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https://www.readbyqxmd.com/read/29731958/main-implications-related-to-the-switch-to-brca-1-2-tumor-testing-in-ovarian-cancer-patients-a-proposal-of-a-consensus
#1
Ettore Capoluongo, Giovanni Scambia, Jean-Marc Nabholtz
Background: Since the approval of the first poly (adenosine diphosphate [ADP]) ribose polymerase inhibitor (PARPi; olaparib [Lynparza™]) for platinum-sensitive relapsed high grade ovarian cancer, with either germline or somatic BRCA1/2 deleterious variants, the strategies for BRCA1/2 are dynamically changing. Along with germline testing within the context of familial or sporadic ovarian cancer, patients are now being referred for BRCA1/2 genetic assay above all for treatment decisions: in this setting tumour BRCA assay can allow to identify an estimated 3-9% of patients with peculiar somatic BRCA1/2 mutations...
April 13, 2018: Oncotarget
https://www.readbyqxmd.com/read/29582690/olaparib-for-the-treatment-of-breast-cancer
#2
Gaia Griguolo, Maria Vittoria Dieci, Valentina Guarneri, PierFranco Conte
Mutations in BRCA1 and BRCA2 genes account for around 2-3% of breast cancer events and more than 10% of triple negative breast cancers. Olaparib (Lynparza®), an orally administered PARP inhibitor, demonstrated clinical benefit in a phase III trial for mutated BRCA-positive HER2 negative metastatic breast cancer. Areas covered: This review gives an overview of available preclinical and clinical data regarding olaparib, including its chemistry, mechanism of action, pharmacokinetics and pharmacodynamics, and evidence supporting antitumor efficacy and safety profile in breast cancer patients...
June 2018: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/29572254/parp1-targeted-radiotherapy-in-mouse-models-of-glioblastoma
#3
Stephen A Jannetti, Giuseppe Carlucci, Brandon Carney, Susanne Kossatz, Larissa Shenker, Lukas M Carter, Beatriz Salinas, Christian Brand, Ahmad Sadique, Patrick L Donabedian, Kristen M Cunanan, Mithat Gönen, Vladimir Ponomarev, Brian M Zeglis, Mark M Souweidane, Jason S Lewis, Wolfgang A Weber, John L Humm, Thomas Reiner
The DNA repair enzyme PARP1 is over-expressed in glioblastoma, with overall low expression in healthy brain tissue. Paired with the availability of specific molecularly targeted small molecules for this biomarker, PARP1 is a near-ideal target for novel radiotherapeutics. A successful PARP1-targeted radiotherapeutic would induce DNA damage and apoptosis in cancer cells, while sparing healthy brain tissue. We synthesized a 131 I-labeled poly(ADP-ribose) polymerase 1 (PARP1) therapeutic and investigated its pharmacology using in vitro and in vivo methodologies...
March 23, 2018: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/29248130/guidance-statement-on-brca1-2-tumor-testing-in-ovarian-cancer-patients
#4
REVIEW
Ettore Capoluongo, Gillian Ellison, José Antonio López-Guerrero, Frederique Penault-Llorca, Marjolijn J L Ligtenberg, Susana Banerjee, Christian Singer, Eitan Friedman, Birgid Markiefka, Peter Schirmacher, Reinhard Büttner, Christi J van Asperen, Isabelle Ray-Coquard, Volker Endris, Suzanne Kamel-Reid, Natalie Percival, Jane Bryce, Benno Röthlisberger, Richie Soong, David Gonzalez de Castro
The approval, in 2015, of the first poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi; olaparib, Lynparza) for platinum-sensitive relapsed high-grade ovarian cancer with either germline or somatic BRCA1/2 deleterious mutations is changing the way that BRCA1/2 testing services are offered to patients with ovarian cancer. Ovarian cancer patients are now being referred for BRCA1/2 genetic testing for treatment decisions, in addition to familial risk estimation, and irrespective of a family history of breast or ovarian cancer...
June 2017: Seminars in Oncology
https://www.readbyqxmd.com/read/28213892/opportunities-for-the-repurposing-of-parp-inhibitors-for-the-therapy-of-non-oncological-diseases
#5
REVIEW
Nathan A Berger, Valerie C Besson, A Hamid Boulares, Alexander Bürkle, Alberto Chiarugi, Robert S Clark, Nicola J Curtin, Salvatore Cuzzocrea, Ted M Dawson, Valina L Dawson, György Haskó, Lucas Liaudet, Flavio Moroni, Pál Pacher, Peter Radermacher, Andrew L Salzman, Solomon H Snyder, Francisco Garcia Soriano, Robert P Strosznajder, Balázs Sümegi, Raymond A Swanson, Csaba Szabo
The recent clinical availability of the PARP inhibitor olaparib (Lynparza) opens the door for potential therapeutic repurposing for non-oncological indications. Considering (a) the preclinical efficacy data with PARP inhibitors in non-oncological diseases and (b) the risk-benefit ratio of treating patients with a compound that inhibits an enzyme that has physiological roles in the regulation of DNA repair, we have selected indications, where (a) the severity of the disease is high, (b) the available therapeutic options are limited, and (c) the duration of PARP inhibitor administration could be short, to provide first-line options for therapeutic repurposing...
