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https://www.readbyqxmd.com/read/29138572/current-status-of-poly-adp-ribose-polymerase-inhibitors-and-future-directions
#1
REVIEW
Akihiro Ohmoto, Shinichi Yachida
Inhibitors of poly(ADP-ribose) polymerases (PARPs), which play a key role in DNA damage/repair pathways, have been developed as antitumor agents based on the concept of synthetic lethality. Synthetic lethality is the idea that cell death would be efficiently induced by simultaneous loss of function of plural key molecules, for example, by exposing tumor cells with inactivating gene mutation of BRCA-mediated DNA repair to chemically induced inhibition of PARPs. Indeed, three PARP inhibitors, olaparib, rucaparib and niraparib have already been approved in the US or Europe, mainly for the treatment of BRCA-mutant ovarian cancer...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29054544/-abnormalities-of-dna-repair-and-gynecological-cancers
#2
REVIEW
Aurélie Auguste, Alexandra Leary
The demonstration of frequent defects in the DNA damage response in high grade ovarian cancer has paved the way for a new therapeutic approach aimed at exploiting this unique vulnerability. The efficacy of poly (ADP) ribose polymerase inhibitors (PARPi) in patients with homologous recombination (HR) DNA repair deficient ovarian cancer (OC) resulting from a BRCA1/2 mutation has provided the proof of concept for synthetic lethality. Thus, olaparib is now approved by the EMA as maintenance therapy after response to a platinum regimen for patients with recurrent, platinum-sensitive, high-grade serous, BRCA1/2-mutated ovarian cancer...
October 17, 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/29037805/tolerance-and-toxicity-of-the-parp-inhibitor-olaparib-in-older-women-with-epithelial-ovarian-cancer
#3
Lauren E Dockery, William P Tew, Kai Ding, Kathleen N Moore
OBJECTIVES: The objective of this study was to determine the overall tolerability and toxicity of olaparib capsules among older (≥65years) patients with recurrent ovarian cancer treated on 8 completed prospective trials of olaparib. METHODS: An ancillary data analysis of 398 patients with recurrent ovarian cancer enrolled on eight prospective trials of olaparib capsules was performed. Patients aged 65years and older were stratified into age groups by 5year increments (ages 65-69, 70-74, ≥75years) and compared to those <65...
October 13, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28994564/targeted-therapy-for-ovarian-cancer-the-rapidly-evolving-landscape-of-parp-inhibitor-use
#4
Christine Walsh
INTRODUCTION: PARP (poly(ADP-ribose) polymerase) inhibitors are a targeted therapy option for ovarian cancer. The goal of this review was to organize and summarize the clinical trials evaluating PARP inhibitor therapy in ovarian cancer as monotherapy, maintenance therapy after partial or complete remission to therapy or as a part of a combination regimen. EVIDENCE ACQUISITION: PubMed, ClinicalTrials.gov, data from the United States Food and Drug Administration (US FDA) and proceedings from scientific conferences were searched for published and unpublished data pertaining to clinical trials and approvals of PARP inhibitor use in ovarian cancer...
October 9, 2017: Minerva Ginecologica
https://www.readbyqxmd.com/read/28829762/characterisation-of-the-novel-deleterious-rad51c-p-arg312trp-variant-and-prioritisation-criteria-for-functional-analysis-of-rad51c-missense-changes
#5
Javier Gayarre, Paloma Martín-Gimeno, Ana Osorio, Beatriz Paumard, Alicia Barroso, Victoria Fernández, Miguel de la Hoya, Alejandro Rojo, Trinidad Caldés, José Palacios, Miguel Urioste, Javier Benítez, María J García
BACKGROUND: Despite a high prevalence of deleterious missense variants, most studies of RAD51C ovarian cancer susceptibility gene only provide in silico pathogenicity predictions of missense changes. We identified a novel deleterious RAD51C missense variant (p.Arg312Trp) in a high-risk family, and propose a criteria to prioritise RAD51C missense changes qualifying for functional analysis. METHODS: To evaluate pathogenicity of p.Arg312Trp variant we used sequence homology, loss of heterozygosity (LOH) and segregation analysis, and a comprehensive functional characterisation...
