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Ovarian poly

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
Isabella Faraoni, Francesca Aloisio, Antonio De Gabrieli, Maria Irno Consalvo, Serena Lavorgna, Maria Teresa Voso, Francesco Lo-Coco, Grazia Graziani
Olaparib is a potent orally bioavailable poly(ADP-ribose) polymerase inhibitor (PARPi), approved for BRCA-mutated ovarian and breast cancers. We recently showed that olaparib at clinically achievable concentrations exerts anti-proliferative and pro-apoptotic effects in vitro as monotherapy against primary acute myeloid leukemia (AML) blasts, while sparing normal bone marrow (BM) hematopoietic cells. Since AML expresses low levels of death receptors that may contribute to apoptosis resistance, in this study we investigated whether the anti-leukemia activity of olaparib involves modulation of FAS and TRAIL receptors DR5 and DR4...
March 8, 2018: Cancer Letters
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
Fu Hua, Chang-Hua Li, Xiao-Gang Chen, Xiao-Ping Liu
Ovarian cancer is the main cause of gynecological cancer‑associated mortality around the world. Despite initial responses to chemotherapy, frequent relapse occurs. Daidzein is an important flavonoid and has been shown to exhibit a diversity of pharmacological properties, including antimicrobial and anticancer activities. However, information on the anticancer activity of daidzein against ovarian cancer remains limited. Therefore, the present study evaluated the anticancer activity of daidzein against a panel of human ovarian cancer cell lines and one normal ovarian cell line (Moody)...
March 5, 2018: International Journal of Molecular Medicine
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
Francesca Citossi, Thomas Smith, Jong Bong Lee, Joel Segal, Pavel Gershkovich, Michael John Stocks, Tracey D Bradshaw, Barrie Kellam, Maria Marlow
Low molecular weight gelators (LMWGs) of chemotherapeutic drugs represent a valid alternative to the existing poly-mer-based formulations used for targeted delivery of anticancer drugs. Herein we report the design and development of novel self-assembling gelators of the antitumour benzothiazole 5F 203 (1). Two different types of derivatives of 1 were synthesized, formed by an amide (2) and a carbamate (3a-3d) linker, respectively, which showed potent in vitro anti-tumour activity against MCF-7 mammary and IGROV-1 ovarian carcinoma cells...
March 5, 2018: Molecular Pharmaceutics
Monica Hagan Vetter, John L Hays
PURPOSE: Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer death in the United States. Most patients will ultimately fail platinum-based chemotherapy and have the disease recur. Interest is increasing in the use of targeted therapies in the treatment of EOC. This review focuses on the current use of targeted therapeutics in EOC as well as future directions. METHODS: A literature search of Medline and PubMed was conducted (January 2000-October 2017) to identify recent reports of targeted drugs in EOC...
February 23, 2018: Clinical Therapeutics
Dong Hoon Suh, Miseon Kim, Kyung Hun Lee, Keun Yong Eom, Maj Kamille Kjeldsen, Mansoor Raza Mirza, Jae Weon Kim
In 2017, 10 topics were selected as major clinical research advances in gynecologic oncology. For cervical cancer, efficacy and safety analysis results of a 9-valent human papillomavirus (HPV) vaccine and long-term impact of reduced dose of quadrivalent vaccine were updated. Brief introduction of KEYNOTE trials of pembrolizumab, a monoclonal antibody that blocks the interaction between programmed death (PD)-1 and its ligands, PD-L1 and PD-L2, followed. Tailored surveillance programs for gynecologic cancer related with Lynch syndrome and update on sentinel lymph node mapping were reviewed for uterine corpus cancer...
March 2018: Journal of Gynecologic Oncology
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
Sabire Güler, Berrin Zik
Capsaicin is the pungent ingredient in red peppers. Due to the effects on the sensory nerve fibers, capsaicin has been used to treat pain and inflammation associated with a variety of diseases including rheumatoid arthritis and diabetic neuropathy, obesity, and cardiovascular and gastrointestinal conditions. Despite the extensive publications on different systems, the studies of the effects on the ovary are very limited. The present study was conducted to examine the possible proliferative and/or apoptotic effects of various doses of capsaicin on primarily derived granulosa cells...
February 17, 2018: Cell and Tissue Research
Nitika Gupta, Shilpa Bhandari, Pallavi Agrawal, Ishita Ganguly, Aparna Singh
Objective: This study aims to study the difference in etiology and outcome in terms of implantation rate and abortion rate in fresh (self-stimulated) versus frozen (oocyte donation cycle) in vitro fertilization (IVF) and in transient versus persistent fluid. Material and Methods: This retrospective study was conducted in the Department of Reproductive Medicine of tertiary care center from January 2012 to November 2015. Data were collected retrospectively from the departmental files...
October 2017: Journal of Human Reproductive Sciences
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
Erfaneh Ghassami, Jaleh Varshosaz, Ali Jahanian-Najafabadi, Mohsen Minaiyan, Parvin Rajabi, Effat Hayati
Purpose: Epithelixal ovarian cancer is the fourth cause of cancer death in developed countries with 77% of ovarian cancer cases diagnosed with regional or distant metastasis, with poor survival rates. Docetaxel (DTX) is a well-known anticancer agent, with clinically proven efficacy in several malignancies, including ovarian cancer. However, the adverse effects caused by the active ingredient or currently marketed formulations could even deprive the patient of the advantages of treatment...
2018: International Journal of Nanomedicine
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
May Thuu Mon, Supachai Yodkeeree, Wanisa Punfa, Wilart Pompimon, Pornngarm Limtrakul
Crebanine (CN), tetrahydropalmatine (THP), O-methylbulbocapnine (OMBC) and N-methyl tetrahydropalmatine (NMTHP) are isoquinoline derived natural alkaloids isolated from tubers of Stephania venosa. We investigated chemo-sensitizing effects of these alkaloids in ovarian cancer cells and evaluated underlying molecular mechanisms involved in chemo-sensitivity. Detection of cell apoptosis was evaluated by using flow cytometry. Cell viability was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay...
2018: Chemical & Pharmaceutical Bulletin
Swati Chaurasiya, Vijay Mishra
OBJECTIVES: Above 10 million people are suffering from cancers every year. As per American Cancer Society, more than 22 440 new cases and 14 080 deaths were reported from ovarian cancer yearly worldwide. This review explores the current status, challenges and future perspectives of tumour-targeted theranostic nanoparticles (NPs). KEY FINDINGS: Most of the ovarian malignancy cases are uncovered after the disease is in a difficult state due to poor screening techniques and non-specific symptoms...
January 30, 2018: Journal of Pharmacy and Pharmacology
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