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Parp inhibitor ovarian ca

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https://www.readbyqxmd.com/read/28425306/therapeutic-targeting-and-patient-selection-for-cancers-with-homologous-recombination-defects
#1
Francien Talens, Mathilde Jalving, Jourik A Gietema, Marcel A T M van Vugt
DNA double-strand breaks (DSBs) are toxic DNA lesions that can be repaired by non-homologous end-joining (NHEJ) or homologous recombination (HR). Mutations in HR genes elicit a predisposition to cancer; yet, they also result in increased sensitivity to certain DNA damaging agents and poly (ADP-ribose) polymerase (PARP) inhibitors. To optimally implement PARP inhibitor treatment, it is important that patients with HR-deficient tumors are adequately selected. Areas covered: Herein, the authors describe the HR pathway mechanistically and review the treatment of HR-deficient cancers, with a specific focus on PARP inhibition for BRCA1/2-mutated breast and ovarian cancer...
April 20, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28414200/combining-53bp1-with-brca1-as-a-biomarker-to-predict-the-sensitivity-of-poly-adp-ribose-polymerase-parp-inhibitors
#2
Zhong-Min Yang, Xue-Mei Liao, Yi Chen, Yan-Yan Shen, Xin-Ying Yang, Yi Su, Yi-Ming Sun, Ying-Lei Gao, Jian Ding, Ao Zhang, Jin-Xue He, Ze-Hong Miao
Over half of patients with BRCA1-deficient cancers do not respond to treatment with poly(ADP-ribose) polymerase (PARP) inhibitors. In this study, we report that a combination of 53BP1 and BRCA1 may serve as a biomarker of PARP inhibitor sensitivity. Based on the mRNA levels of four homologous recombination repair (HR) genes and PARP inhibitor sensitivity, we selected BRCA1-deficient MDA-MB-436 cells to conduct RNA interference. Reducing expression of 53BP1, but not the other three HR genes, was found to lower simmiparib sensitivity...
April 17, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28404569/analysis-suggests-wider-use-for-parp-inhibitors
#3
(no author information available yet)
Researchers have developed a new tool, HRDetect, to pinpoint tumors that display BRCA deficiency but don't harbor BRCA1/2 mutations. Evaluating their method in breast, ovarian, and pancreatic cancers, they identified patients whose tumors were potentially vulnerable to PARP inhibition but who didn't carry these mutations.
April 12, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28403964/-can-new-molecular-profiles-in-epithelial-ovarian-cancer-modify-therapeutics
#4
REVIEW
V Lavoué, A Rousselin, S Delplanque, M Pinsard, S Henno, F Foucher, J Levêque, T de la Motte Rouge
Epithelial ovarian cancer (EOC) affects 4500 women a year in France, with a survival of 30% at 5 years. Treatment is based on extensive surgery and chemotherapy. Around 15% of EOCs are due to genetic mutation predisposition essentially with mutated BRCA1 and BRCA2 genes. Four histological subtypes are described (serous, endometrioid, and mucinous cells to clear), corresponding to different carcinogenesis and distinct molecular mutations. High-grade serous EOCs have a mutation of the BRCA genes in 20-30% of cases...
February 2017: J Gynecol Obstet Hum Reprod
https://www.readbyqxmd.com/read/28392129/poly-adp-ribose-polymerase-parp-inhibitors-as-treatment-versus-maintenance-in-ovarian-carcinoma
#5
EDITORIAL
Whitney S Graybill, Bhavana Pothuri, Dana M Chase, Bradley J Monk
No abstract text is available yet for this article.
April 6, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28388401/parp-inhibitors-for-cancer-therapy
#6
Ken Y Lin, W Lee Kraus
Rucaparib is an inhibitor of nuclear poly (ADP-ribose) polymerases (inhibition of PARP-1 > PARP-2 > PARP-3), following a similar drug, Olaparib. It disrupts DNA repair and replication pathways (and possibly transcription), leading to selective killing of cancer cells with BRCA1/2 mutations. Rucaparib is approved for recurrent ovarian cancers with germline or somatic mutations in BRCA1/2.
