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ovarian cancer drug resistance drugs

Radoslav Chekerov, Felix Hilpert, Sven Mahner, Ahmed El-Balat, Philipp Harter, Nikolaus De Gregorio, Claudius Fridrich, Susanne Markmann, Jochem Potenberg, Ralf Lorenz, Guelten Oskay-Oezcelik, Marcus Schmidt, Petra Krabisch, Hans-Joachim Lueck, Rolf Richter, Elena Ioana Braicu, Andreas du Bois, Jalid Sehouli
BACKGROUND: Antiangiogenic therapy has known activity in ovarian cancer. The investigator-initiated randomised phase 2 TRIAS trial assessed the multi-kinase inhibitor sorafenib combined with topotecan and continued as maintenance therapy for platinum-resistant or platinum-refractory ovarian cancer. METHODS: We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 trial at 20 sites in Germany. Patients (≥18 years) with platinum-resistant ovarian cancer previously treated with two or fewer chemotherapy lines for recurrent disease were stratified (first vs later relapse) in block sizes of four and randomly assigned (1:1) using a web-generated response system to topotecan (1·25 mg/m2 on days 1-5) plus either oral sorafenib 400 mg or placebo twice daily on days 6-15, repeated every 21 days for six cycles, followed by daily maintenance sorafenib or placebo for up to 1 year in patients without progression...
August 9, 2018: Lancet Oncology
Yosup Rew, Xiaohui Du, John Eksterowicz, Haiying Zhou, Nadine Jahchan, Liusheng Zhu, Xuelei Yan, Hiroyuki Kawai, Lawrence R McGee, Julio C Medina, Tom Huang, Chelsea Chen, Tatiana Zavorotinskaya, Dena Sutimantanapi, Joanna Waszczuk, Erica Jackson, Elizabeth Huang, Qiuping Ye, Valeria R Fantin, Daqing Sun
The glucocorticoid receptor (GR) has been linked to therapy resistance across a wide range of cancer types. Preclinical data suggest that antagonists of this nuclear receptor may enhance the activity of anti-cancer therapy. The first-generation GR antagonist mifepristone is currently undergoing clinical evaluation in various oncology settings. Structure-based modification of mifepristone led to the discovery of ORIC-101 (28), a highly potent steroidal GR antagonist with reduced androgen receptor (AR) agonistic activity amenable for dosing in androgen receptor positive tumors, and with improved CYP2C8 and CYP2C9 inhibition profile to minimize drug-drug interaction potential...
August 9, 2018: Journal of Medicinal Chemistry
Chengqiong Mao, Yan Zhao, Fang Li, Zibo Li, Shaomin Tian, Waldemar Debinski, Xin Ming
Drug resistance remains a formidable challenge to cancer therapy. P-glycoprotein (Pgp) contributes to multidrug resistance in numerous cancers by preventing accumulation of anticancer drugs in cancer cells. Strategies to overcome this resistance have been vigorously sought for over 3 decades, yet clinical solutions do not exist. The main reason for the failure is lack of cancer specificity of small-molecule Pgp inhibitors, thus causing severe toxicity in normal tissues. In this study, Pgp-targeted photodynamic therapy (PDT) was developed to achieve superior cancer specificity through antibody targeting plus locoregional light activation...
August 3, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Juanjuan Liu, Mingjun Zheng, Yue Qi, Huimin Wang, Miao Liu, Qing Liu, Bei Lin
The present study aimed to investigate the association between Lewis(y) antigen and chemoresistance in ovarian cancer and to elucidate the underlying molecular mechanisms. Lewis(y) expression in chemoresistant ovarian cancer tissues and cells was detected by immunohistochemistry. α1,2‑fucosyltransferase (FUT1) expression in different ovarian cancer chemotherapy-resistant cells was analyzed by reverse transcription-quantitative PCR (RT-qPCR). Genes differentially expressed in the chemoresistant and sensitive groups were screened using a gene chip followed by validation using RT-qPCR and western blot analysis...