September 26, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28823141/targeted-therapy-of-ovarian-cancer-including-immune-check-point-inhibitor
#6
REVIEW
Jin Young Kim, Chi Heum Cho, Hong Suk Song
Epithelial ovarian cancer is the eighth most common cause of cancer-related deaths in women because most patients present with advanced stage disease at the time of diagnosis. Although cytoreductive surgery and platinum-based chemotherapy remain the gold standards of treatment, the recurrence rate of ovarian cancer remains high. Attempts to improve this standard two-drug chemotherapy by adding a third cytotoxic drug have failed to affect either progression-free survival or overall survival and have resulted in an increase in toxic side effects...
September 2017: Korean Journal of Internal Medicine
https://www.readbyqxmd.com/read/28812596/targeted-therapies-solo2-confirms-olaparib-maintenance-in-ovarian-cancer
#7
Lisa Hutchinson
No abstract text is available yet for this article.
October 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/28780754/fda-approval-of-parp-inhibitors-and-the-impact-on-genetic-counseling-and-genetic-testing-practices
#8
Kathryn M Buchtel, Kristen J Vogel Postula, Shelly Weiss, Carmen Williams, Mario Pineda, Scott M Weissman
In December 2014, the FDA approved olaparib, a poly(ADP-ribose) polymerase inhibitor (PARPi) for ovarian cancer patients who have failed three or more lines of chemotherapy and have a germline BRCA1/2 mutation identified through a companion diagnostic test (BRACAnalysis CDx™ (CDx™)) offered exclusively by Myriad Genetic Laboratories. This study explored the impact of PARPi/CDx™ on genetic counselors' (GCs) counseling and testing practices. One hundred twenty three GCs responded to an online survey regarding pre- and post-FDA approval referral patterns, testing strategies/influences, and anecdotal experiences with insurance coverage of PARPi for BRCA1/2 positive patients through a non-CDx™ platform...
August 5, 2017: Journal of Genetic Counseling
https://www.readbyqxmd.com/read/28770827/discovery-of-potent-2-4-difluoro-linker-poly-adp-ribose-polymerase-1-inhibitors-with-enhanced-water-solubility-and-in-vivo-anticancer-efficacy
#9
Wen-Hua Chen, Shan-Shan Song, Ming-Hui Qi, Xia-Juan Huan, Ying-Qing Wang, Hualiang Jiang, Jian Ding, Guo-Bin Ren, Ze-Hong Miao, Jian Li
Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially in breast and ovarian cancers; tumor cells that are deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, we identified a series of 2,4-difluorophenyl-linker analogs (15-55) derived from olaparib as novel PARP1 inhibitors. Four potent analogs 17, 43, 47, and 50 (IC50=2.2-4.4 nmol/L) effectively inhibited the proliferation of Chinese hamster lung fibroblast V-C8 cells (IC50=3...
November 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28756516/synthetic-lethality-in-malignant-pleural-mesothelioma-with-parp1-inhibition
#10
Gayathri Srinivasan, Gurjit Singh Sidhu, Elizabeth A Williamson, Aruna S Jaiswal, Nasreen Najmunnisa, Keith Wilcoxen, Dennie Jones, Thomas J George, Robert Hromas
Malignant pleural mesotheliomas (MPM) are most often surgically unresectable, and they respond poorly to current chemotherapy and radiation therapy. Between 23 and 64% of malignant pleural mesothelioma have somatic inactivating mutations in the BAP1 gene. BAP1 is a homologous recombination (HR) DNA repair component found in the BRCA1/BARD1 complex. Similar to BRCA1/2 deficient cancers, mutation in the BAP1 gene leads to a deficient HR pathway and increases the reliance on other DNA repair pathways. We hypothesized that BAP1-mutant MPM would require PARP1 for survival, similar to the BRCA1/2 mutant breast and ovarian cancers...
October 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28754483/olaparib-tablets-as-maintenance-therapy-in-patients-with-platinum-sensitive-relapsed-ovarian-cancer-and-a-brca1-2-mutation-solo2-engot-ov21-a-double-blind-randomised-placebo-controlled-phase-3-trial
#11
RANDOMIZED CONTROLLED TRIAL
Eric Pujade-Lauraine, Jonathan A Ledermann, Frédéric Selle, Val Gebski, Richard T Penson, Amit M Oza, Jacob Korach, Tomasz Huzarski, Andrés Poveda, Sandro Pignata, Michael Friedlander, Nicoletta Colombo, Philipp Harter, Keiichi Fujiwara, Isabelle Ray-Coquard, Susana Banerjee, Joyce Liu, Elizabeth S Lowe, Ralph Bloomfield, Patricia Pautier
BACKGROUND: Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, has previously shown efficacy in a phase 2 study when given in capsule formulation to all-comer patients with platinum-sensitive, relapsed high-grade serous ovarian cancer. We aimed to confirm these findings in patients with a BRCA1 or BRCA2 (BRCA1/2) mutation using a tablet formulation of olaparib. METHODS: This international, multicentre, double-blind, randomised, placebo-controlled, phase 3 trial evaluated olaparib tablet maintenance treatment in platinum-sensitive, relapsed ovarian cancer patients with a BRCA1/2 mutation who had received at least two lines of previous chemotherapy...
