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Parp inhibitor ovarian ca

Francesca Vena, Ruochen Jia, Arman Esfandiari, Juan J Garcia-Gomez, Manuel Rodriguez-Justo, Jianguo Ma, Sakeena Syed, Lindsey Crowley, Brian Elenbaas, Samantha Goodstal, John A Hartley, Daniel Hochhauser
Targeting the DNA damage response (DDR) in tumors with defective DNA repair is a clinically successful strategy. The RAS/RAF/MEK/ERK signalling pathway is frequently deregulated in human cancers. In this study, we explored the effects of MEK inhibition on the homologous recombination pathway and explored the potential for combination therapy of MEK inhibitors with DDR inhibitors and a hypoxia-activated prodrug. We studied effects of combining pimasertib, a selective allosteric inhibitor of MEK1/2, with olaparib, a small molecule inhibitor of poly (adenosine diphosphate [ADP]-ribose) polymerases (PARP), and with the hypoxia-activated prodrug evofosfamide in ovarian and pancreatic cancer cell lines...
February 20, 2018: Oncotarget
Pingping Fang, Jill A Madden, Lisa Neums, K Ryan Moulder, M Laird Forrest, Jeremy Chien
FOXM1 transcription factor network is activated in over 84% of cases in high-grade serous ovarian cancer (HGSOC), and FOXM1 upregulates the expression of genes involved in the homologous recombination (HR) DNA damage and repair (DDR) pathway. However, the role of FOXM1 in poly (ADP-ribose) polymerase (PARP) inhibitor response has not yet been studied. The present study demonstrates that PARP inhibitor (PARPi), olaparib, induces the expression and nuclear localization of FOXM1. Based on ChIP-qPCR, olaparib enhances the binding of FOXM1 to genes involved in HR repair...
March 15, 2018: Molecular Cancer Research: MCR
Natalie Herold, Barbara Wappenschmidt, Birgid Markiefka, Katharina Keupp, Sandra Kröber, Eric Hahnen, Rita Schmutzler, Kerstin Rhiem
Non-small cell neuroendocrine carcinomas (NSCNEC) account for 2% of gynecological cancer cases and are associated with a poor prognosis due to delayed diagnosis and aggressive tumor behavior. BRCA2 -associated ovarian carcinomas predominantly possess a high-grade serous phenotype, which respond to platinum and targeted therapy with PARP inhibitors. Presented here is the case of an adult patient with NSCNEC of the ovaries associated with a deleterious BRCA2 germline mutation. The pathogenic mutation was also confirmed on the somatic level, while the wild-type allele had a high variant fraction, suggesting loss of heterozygosity...
April 2018: Oncology Letters
Belinda Rahman, Anne Lanceley, Rebecca S Kristeleit, Jonathan A Ledermann, Michelle Lockley, Mary McCormack, Tim Mould, Lucy Side
BACKGROUND: Ovarian cancer is the fifth most common cause of cancer death for women in the UK. Up to 18% of cases can be attributed to germline mutations in BRCA1 and BRCA2 genes. Identifying patients who carry a BRCA mutation provides important information about potential response to treatment and eligibility for therapies such as poly ADP ribose polymerase (PARP) inhibitors. Implementation of systematic genetic testing of patients with ovarian cancer via oncology clinics (mainstreamed genetic testing, MGT) is increasing...
March 13, 2018: Journal of Medical Genetics
Laura Cortesi, Angela Toss, Iole Cucinotto
The standard of treatment for advanced ovarian cancer is represented by optimal surgical debulking preceded or followed by chemotherapeutic regimens including taxanes and platinum agents, possibly associated with bevacizumab and/or intraperitoneal therapy. Despite this comprehensive treatment strategy, almost 75% of patients relapse or progress and are therefore candidates for a second-line treatment, showing, at this point, less chemo-sensitivity and worse prognosis. An interesting approach to improve outcomes of these patients has been developed in the last decade, in BRCA-related ovarian cancer...