April 6, 2017: Cell
https://www.readbyqxmd.com/read/28350129/apoptosis-is-augmented-in-high-grade-serous-ovarian-cancer-by-the-combined-inhibition-of-bcl-2-bcl-xl-and-parp
#7
Takuhei Yokoyama, Elise C Kohn, Ethan Brill, Jung-Min Lee
The aim of our study was to evaluate possible synergistic cytotoxic effects of the combination treatment with the BH3-mimetic ABT-263 and the PARP inhibitor BMN 673 in high-grade serous ovarian cancer (HGSOC) cells using clinically achievable concentrations of each drug. In vitro cytotoxic effects of ABT-263 and BMN 673 were assessed by XTT assay in three HGSOC cell lines: OVCAR3, OVCAR8, and OV90 cells. Combination index values and synergy/antagonism volumes were used to determine synergy. The drug effects on DNA damage accumulation, cell cycle progression, apoptosis induction, and expression levels of Bcl-2 family proteins were examined to dissect molecular mechanisms...
March 15, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28325851/new-quantitative-mass-spectrometry-approaches-reveal-different-adp-ribosylation-phases-dependent-on-the-levels-of-oxidative-stress
#8
Vera Bilan, Nathalie Selevsek, Hans A V Kistemaker, Jeannette Abplanalp, Roxane Feurer, Dmitri V Filippov, Michael O Hottiger
Oxidative stress is a potent inducer of protein ADP-ribosylation. Although individual oxidative stress-induced ADP-ribosylated proteins have been identified, it is so far not clear, to which extent different degrees of stress severity quantitatively and qualitatively alter ADP-ribosylation, respectively. Here, we investigated both quantitative and qualitative changes of the hydrogen peroxide (H2O2)-induced ADP-ribosylome using a label-free shotgun quantification and a parallel reaction monitoring (PRM) mass spectrometry approach for a selected number of identified ADP-ribosylated peptides...
March 21, 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28303528/human-mass-balance-study-and-metabolite-profiling-of-14-c-niraparib-a-novel-poly-adp-ribose-polymerase-parp-1-and-parp-2-inhibitor-in-patients-with-advanced-cancer
#9
Lotte van Andel, Z Zhang, S Lu, V Kansra, S Agarwal, L Hughes, M M Tibben, A Gebretensae, L Lucas, M J X Hillebrand, H Rosing, J H M Schellens, J H Beijnen
Niraparib is an investigational oral, once daily, selective poly(ADP-Ribose) polymerase (PARP)-1 and PARP-2 inhibitor. In the pivotal Phase 3 NOVA/ENGOT/OV16 study, niraparib met its primary endpoint of improving progression-free survival (PFS) for adult patients with recurrent, platinum sensitive, ovarian, fallopian tube, or primary peritoneal cancer in complete or partial response to platinum-based chemotherapy. Significant improvements in PFS were seen in all patient cohorts regardless of biomarker status...
March 16, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28299955/niraparib-for-the-treatment-of-ovarian-cancer
#10
REVIEW
Yada Kanjanapan, Stephanie Lheureux, Amit M Oza
Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are being developed in maintenance and recurrence treatment settings in ovarian cancer. They inhibit single-stranded DNA repair, inducing synthetic lethality in cells with underlying homologous recombination deficiency (HRD). Marked responses are seen in ovarian cancers with breast cancer gene 1 (BRCA1) or 2 (BRCA2) mutation, although up to 50% of high-grade serous ovarian cancers (HGSOC) have HRD may also benefit. Areas covered: This review focuses on niraparib (oral PARP I and II inhibitor), its clinical testing in ovarian cancer, including the Myriad MyChoice HRD test as a potential companion diagnostic...
April 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28288110/hrdetect-is-a-predictor-of-brca1-and-brca2-deficiency-based-on-mutational-signatures
#11
Helen Davies, Dominik Glodzik, Sandro Morganella, Lucy R Yates, Johan Staaf, Xueqing Zou, Manasa Ramakrishna, Sancha Martin, Sandrine Boyault, Anieta M Sieuwerts, Peter T Simpson, Tari A King, Keiran Raine, Jorunn E Eyfjord, Gu Kong, Åke Borg, Ewan Birney, Hendrik G Stunnenberg, Marc J van de Vijver, Anne-Lise Børresen-Dale, John W M Martens, Paul N Span, Sunil R Lakhani, Anne Vincent-Salomon, Christos Sotiriou, Andrew Tutt, Alastair M Thompson, Steven Van Laere, Andrea L Richardson, Alain Viari, Peter J Campbell, Michael R Stratton, Serena Nik-Zainal
Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. In other cancer types, germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2-deficient tumors have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns, or 'mutational signatures', were associated with BRCA1/BRCA2 dysfunction...