January 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/27931843/parp-inhibitor-combination-therapy
#6
REVIEW
Amy Dréan, Christopher J Lord, Alan Ashworth
In 2014, olaparib (Lynparza) became the first PARP (Poly(ADP-ribose) polymerase) inhibitor to be approved for the treatment of cancer. When used as single agents, PARP inhibitors can selectively target tumour cells with BRCA1 or BRCA2 tumour suppressor gene mutations through synthetic lethality. However, PARP inhibition also shows considerable promise when used together with other therapeutic agents. Here, we summarise both the pre-clinical and clinical evidence for the utility of such combinations and discuss the future prospects and challenges for PARP inhibitor combinatorial therapies...
December 2016: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/27821315/current-perspectives-on-recommendations-for-brca-genetic-testing-in-ovarian-cancer-patients
#7
REVIEW
Ignace Vergote, Susana Banerjee, Anne-Marie Gerdes, Christi van Asperen, Christian Marth, Fatima Vaz, Isabelle Ray-Coquard, Dominique Stoppa-Lyonnet, Antonio Gonzalez-Martin, Jalid Sehouli, Nicoletta Colombo
Traditionally, BRCA genetic testing has been undertaken to identify patients and family members at future risk of developing cancer and patients have been referred for testing based on family history. However, the now recognised risk of ovarian cancer (OC) patients, even those with no known family history, harbouring a mutation in BRCA1/2, together with the first poly adenosine diphosphate ribose polymerase inhibitor (PARPi; olaparib [Lynparza]) being licenced for the treatment of BRCA-mutated OC, has led to reconsideration of referral criteria for OC patients...
December 2016: European Journal of Cancer
https://www.readbyqxmd.com/read/27705909/parp1-inhibitor-olaparib-lynparza-exerts-synthetic-lethal-effect-against-ligase-4-deficient-melanomas
#8
Małgorzata Czyż, Monika Toma, Anna Gajos-Michniewicz, Kinga Majchrzak, Grazyna Hoser, Janusz Szemraj, Margaret Nieborowska-Skorska, Phil Cheng, Daniel Gritsyuk, Mitchell Levesque, Reinhard Dummer, Tomasz Sliwinski, Tomasz Skorski
Cancer including melanoma may be ''addicted" to double strand break (DSB) repair and targeting this process could sensitize them to the lethal effect of DNA damage. PARP1 exerts an important impact on DSB repair as it binds to both single- and double- strand breaks. PARP1 inhibitors might be highly effective drugs triggering synthetic lethality in patients whose tumors have germline or somatic defects in DNA repair genes. We hypothesized that PARP1-dependent synthetic lethality could be induced in melanoma cells displaying downregulation of DSB repair genes...
November 15, 2016: Oncotarget
https://www.readbyqxmd.com/read/27422301/safety-and-tolerability-of-the-olaparib-tablet-formulation-in-japanese-patients-with-advanced-solid-tumours
#9
MULTICENTER STUDY
Kan Yonemori, Kenji Tamura, Makoto Kodaira, Koshi Fujikawa, Tamotsu Sagawa, Taito Esaki, Tsuyoshi Shirakawa, Fumihiko Hirai, Yuki Yokoi, Toshio Kawata, Ben Hatano, Yasuo Takahashi
PURPOSE: This was the first Phase I study to assess the safety and tolerability of the tablet formulation of olaparib (Lynparza™), an oral poly(ADP-ribose) polymerase inhibitor, in Japanese patients with advanced solid tumours. The pharmacokinetic profile and antitumour activity of olaparib tablets were also assessed. METHODS: In this open-label, multicentre study (D081BC00001; NCT01813474), a single dose of olaparib (200 or 300 mg, tablets) was administered on day 1, followed 48 h afterwards by multiple dosing (200 or 300 mg twice daily [bid]) for 28-day cycles...