July 20, 2018: International Journal of Oncology
Tadahiro Shoji, Shinichi Komiyama, Junzo Kigawa, Hiroshi Tanabe, Kazuyoshi Kato, Hiroaki Itamochi, Hiroyuki Fujiwara, Shoji Kamiura, Tetsutaro Hamano, Toru Sugiyama
BACKGROUND: We present the study rationale and design of the JGOG3023 study, an open-label, parallel-arm, randomized, phase II trial that aimed to assess the efficacy and safety of chemotherapy with or without bevacizumab in patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who were previously treated with bevacizumab for front-line or platinum-sensitive ovarian cancer. We hypothesize that patients treated with a combination of single-agent chemotherapy and bevacizumab will show improved progression-free survival (PFS) compared with those treated with single-agent chemotherapy alone, in the setting beyond disease progression following prior bevacizumab treatment...
July 31, 2018: BMC Cancer
Nicola S Meagher, Klaus Schuster, Andreas Voss, Timothy Budden, Chi Nam Ignatius Pang, Anna deFazio, Susan J Ramus, Michael L Friedlander
OBJECTIVE: Advanced stage mucinous ovarian cancers are diagnostically and therapeutically challenging. Histotype specific trials have failed due to low recruitment after excluding non-ovarian primaries. Mucinous ovarian cancers are commonly metastatic from other sites however lack definitive diagnostic markers. We suggest a classification of mucinous ovarian cancers of uncertain primary origin 'MO-CUPs' in clinical trials. This study aims to identify drug targets to guide treatment and future trials...
July 24, 2018: Gynecologic Oncology
Hitoshi Sase, Yoshito Nakanishi, Satoshi Aida, Kana Horiguchi-Takei, Nukinori Akiyama, Toshihiko Fujii, Kiyoaki Sakata, Toshiyuki Mio, Masahiro Aoki, Nobuya Ishii
Fibroblast growth factor receptor 2 (FGFR2) gene is frequently amplified in gastric cancer. Recently, targeting FGFR2 has drawn attention as a form of gastric cancer therapy, and FGFR-selective inhibitors have shown promising efficacy in clinical studies. Because overcoming acquired resistance is a common problem with molecular targeting drugs, we investigated a resistant mechanism of FGFR inhibitors using the gastric cancer cell line SNU-16, which harbors FGFR2 amplification. We established single cell clones of FGFR inhibitor-resistant SNU-16 (AZD-R) by continuous exposure to AZD4547, a selective FGFR inhibitor...
July 25, 2018: Molecular Cancer Therapeutics
Qiong Wu, Meiqin Zhang, Hong Luo, Tao Yi
To observe the growth inhibition of subcutaneous ovarian cancer xenografts in nude mice and mechanisms by ultrasound irradiation with honokiol-loaded poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL, PCEC) microbubbles (HK-PCEC-MB) as a promising therapeutic approach to ovarian tumor. HK-PCEC-MB were prepared using the double-emulsion solvent evaporation technique. Particles were characterized with regard to shape, size, distribution and surface potential using dynamic light scattering and the Malvern Zetasizer ZS90 system...
October 1, 2018: Journal of Biomedical Nanotechnology
Peixin Dong, Ying Xiong, Junming Yue, Sharon J B Hanley, Hidemichi Watari
B7H3 (also known as CD276, an immune checkpoint molecule) is aberrantly overexpressed in many types of cancer, and such upregulation is generally associated with a poor clinical prognosis. Recent discoveries indicate a crucial role for B7H3 in promoting carcinogenesis and metastasis. This review will focus on the latest developments relating specifically to the oncogenic activity of B7H3 and will describe the upstream regulators and downstream effectors of B7H3 in cancer. Finally, we discuss the emerging roles of microRNAs (miRNAs) in inhibiting B7H3-mediated tumor promotion...