September 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28747513/repression-of-bet-activity-sensitizes-homologous-recombination-proficient-cancers-to-parp-inhibition
#12
Lu Yang, Youyou Zhang, Weiwei Shan, Zhongyi Hu, Jiao Yuan, Jingjiang Pi, Yueying Wang, Lingling Fan, Zhaoqing Tang, Chunsheng Li, Xiaowen Hu, Janos L Tanyi, Yi Fan, Qihong Huang, Kathleen Montone, Chi V Dang, Lin Zhang
Strategies to enhance response to poly(adenosine diphosphate-ribose) polymerase inhibitor (PARPi) in primary and acquired homologous recombination (HR)-proficient tumors would be a major advance in cancer care. We used a drug synergy screen that combined a PARPi, olaparib, with 20 well-characterized epigenetic drugs and identified bromodomain and extraterminal domain inhibitors (BETis; JQ1, I-BET762, and OTX015) as drugs that acted synergistically with olaparib in HR-proficient cancer cells. Functional assays demonstrated that repressed BET activity reduces HR and thus enhances PARPi-induced DNA damage in cancer cells...
July 26, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28706762/metastatic-breast-cancer-with-brca-mutation-discovered-by-next-generation-sequencing-responding-to-olaparib
#13
Wajeeha Rizvi, Phu Truong, Quoc Truong
Breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) mutations are associated with hereditary breast and ovarian cancer syndromes (HBOC). However, certain individuals with breast cancer do not meet high-risk factors for hereditary breast cancer screening based on age, family history, and biology of malignancy. We present a patient with relapsed breast cancer who developed progressive disease with significant tumor burden causing a recurrent pleural effusion. Next-generation sequencing (NGS) done on a tumor biopsy was positive for the BRCA2 mutation...
June 11, 2017: Curēus
https://www.readbyqxmd.com/read/28695500/quantification-of-parp-activity-in-human-tissues-ex-vivo-assays-in-blood-cells-and-immunohistochemistry-in-human-biopsies
#14
Eszter M Horvath, Zsuzsanna K Zsengellér, Csaba Szabo
Poly(ADP-ribosyl)ation of proteins is a posttranslational modification mediated by poly(ADP-ribose) polymerases (PARPs) that use NAD(+) as substrate to form the negatively charged polymer of poly(ADP-ribose) (PAR). After DNA damage, PARP-1 is responsible for approximately 90% of the total cellular PARylation activity. Numerous studies showed activation of PARP-1 in various conditions associated with oxidative and nitrosative stress, such as ischemia-reperfusion injury, diabetes mellitus, and inflammation, and also proved the beneficial effects of PARP inhibitors...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28692916/discovery-mechanism-and-metabolism-studies-of-2-3-difluorophenyl-linker-containing-parp1-inhibitors-with-enhanced-in%C3%A2-vivo-efficacy-for-cancer-therapy
#15
Wenhua Chen, Ne Guo, Minghui Qi, Haiying Dai, Minghuang Hong, Longfei Guan, Xiajuan Huan, Shanshan Song, Jinxue He, Yingqing Wang, Yong Xi, Xinying Yang, Yanyan Shen, Yi Su, Yiming Sun, Yinglei Gao, Yi Chen, Jian Ding, Yun Tang, Guobin Ren, Zehong Miao, Jian Li
Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially breast and ovarian cancers, and tumor cell lines deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, with the help of molecular docking, we identified a novel series of 2,3-difluorophenyl-linker analogues (15-54) derived from olaparib (1) as PARP1 inhibitors. Lead optimization led to the identification of 47, which showed high selectivity and high potency against PARP1 enzyme (IC50 = 1...