September 2016: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/27385701/olaparib-for-the-treatment-of-brca-mutated-advanced-ovarian-cancer
#10
REVIEW
Marklie Munroe, Jill Kolesar
PURPOSE: The pharmacology, clinical efficacy, safety, dosage and administration, and role in therapy of olaparib, a first-in-class treatment for advanced treatment-refractory ovarian cancer, are reviewed. SUMMARY: Olaparib (Lynparza, AstraZeneca) is an oral inhibitor of poly(ADP-ribose) polymerase (PARP) proteins that play a key role in DNA repair and genomic stability. Olaparib is indicated for use in treating certain patients with advanced, recurrent ovarian cancer who have mutations of the breast cancer 1 gene (BRCA1) or breast cancer 2 gene (BRCA2)...
July 15, 2016: American Journal of Health-system Pharmacy: AJHP
https://www.readbyqxmd.com/read/27267353/incorporating-parp-inhibitors-into-clinical-routine-a-tailored-treatment-strategy-to-tackle-ovarian-cancer
#11
REVIEW
E De Jaeghere, K Vandecasteele, K Claes, A Makar, P Tummers, V Cocquyt, Hannelore Denys
DNA repair mechanisms play a key role in oncogenesis and cancer progression in women with BRCA mutation-positive (BRCAm) ovarian cancer (OC). The BRCA1/2 and poly(ADP-ribose) polymerase (PARP) proteins are considered the foremost mediators among the various components of double-strand and single-strand repair, respectively. A series of new therapeutic drugs that target PARP have been developed for BRCAm OC. This class of agents provokes tumour-specific cytotoxicity with minimal side effects by inducing synthetic lethality, of which they are the first clinical example...
February 2017: Acta Clinica Belgica
https://www.readbyqxmd.com/read/27062051/olaparib-maintenance-therapy-in-patients-with-platinum-sensitive-relapsed-serous-ovarian-cancer-and-a-brca-mutation-overall-survival-adjusted-for-postprogression-poly-adenosine-diphosphate-ribose-polymerase-inhibitor-therapy
#12
RANDOMIZED CONTROLLED TRIAL
Ursula A Matulonis, Philipp Harter, Charlie Gourley, Michael Friedlander, Ignace Vergote, Gordon Rustin, Clare Scott, Werner Meier, Ronnie Shapira-Frommer, Tamar Safra, Daniela Matei, Anitra Fielding, Stuart Spencer, David Parry, Lynda Grinsted, Jonathan A Ledermann
BACKGROUND: Maintenance treatment with the oral poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor olaparib (Lynparza) in Study 19 (study number, D0810C00019; ClinicalTrials.gov identifier, NCT00753545) significantly improved progression-free survival in comparison with a placebo for patients with platinum-sensitive, relapsed serous ovarian cancer with a BRCA1/2 mutation (BRCAm), but an interim analysis revealed no statistically significant overall survival (OS) benefit. However, 23% of the patients receiving the placebo switched to a PARP inhibitor after progression...
June 15, 2016: Cancer
https://www.readbyqxmd.com/read/26961146/olaparib-monotherapy-in-patients-with-advanced-relapsed-ovarian-cancer-and-a-germline-brca1-2-mutation-a-multistudy-analysis-of-response-rates-and-safety
#13
U A Matulonis, R T Penson, S M Domchek, B Kaufman, R Shapira-Frommer, M W Audeh, S Kaye, L R Molife, K A Gelmon, J D Robertson, H Mann, T W Ho, R L Coleman
BACKGROUND: The PARP inhibitor olaparib (Lynparza™) demonstrates antitumor activity in women with relapsed ovarian cancer and a germline BRCA1/2 mutation (gBRCAm). Data from olaparib monotherapy trials were used to explore the treatment effect of olaparib in patients with gBRCAm ovarian cancer who had received multiple lines of prior chemotherapy. PATIENTS AND METHODS: This analysis evaluated pooled data from two phase I trials [NCT00516373 (study 2); NCT00777582 (study 24)] and four phase II trials [NCT00494442 (study 9); NCT00628251 (study 12); NCT00679783 (study 20); NCT01078662 (study 42)] that recruited women with relapsed ovarian, fallopian tube or peritoneal cancer...
June 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/26938702/olaparib-lynparza-for-advanced-ovarian-cancer
#14
REVIEW
(no author information available yet)
No abstract text is available yet for this article.