2018: Frontiers in Oncology
Kristen E Clements, Tanay Thakar, Claudia M Nicolae, Xinwen Liang, Hong-Gang Wang, George-Lucian Moldovan
BRCA proteins are essential for homologous recombination (HR) DNA repair, and their germline or somatic inactivation is frequently observed in human tumors. Understanding the molecular mechanisms underlying the response of BRCA-deficient tumors to chemotherapy is paramount for developing improved personalized cancer therapies. While PARP inhibitors have been recently approved for treatment of BRCA-mutant breast and ovarian cancers, not all patients respond to this therapy, and resistance to these novel drugs remains a major clinical problem...
July 19, 2018: Nucleic Acids Research
Federica Alessandrini, Laura Pezzè, Daniel Menendez, Michael A Resnick, Yari Ciribilli
Breast cancer treatment often includes Doxorubicin as adjuvant as well as neoadjuvant chemotherapy. Despite its cytotoxicity, cells can develop drug resistance to Doxorubicin. Uncovering pathways and mechanisms involved in drug resistance is an urgent and critical aim for breast cancer research oriented to improve treatment efficacy. Here we show that Doxorubicin and other chemotherapeutic drugs induce the expression of ETV7, a transcriptional repressor member of ETS family of transcription factors. The ETV7 expression led to DNAJC15 down-regulation, a co-chaperone protein whose low expression was previously associated with drug resistance in breast and ovarian cancer...
August 2018: Neoplasia: An International Journal for Oncology Research
Chang Liu, Xie Zeng, Zijian An, Yunchen Yang, Maxwell Eisenbaum, Xiaodong Gu, Josep M Jornet, Grace K Dy, Mary E Reid, Qiaoqiang Gan, Yun Wu
Exosomes are small extracellular vesicles released by cells for cell-cell communication. They play important roles in cancer development, metastasis, and drug resistance. Exosomal proteins have been demonstrated by many studies as promising biomarkers for cancer screening, diagnosis, and monitoring. Among many detection techniques, surface plasmon resonance (SPR) is a highly sensitive, label-free, and real-time optical detection method. Commercial prism-based wavelength/angular-modulated SPR sensors afford high sensitivity and resolution, but their large footprint and high cost limit their adaptability for clinical settings...
July 31, 2018: ACS Sensors
Jürgen Weinreich, Florian Struller, Iaroslav Sautkin, Shalva Giuashvili, Marc Reymond, Alfred Königsrainer, Timm C Schott
We performed an in-vitro study testing the chemosensitivity of peritoneal cancer cell lines (SW620, HCT116, MKN45, 23,132/87, OAW42) to various cytostatic drug regimens. A duplex drug, characterized by reversible linking of the antimetabolites 2'-deoxy-5-fluorouridine (5-FdU) and 3'-C-ethynylcytidine (ECyd), was compared to oxaliplatin or to cisplatin plus doxorubicin. The experiments were designed to reflect the conditions of intraperitoneal chemotherapy. CASY® (Cell Analysis System) technology was used to compare the impact of incubation temperature/duration and drug concentration on the viability of the cancer cell lines versus normal human dermal fibroblasts...
July 18, 2018: Investigational New Drugs
Chi Yue, Ran-Hong Li, Chen Chen, Hui Liu
OBJECTIVE: To research the expression of X-linked inhibitor of apoptosis protein gene ( XIAP ) on paclitaxel resistance in ovarian cancer. METHODS: A2780 and A2780/T cells were treated with paclitaxel respectively at the concentrations of 5 ng/mL,10 ng/mL,20 ng/mL , 40 ng/mL,80 ng/mL,160 ng/mL,320 ng/mL,then the inhibition rate of cells were detected by MTT assay. The expression of XIAP mRNA and protein among the A2780 and A2780/T cells treated respectively with paclitaxel at the concentration of 100 ng/mL was detected by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) and Western blot...