September 29, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28631775/-innovations-in-the-treatment-of-ovarian-cancer-analysis-of-the-therapeutic-development-from-platinum-to-immunotherapy
#16
Gesuino Angius, Pierangela Sepe, Anselmo Papa, Silverio Tomao, Federica Tomao
Ovarian cancer is the seventh most common cancer in women. The therapeutic approach provides for an appropriate integration between surgery and chemotherapy. Surgery is an important step for diagnosis, staging and therapy, aiming at the complete cytoreduction of all macroscopic visible disease. At the moment, adjuvant and first-line chemotherapy has as a standard the carboplatin-paclitaxel combination. Further, the addition of bevacizumab in the advanced stage (IIIB-IV) is strongly recommended. Despite the initial effectiveness, however, 70-80% of patients develop relapsed disease within the first two years and require subsequent treatment lines that have palliative, rather than curative purposes and that seek to reach a chronic state for the disease...
June 2017: Recenti Progressi in Medicina
https://www.readbyqxmd.com/read/28626402/effect-of-the-combination-of-trabectedin-and-pegylated-liposomal-doxorubicin-in-a-brca2-mutation-carrier-with-recurrent-platinum-sensitive-ovarian-cancer
#17
María Jesús Rubio Pérez
INTRODUCTION: The current standard of care for ovarian cancer is optimal cytoreduction with adjuvant chemotherapy based on a platinum/taxane combination. Although the response rate to this therapy is high, most patients ultimately relapse. Response to second-line therapy and prognosis are linked to the platinum-free interval (PFI); when both improve, the PFI increases. As a result, there is an increasing interest in the PFI extension strategies including platinum-free combinations. CASE PRESENTATION: A 50-year-old postmenopausal woman presented with ovarian serous carcinoma with peritoneal carcinomatosis...
May 2017: Case Reports in Oncology
https://www.readbyqxmd.com/read/28625312/traitement-des-rechutes-tardives-du-cancer-de-l%C3%A2-ovaire
#18
Anne Floquet, Dominique Berton-Rigaud, Gwenael Ferron, Gilles Freyer, Anne Claire Hardy-Bessard, Benoit You
Despite large improvements in treatment efficacy, the cure rate of ovarian cancer has not radically changed. Relapses both remain frequent and are still synonymous with chronic disease. Most of them are platinum-sensitive, and can be successfully treated with successive lines of chemotherapy. Surgery may have a role to play but its real impact, population selection criteria, and adequate timing still have to be established. Regarding medical treatments, the availability of new targeted therapeutics, such as bevacizumab and olaparib, complicates decision making...
May 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/28625311/cancers-de-l%C3%A2-ovaire-brca-mut%C3%A3-consultation-d%C3%A2-oncog%C3%A3-n%C3%A3-tique-et-prescription-des-inhibiteurs-de-parp
#19
Laurence Gladieff, Dominique Stoppa Lyonnet, Alain Lortholary, Alexandra Leary, Catherine Genestie, Isabelle Ray-Coquard
GENETIC COUNSELING AND PARP INHIBITORS PRESCRIPTION: Upon the availability of the PARP inhibitors in relapsed ovarian carcinoma, the pathways of the oncogenetic counseling were modified. Any research for a constitutional alteration of the BRCA1 and BRCA2 genes must be accompanied by an oncogenetic counseling. BRCA testing is recommended from the diagnosis to every woman with an ovarian or fallopian tube or peritoneum of high grade adenocarcinoma, whatever the age at the diagnosis and her family history. In case of sensitive relapse or potential inclusion in a clinical trial and in the absence of preliminary constitutional research, the oncogenetic counseling is organized according to a fast track pathway and a somatic analysis can be realized in parallel...
May 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/28604461/chemosensitivity-of-brca1-mutated-ovarian-cancer-cells-and-established-cytotoxic-agents
#20
Caroline van Haaften, Jaap van Eendenburg, Arnoud Boot, Willem E Corver, Lucien Haans, Tom van Wezel, J Baptist Trimbos
OBJECTIVE: Serous adenocarcinomas that arise in patients with inherited mutations in the tumor suppressor genes BRCA1 and BRCA2 are initially well treatable with platinum/paclitaxel. For recurrent disease in patients with BRCA1 or BRCA2 mutations, olaparib treatment is available. To study additional therapeutic regimens, a better understanding of the cellular and molecular mechanisms of the tumors in in vitro models is important. METHODS/MATERIALS: From a high-grade serous ovarian tumor of a BRCA1 mutation carrier, we established 3 distinct cell line subclones, OVCA-TR3...
June 10, 2017: International Journal of Gynecological Cancer
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