March 7, 2018: Current Cancer Drug Targets
Gloria Mittica, Eleonora Ghisoni, Gaia Giannone, Sofia Genta, Massimo Aglietta, Anna Sapino, Giorgio Valabrega
BACKGROUND: Treatment of Epithelial Ovarian Cancer (EOC), historically based on surgery and platinum doublet chemotherapy, is associated with high risk of relapse and poor prognosis for recurrent disease. In this landscape, the innovative treatment with PARP inhibitors (PARPis) demonstrated an outstanding activity in EOC, and is currently changing clinical practice in BRCA mutant patients. OBJECTIVES: To highlight the mechanism of action, pharmacokinetics, clinical activity, indications and current strategies of development of Olaparib, Niraparib, Rucaparib, Talazoparib and Veliparib, the 5 most relevant PARPis...
March 5, 2018: Recent Patents on Anti-cancer Drug Discovery
Gonzalo Hernández, María José Ramírez, Jordi Minguillón, Paco Quiles, Gorka Ruiz de Garibay, Miriam Aza-Carmona, Massimo Bogliolo, Roser Pujol, Rosario Prados-Carvajal, Juana Fernández, Nadia García, Adrià López, Sara Gutiérrez-Enríquez, Orland Diez, Javier Benítez, Mónica Salinas, Alex Teulé, Joan Brunet, Paolo Radice, Paolo Peterlongo, Detlev Schindler, Pablo Huertas, Xose S Puente, Conxi Lázaro, Miquel Àngel Pujana, Jordi Surrallés
BRCA1 is a tumor suppressor that regulates DNA repair by homologous recombination. Germline mutations in BRCA1 are associated with increased risk of breast and ovarian cancer and BRCA1 deficient tumors are exquisitely sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. Therefore, uncovering additional components of this DNA repair pathway is of extreme importance for further understanding cancer development and therapeutic vulnerabilities. Here, we identify EDC4, a known component of processing-bodies and regulator of mRNA decapping, as a member of the BRCA1-BRIP1-TOPBP1 complex...
March 6, 2018: Nature Communications
Mehran Makvandi, Austin Pantel, Lauren Schwartz, Erin Schubert, Kuiying Xu, Chia-Ju Hsieh, Catherine Hou, Hyoung Kim, Chi-Chang Weng, Harrison Winters, Robert Doot, Michael D Farwell, Daniel A Pryma, Roger A Greenberg, David A Mankoff, Fiona Simpkins, Robert H Mach, Lilie L Lin
BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors are effective in a broad population of ovarian cancer patients, however resistance caused by low enzyme expression of the drug target, poly(ADP-ribose) polymerase 1 (PARP-1), remains to be clinically evaluated in this context. We hypothesize that PARP-1 expression is variable in ovarian cancer and can be quantified in primary and metastatic disease using a novel positron emitting tomography (PET) imaging agent. METHODS: We used a translational approach to describe the significance of PET imaging of PARP-1 in ovarian cancer...
March 6, 2018: Journal of Clinical Investigation
Robert D Morgan, Andrew R Clamp, D Gareth R Evans, Richard J Edmondson, Gordon C Jayson
PURPOSE: Poly(ADP-ribose) polymerase inhibitors (PARPi) have changed the management of high-grade serous ovarian cancer (HGSOC). The rationale for the development of PARPi was based on the concept of synthetic lethality, in which a cell can survive a deficiency of one gene/gene product, but may die if there is a deficiency in a combination of genes/gene products. In women with BRCA1/2 deficiency within their ovarian cancer tissue, inhibition of PARP imposes an intolerable burden of DNA damage repair deficiency and may induce cell death...
February 20, 2018: Cancer Chemotherapy and Pharmacology
Shigeaki Sunada, Akira Nakanishi, Yoshio Miki
Germ-line mutations in breast cancer susceptibility gene 1 or 2 (BRCA1 or BRCA2) significantly increase cancer risk in hereditary breast and ovarian cancer syndrome (HBOC). Both genes function in the homologous recombination (HR) pathway of DNA double-strand break (DSB) repair process. Therefore, the DNA-repair defect characteristic in cancer cells brings therapeutic advantage for Poly(ADP-ribose) polymerase (PARP) inhibitor-induced synthetic lethality. The PARP inhibitor-based therapeutics initially causes cancer lethality but acquired resistance mechanisms have been found and need to be elucidated...