May 2018: Sichuan da Xue Xue Bao. Yi Xue Ban, Journal of Sichuan University. Medical Science Edition
Xi-Ping Zhang, Qi-Hui Cheng, Hong-Jian Yang, En-Qi Qiao
With abilities to renew themselves and lead to heterogeneity of tumors, cancer stem cells (CSCs) are similar to stem cells. As three leading causes of death that endanger women's health, breast cancer, ovarian cancer and cervical cancer are characterized by high degree of malignancy, metastasis and recurrence. Associated with women's fertility, these three malignancies are common and representative among females. These years, research findings have suggested that CSCs are closely connected with many cancers (including aforementioned three malignancies) and several processes of tumors such as their genesis and development...
July 17, 2018: Pathology Oncology Research: POR
Xifeng Xiong, Jinli Zhang, Xing Hua, Wenjuan Cao, Shengnan Qin, Libing Dai, Wei Liu, Zhi Zhang, Xiaojian Li, Zhihe Liu
Epithelial ovarian cancer (EOC) is the fifth most common malignancy in women, with a 5-year mortality of >70% in North America. As the symptoms are often not observed until the cancer has spread extensively, few women are diagnosed at an early stage of disease. Large-scale gene expression analyses have identified molecular subtypes within high-grade ovarian cancer with variable survival rates and drug resistance. The understanding of gene expression, the mechanisms underlying cancer processes and drug resistances have facilitated the development of targeted therapies...
August 2018: Oncology Letters
Hsiang-Ju Chen, Rui-Lan Huang, Phui-Ly Liew, Po-Hsuan Su, Lin-Yu Chen, Yu-Chun Weng, Cheng-Chang Chang, Yu-Chi Wang, Michael Wing-Yan Chan, Hung-Cheng Lai
Ovarian high-grade serous carcinoma (HGSC) is the most lethal gynecological malignancy. Prevailing evidences suggest that drug resistance and recurrence of ovarian HGSC are caused by the presence of cancer stem cells. Therefore, targeting cancer stems is appealing, however, all attempts to date, have failed. To circumvent this limit, we analyzed differential transcriptomes at early differentiation of ovarian HGSC stem cells and identified the developmental transcription factor GATA3 as highly expressed in stem, compared to progenitor cells...
July 14, 2018: International Journal of Cancer. Journal International du Cancer
Niamh Mc Namee, Lorraine O'Driscoll
Extracellular vesicles (EVs) including exosomes, microvesicles, oncosomes, and microparticles have been associated with communicating anti-cancer drug-resistance. The in vitro, pre-clinical in vivo and patients' data linking EVs to drug-resistance (and the specific drugs involved) in breast cancer, prostate cancer, lung cancer, ovarian cancer, haematological malignancies, colorectal cancer, gastric cancer, pancreatic cancer, glioblastoma, neuroblastoma, melanoma, kidney cancer and osteosarcoma. Details of the mechanisms by which the resistance seems to be occurring (e...
July 9, 2018: Biochimica et Biophysica Acta
Xinyan Chen, Yumei Chen, Xueyan Lin, Shan Su, Xiaoman Hou, Qian Zhang, Yongjie Tian
BACKGROUND & OBJECTIVE: Many targeted ovarian cancer patients are resistant to olaparib treatment. Here we seek to understand the underlying molecular events and search for potential combinational therapeutics to surmount the intrinsic olaparib resistance in human ovarian cancer. METHODS: The cytotoxicity was determined by the MTT assay and cell viability was measured using Cell Counting Kit-8 (CCK-8). Protein expressions of ERK, P38, JNK, ERK5, LC3, N-CADHERIN, α-SMA were determined by western blotting...
July 12, 2018: Current Pharmaceutical Biotechnology
Jia-Juan Tu, Le Ou-Yang, Xiaohua Hu, Xiao-Fei Zhang
Understanding how gene dependency networks rewire between different disease states is an important task in genomic research. Although many computational methods have been proposed to undertake this task via differential network analysis, most of them are designed for a predefined data type. With the development of the high throughput technologies, gene activity measurements can be collected from different aspects (e.g., mRNA expression and DNA mutation). Different data types might share some common characteristics and include certain unique properties...
May 9, 2018: IEEE/ACM Transactions on Computational Biology and Bioinformatics
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