February 29, 2016: Medical Letter on Drugs and Therapeutics
https://www.readbyqxmd.com/read/26779812/blocking-c-met-mediated-parp1-phosphorylation-enhances-anti-tumor-effects-of-parp-inhibitors
#15
Yi Du, Hirohito Yamaguchi, Yongkun Wei, Jennifer L Hsu, Hung-Ling Wang, Yi-Hsin Hsu, Wan-Chi Lin, Wen-Hsuan Yu, Paul G Leonard, Gilbert R Lee, Mei-Kuang Chen, Katsuya Nakai, Ming-Chuan Hsu, Chun-Te Chen, Ye Sun, Yun Wu, Wei-Chao Chang, Wen-Chien Huang, Chien-Liang Liu, Yuan-Ching Chang, Chung-Hsuan Chen, Morag Park, Philip Jones, Gabriel N Hortobagyi, Mien-Chie Hung
Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapeutics for many diseases, including cancer, in clinical trials. One PARP inhibitor, olaparib (Lynparza, AstraZeneca), was recently approved by the FDA to treat ovarian cancer with mutations in BRCA genes. BRCA1 and BRCA2 have essential roles in repairing DNA double-strand breaks, and a deficiency of BRCA proteins sensitizes cancer cells to PARP inhibition. Here we show that the receptor tyrosine kinase c-Met associates with and phosphorylates PARP1 at Tyr907 (PARP1 pTyr907 or pY907)...
February 2016: Nature Medicine
https://www.readbyqxmd.com/read/26669452/the-development-of-parp-inhibitors-in-ovarian-cancer-from-bench-to-bedside
#16
REVIEW
Yvette Drew
The nuclear enzyme poly (ADP-ribose) polymerase (PARP) represents an important novel target in the treatment of ovarian cancer. This article charts over 50 years of research from the discovery of the first PARP enzyme in 1963, to the approval and licensing in 2015 of the first PARP inhibitor, olaparib (Lynparza), in the treatment of BRCA-mutated ovarian cancer.
December 15, 2015: British Journal of Cancer
https://www.readbyqxmd.com/read/26590714/targeting-the-dna-damage-response-in-cancer
#17
REVIEW
Mark J O'Connor
An underlying hallmark of cancers is their genomic instability, which is associated with a greater propensity to accumulate DNA damage. Historical treatment of cancer by radiotherapy and DNA-damaging chemotherapy is based on this principle, yet it is accompanied by significant collateral damage to normal tissue and unwanted side effects. Targeted therapy based on inhibiting the DNA damage response (DDR) in cancers offers the potential for a greater therapeutic window by tailoring treatment to patients with tumors lacking specific DDR functions...
November 19, 2015: Molecular Cell
https://www.readbyqxmd.com/read/26424664/concepts-and-molecular-aspects-in-the-polypharmacology-of-parp-1-inhibitors
#18
REVIEW
Daniela Passeri, Emidio Camaioni, Paride Liscio, Paola Sabbatini, Martina Ferri, Andrea Carotti, Nicola Giacchè, Roberto Pellicciari, Antimo Gioiello, Antonio Macchiarulo
Recent years have witnessed a renewed interest in PARP-1 inhibitors as promising anticancer agents with multifaceted functions. Particularly exciting developments include the approval of olaparib (Lynparza) for the treatment of refractory ovarian cancer in patients with BRCA1/2 mutations, and the increasing understanding of the polypharmacology of PARP-1 inhibitors. The aim of this review article is to provide the reader with a comprehensive overview of the distinct levels of the polypharmacology of PARP-1 inhibitors, including 1) inter-family polypharmacology, 2) intra-family polypharmacology, and 3) multi-signaling polypharmacology...
June 20, 2016: ChemMedChem
https://www.readbyqxmd.com/read/26292709/bracanalysis-cdx-as-a-companion-diagnostic-tool-for-lynparza
#19
REVIEW
Camille C Gunderson, Kathleen N Moore
Lynparza and its companion diagnostic test, BRACAnalysis were approved by the US FDA in December 2014 for recurrent ovarian cancer in women with a germline BRCA mutation. Women with a deleterious BRCA mutation are predisposed to ovarian cancer due to deficient homologous recombination repair. Inhibition of the PARP enzyme forces use of an alternate error-prone pathway for repair; PARP trapping is another mechanism utilized that blocks cellular replication by trapping inactivated PARP onto single-stranded DNA breaks...
2015: Expert Review of Molecular Diagnostics
https://www.readbyqxmd.com/read/26272246/bracanalysis-cdx-as-a-companion-diagnostic-tool-for-lynparza
#20
Camille C Gunderson, Kathleen N Moore
Lynparza and its companion diagnostic test, BRACAnalysis were approved by the US FDA in December 2014 for recurrent ovarian cancer in women with a germline BRCA mutation. Women with a deleterious BRCA mutation are predisposed to ovarian cancer due to deficient homologous recombination repair. Inhibition of the PARP enzyme forces use of an alternate error-prone pathway for repair; PARP trapping is another mechanism utilized that blocks cellular replication by trapping inactivated PARP onto single-stranded DNA breaks...
August 13, 2015: Expert Review of Molecular Diagnostics
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