February 10, 2018: Cancer Science
Kathleen N Moore, Mansoor Raza Mirza, Ursula A Matulonis
Niraparib is an oral poly(ADP ribose) polymerase (PARP) inhibitor that is currently approved by the United States Food and Drug Administration (US FDA) as well as recently approved by the European Medicines Agency (EMA) for the maintenance treatment of women with recurrent ovarian cancer who are in complete or partial response to platinum-based chemotherapy. The mechanisms of action of niraparib include inhibition of PARP enzymatic activity as well as increased formation of PARP-DNA complexes through "trapping" the PARP enzyme on damaged DNA...
January 31, 2018: Gynecologic Oncology
Anne-Christine Wong Te Fong, Parames Thavasu, Sladjana Gagrica, Karen E Swales, Martin O Leach, Sabina C Cosulich, Yuen-Li Chung, Udai Banerji
Activation of the PI3K/mTOR pathway has been shown to be correlated with resistance to chemotherapy in ovarian cancer. We aimed to investigate the effects of combining inhibition of mTORC1 and 2 using the mTOR kinase inhibitor vistusertib (AZD2014) with paclitaxel in in vitro and in vivo ovarian cancer models. The combination of vistusertib and paclitaxel on cell growth was additive in a majority of cell lines in the panel ( n = 12) studied. A cisplatin- resistant model (A2780Cis) was studied in vitro and in vivo ...
December 26, 2017: Oncotarget
Heidi J Gray, Katherine Bell-McGuinn, Gini F Fleming, Mihaela Cristea, Hao Xiong, Danielle Sullivan, Yan Luo, Mark D McKee, Wijith Munasinghe, Lainie P Martin
OBJECTIVE: Determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of veliparib combined with carboplatin and gemcitabine in patients with advanced ovarian cancer and other nonhematologic malignancies. METHODS: In this phase I study, patients with metastatic or unresectable solid tumors and ≤2 prior chemotherapy regimens received veliparib combined with carboplatin area under the curve (AUC) 4 on day 1 and gemcitabine 800mg/m2 on days 1 and 8 of a 21-day cycle for maximum 10cycles, followed by optional veliparib maintenance therapy...
March 2018: Gynecologic Oncology
Ethan Brill, Takuhei Yokoyama, Jayakumar Nair, Minshu Yu, Yeong-Ran Ahn, Jung-Min Lee
PARP inhibitors (PARPi) have been effective in high-grade serous ovarian cancer (HGSOC), although clinical activity is limited against BRCA wild type HGSOC. The nearly universal loss of normal p53 regulation in HGSOCs causes dysfunction in the G1/S checkpoint, making tumor cells reliant on Chk1-mediated G2/M cell cycle arrest for DNA repair. Therefore, Chk1 is a reasonable target for a combination strategy with PARPi in treating BRCA wild type HGSOC. Here we investigated the combination of prexasertib mesylate monohydrate (LY2606368), a Chk1 and Chk2 inhibitor, and a PARP inhibitor, olaparib, in HGSOC cell lines (OVCAR3, OV90, PEO1 and PEO4) using clinically attainable concentrations...
December 19, 2017: Oncotarget
Yuanli Zhen, Yonghao Yu
Poly-ADP-ribosylation (PARylation) is a protein posttranslational modification (PTM) that is critically involved in many biological processes that are linked to cell stress responses. It is catalyzed by a class of enzymes known as poly-ADP-ribose polymerases (PARPs). In particular, PARP1 is a nuclear protein that is activated upon sensing nicked DNA. Once activated, PARP1 is responsible for the synthesis of a large number of PARylated proteins and initiation of the DNA damage response (DDR) mechanisms. This observation provided the rationale for developing PARP1 inhibitors for the treatment of human malignancies...