April 2017: Nature Medicine
https://www.readbyqxmd.com/read/28273485/clinical-factors-of-response-in-patients-with-advanced-ovarian-cancer-participating-in-early-phase-clinical-trials
#12
Angela George, Rebecca Kristeleit, Saeed Rafii, Caroline O Michie, Rebecca Bowen, Vasiliki Michalarea, Tom van Hagen, Mabel Wong, Grigorios Rallis, L Rhoda Molife, Juanita Lopez, Udai Banerji, Susana N Banerjee, Martin E Gore, Johann S de Bono, Stan B Kaye, Timothy A Yap
Drug resistance to conventional anticancer therapies is almost inevitable in patients with advanced ovarian cancer (AOC), limiting their available treatment options. Novel phase I trial therapies within a dedicated drug development unit may represent a viable alternative; however, there is currently little evidence for patient outcomes in such patients. To address this, we undertook a retrospective review of patients with AOC allocated to phase I trials in the Drug Development Unit at Royal Marsden Hospital (RMH) between June 1998 and October 2010...
March 5, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28258387/-brca-diagnostics-of-ovarian-cancer-molecular-tumor-testing-since-the-introduction-of-parp-inhibitor-therapy
#13
H Löser, C Heydt, R Büttner, B Markiefka
Approximately 9000 women are diagnosed with ovarian cancer in Germany each year. The most common subtype is high-grade serous ovarian cancer. A relevant proportion of these tumors are associated with mutations in the breast and ovarian cancer susceptibility genes (BRCA1 and BRCA2) representing highly penetrant tumor suppressor genes with autosomal inheritance and play a crucial role in DNA repair mechanisms. These patients have predominantly germline mutations and less frequently have somatic BRCA mutations...
March 3, 2017: Der Pathologe
https://www.readbyqxmd.com/read/28250960/homologous-recombination-deficiency-hrd-testing-in-ovarian-cancer-clinical-practice-a-review-of-the-literature
#14
REVIEW
Melissa K Frey, Bhavana Pothuri
Until recently our knowledge of a genetic contribution to ovarian cancer focused almost exclusively on mutations in the BRCA1/2 genes. However, through germline and tumor sequencing an understanding of the larger phenomenon of homologous recombination deficiency (HRD) has emerged. HRD impairs normal DNA damage repair which results in loss or duplication of chromosomal regions, termed genomic loss of heterozygosity (LOH). The list of inherited mutations associated with ovarian cancer continues to grow with the literature currently suggesting that up to one in four cases will have germline mutations, the majority of which result in HRD...
2017: Gynecologic Oncology Research and Practice
https://www.readbyqxmd.com/read/28250726/parp-inhibitors-review-of-mechanisms-of-action-and-brca1-2-mutation-targeting
#15
REVIEW
Karolina N Dziadkowiec, Emilia Gąsiorowska, Ewa Nowak-Markwitz, Anna Jankowska
Poly(ADP-ribose) polymerases have shown true promise in early clinical studies due to reported activity in BRCA-associated cancers. PARP inhibitors may represent a potentially important new class of chemotherapeutic agents directed at targeting cancers with defective DNA-damage repair. In order to widen the prospective patient population that would benefit from PARP inhibitors, predictive biomarkers based on a clear understanding of the mechanism of action are required. In addition, a more sophisticated understanding of the toxicity profile is required if PARP inhibitors are to be employed in the curative, rather than the palliative, setting...
December 2016: Przeglad Menopauzalny, Menopause Review
https://www.readbyqxmd.com/read/28242752/phase-i-dose-escalation-2-part-trial-of-poly-adp-ribose-polymerase-inhibitor-talazoparib-in-patients-with-advanced-germline-brca1-2-mutations-and-selected-sporadic-cancers
#16
Johann de Bono, Ramesh K Ramanathan, Lida Mina, Rashmi Chugh, John Glaspy, Saeed Rafii, Stan Kaye, Jasgit Sachdev, John Heymach, David C Smith, Joshua W Henshaw, Ashleigh Herriott, Miranda Patterson, Nicola J Curtin, Lauren Averett Byers, Zev A Wainberg
Talazoparib inhibits poly(ADP-ribose) polymerase (PARP) catalytic activity, trapping PARP1 on damaged DNA and causing cell death in BRCA1/2-mutated cells. We evaluated talazoparib therapy in this 2-part, phase I, first-in-human trial. Antitumor activity, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of once-daily talazoparib were determined in an open-label, multicenter, dose-escalation study (NCT01286987). The MTD was 1.0 mg/day, with an elimination half-life of 50 hours. Treatment-related adverse events included fatigue (26/71 patients; 37%) and anemia (25/71 patients; 35%)...
