malapelle ◽  
Claudio Bellevicine ◽  
...  
Keyword(s):  
Tissue Microarray ◽  
Large Scale ◽  
Metastatic Lymph Node ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Observer Agreement ◽  
Cell Block ◽  
Multicenter Studies ◽  
Ffpe Samples ◽  
Biomarker Testing

Generally, predictive biomarker tests are clinically validated on histological formalin-fixed, paraffin-embedded (FFPE) samples. In addition to FFPE samples, cytological samples have also emerged as a useful approach to detect predictive biomarkers. However, as of today, despite the promising results reported in the recent literature, their full implementation in routine clinical practice is still lagging owing to a lack of standardized preparatory protocols, challenging assessments of cyto-histological correlation, and variable inter-observer agreement. The aim of this report was to explore the possibility of implementing a large-scale validation of predictive biomarker testing on cytological material. To this aim, we evaluated the technical feasibility of PD-L1 assessment on a cell block (CB)-derived tissue microarray (cbTMA). Consecutive and unselected CBs prepared from metastatic lymph node fine-needle cytology (FNC) samples were retrospectively collected and used for TMA construction. PD-L1 immunohistochemistry (IHC) was carried out on cbTMA sections with the companion diagnostic kit SP263 assay. TMA contained 33 CB-derived cores. A total of 20 sections were hematoxylin and eosin (H&E) stained. Overall, 29 (88%) samples were visible at least in one H&E-stained slide. Four cases out of five sections stained with the SP263 assay (4/29, 13.8%) showed PD-L1 positivity in neoplastic and/or immune cells; remarkably, no unspecific background was observed. Although our study was based on a limited and non-selected series, our findings do provide proof of concept for the use of cbTMA in predictive biomarker testing on cytological material in large-scale post-clinical trial validation studies, multicenter studies, and quality control programs.

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