January 12, 2018: Biochemistry
Kathleen Moore, Zhi-Yi Zhang, Shefali Agarwal, Howard Burris, Manish R Patel, Vikram Kansra
PURPOSE: Niraparib is a highly selective inhibitor of PARP-1 and PARP-2 approved in the United States for maintenance treatment of adult patients with recurrent ovarian cancer in complete or partial response to platinum-based chemotherapy. In this open-label crossover study, we evaluated the effects of food on niraparib pharmacokinetics (PK) and safety. METHODS: Patients received a single 300-mg dose of niraparib either after a high-fat meal or under fasting conditions...
January 10, 2018: Cancer Chemotherapy and Pharmacology
Diane A J van der Biessen, Jourik A Gietema, Maja J A de Jonge, Ingrid M E Desar, Martha W den Hollander, Matthew Dudley, Martin Dunbar, Robert Hetman, Camille Serpenti, Hao Xiong, Rajendar K Mittapalli, Kirsten M Timms, Peter Ansell, Christine K Ratajczak, Stacie Peacock Shepherd, Carla M L van Herpen
Purpose This phase 1 study examined safety, pharmacokinetics (PK), and efficacy of the poly(ADP-ribose) polymerase (PARP) inhibitor ABT-767 in patients with advanced solid tumors and BRCA1/2 mutations or with high-grade serous ovarian, fallopian tube, or primary peritoneal cancer. Methods Patients received ABT-767 monotherapy orally until disease progression or unacceptable toxicity. Dose was escalated from 20 mg once daily to 500 mg twice daily (BID). Dose-limiting toxicities, recommended phase 2 dose (RP2D), food effect, objective response rate, and biomarkers predicting response were determined...
January 8, 2018: Investigational New Drugs
Leonora Wijnandina de Boo, Annelie Johanna Elisabeth Vulink, Monique Elisabeth Martina Maria Bos
Metronomic oral cyclophosphamide has gained increasing interest in recent years as a promising maintenance therapy in advanced, platinum-sensitive, high-grade serous ovarian cancer (HGSOC). Metronomic treatment with cyclophosphamide refers to the frequent, usually daily, administration of a low (oral) dose of cyclophosphamide with no prolonged drug-free breaks. Main advantages of this treatment are the effective reduction of tumour activity, oral administration in an outpatient setting, low cost and the low toxicity profile...
December 2017: Molecular and Clinical Oncology
Sina Eetezadi, James C Evans, Yen Ting Shen, Raquel De Souza, Micheline Piquette-Miller, Christine Allen
Ovarian cancer is the fourth leading cause of death in women in developed countries. Even though patients with the most lethal form of the disease (HGSOC; high grade serous ovarian cancer) respond well to initial treatment, they often relapse with progressively resistant disease. Inhibitors of the poly(ADP-ribose) polymerase (PARP) enzymes are a relatively new class of molecularly targeted small molecule drugs that show promise in overcoming resistance. The present study explores the combination of a DNA damaging agent, doxorubicin (DOX), with the PARP inhibitor, olaparib (OLP) in order to achieve optimal synergy of both drugs in serous ovarian cancer...
December 28, 2017: Molecular Pharmaceutics
Ksenija Nesic, Matthew Wakefield, Olga Kondrashova, Clare L Scott, Iain A McNeish
Genomic instability and mutations are fundamental aspects of human malignancies, leading to progressive accumulation of the hallmarks of cancer. For some time, it has been clear that key mutations may be used both as prognostic and predictive biomarkers, the best-known examples being the presence of germline BRCA1 or BRCA2 mutations, which are not only associated with improved prognosis in ovarian cancer, but are also predictive of response to poly(ADP-ribose) polymerase (PARP) inhibitors. Although biomarkers as specific and powerful as these are rare in human malignancies, next generation sequencing and improved bioinformatic analyses are revealing mutational signatures, broader patterns of alterations in the cancer genome that have the power to reveal information about underlying driver mutational processes...
December 27, 2017: Journal of Pathology
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