February 27, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28223667/-molecular-diagnosis-and-treatment-of-hboc-syndrome
#17
Yoshio Miki
Hereditary breast and ovarian cancer(HBOC)is an inherited cancer caused by mutations of the BRCA1 or BRCA2 genes. BRCA genetic testing is used for HBOC diagnosis and continues to progress such as the annotation of VUS. In HBOC clinical practice, surveillance methods have been established through collaboration between genetic medicine and cancer medicine, and treatment, including options based on genetic diagnosis, has advanced significantly. Furthermore, the analysis of BRCA1 and BRCA2 function has progressed, and a novel therapeutic method based on synthetic lethality, such as a PARP inhibitor use, has been developed...
February 2017: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/28212573/dynamic-variations-in-epithelial-to-mesenchymal-transition-emt-atm-and-slfn11-govern-response-to-parp-inhibitors-and-cisplatin-in-small-cell-lung-cancer
#18
C Allison Stewart, Pan Tong, Robert J Cardnell, Triparna Sen, Lerong Li, Carl M Gay, Fatemah Masrorpour, You Fan, Rasha O Bara, Ying Feng, Yuanbin Ru, Junya Fujimoto, Samrat T Kundu, Leonard E Post, Karen Yu, Yuqiao Shen, Bonnie S Glisson, Ignatio Wistuba, John V Heymach, Don L Gibbons, Jing Wang, Lauren Averett Byers
Small cell lung cancer (SCLC) is one of the most aggressive forms of cancer, with a 5-year survival <7%. A major barrier to progress is the absence of predictive biomarkers for chemotherapy and novel targeted agents such as PARP inhibitors. Using a high-throughput, integrated proteomic, transcriptomic, and genomic analysis of SCLC patient-derived xenografts (PDXs) and profiled cell lines, we identified biomarkers of drug sensitivity and determined their prevalence in patient tumors. In contrast to breast and ovarian cancer, PARP inhibitor response was not associated with mutations in homologous recombination (HR) genes (e...
February 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28176296/brca1-and-brca2-mutations-in-ovarian-cancer-patients-from-china-ethnic-related-mutations-in-brca1-associated-with-an-increased-risk-of-ovarian-cancer
#19
Tingyan Shi, Pan Wang, Caixia Xie, Sheng Yin, Di Shi, Congchong Wei, Wenbin Tang, Rong Jiang, Xi Cheng, Qingyi Wei, Qing Wang, Rongyu Zang
BRCA1/2 are cancer predisposition genes involved in hereditary breast and ovarian cancer (HBOC). Mutation carriers display an increased sensitivity to inhibitors of poly(ADP-ribose) polymerase (PARP). Despite a number of small-size hospital-based studies being previously reported, there is not yet, to our knowledge, precise data of BRCA1/2 mutations among Chinese ovarian cancer patients. We performed a multicenter cohort study including 916 unselected consecutive epithelial ovarian cancer (EOC) patients from eastern China to screen for BRCA1/2 mutations using the next-generation sequencing approach...
May 1, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28118040/parp-1-expression-quantified-by-18-f-fluorthanatrace-a-biomarker-of-response-to-parp-inhibition-adjuvant-to-radiation-therapy
#20
Samuel Sander Effron, Mehran Makvandi, Lilie Lin, Kuiying Xu, Shihong Li, Hsiaoju Lee, Catherine Hou, Daniel A Pryma, Cameron Koch, Robert H Mach
INTRODUCTION: Poly (ADP-ribose) polymerase 1 (PARP-1) is the major target of clinical PARP inhibitors and is a potential predictive biomarker for response to therapy. Due to the limited success of PARP inhibitors as monotherapy, investigators have shifted the clinical role of PARP inhibitors to the adjuvant setting. In this study, we evaluate the radiotracer [(18)F]FluorThanatrace ([(18)F]FTT) as a marker of PARP expression in vitro and the associated biological implications of PARP-1 expression in PARP inhibitor treatment adjuvant to radiation therapy...
February 2017: Cancer Biotherapy & Radiopharmaceuticals
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