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Carboplatin resistant ovarian cancer

Daniela Matei, Sharad Ghamande, Lynda D Roman, Angeles Alvarez Secord, John Nemunaitis, Merry Jennifer Markham, Kenneth P Nephew, Simone Jueliger, Aram Oganesian, Sue Naim, Xiang-Yao Su, Harold N Keer, Mohammad Azab, Gini Fleming
PURPOSE: Epigenetic changes are implicated in acquired resistance to platinum. Guadecitabine is a next-generation hypomethylating agent (HMA). Here we report the clinical results, along with pharmacokinetic (PK) and pharmacodynamic analyses of the phase 1 study of guadecitabine and carboplatin (G+C) in patients with recurrent, platinum resistant high-grade serous ovarian cancer (OC), primary peritoneal carcinoma (PPC), or fallopian tube cancer (FTC). EXPERIMENTAL DESIGN: Guadecitabine was administered once daily on Days 1-5 followed by carboplatin IV on Day 8 of a 28-day cycle...
March 2, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Belinda van Zyl, Denise Tang, Nikola A Bowden
Ovarian cancer has poor survival rate due to a combination of diagnosis at advanced disease stages and disease recurrence as a result of platinum chemotherapy resistance. High grade serous ovarian cancer (HGSOC), the most common ovarian cancer subtype, is conventionally treated with surgery and paclitaxel/carboplatin combination chemotherapy. Initial response rates are 60-80%, but eventually the majority of patients become platinum resistant with subsequent relapses. Extensive research on individual biomarkers of platinum-resistance has revealed many potential targets for the development new treatments...
February 27, 2018: Endocrine-related Cancer
Paulina Cybulska, Jocelyn M Stewart, Azin Sayad, Carl Virtanen, Patricia A Shaw, Blaise Clarke, Natalie Stickle, Marcus Q Bernardini, Benjamin G Neel
High-grade serous ovarian cancer (HGSC) is the leading cause of morbidity and mortality from gynecologic malignancy. Overall survival remains low, due to the nearly ubiquitous emergence of platinum-resistance and the paucity of effective next-line treatments. Current cell culture-based models show limited similarity to HGSC and are therefore unreliable predictive models for pre-clinical evaluation of investigational drugs. This deficiency could help explain the low overall rate of successful drug development and the decades of largely unchanged approaches to HGSC treatment...
February 16, 2018: American Journal of Pathology
Reiko Tasaka, Takeshi Fukuda, Masahiro Shimomura, Yuta Inoue, Takuma Wada, Masaru Kawanishi, Tomoyo Yasui, Toshiyuki Sumi
The standard treatment for ovarian serous carcinoma comprises maximum debulking surgery and platinum-based chemotherapy. Despite the high response rate to chemotherapy, the majority of patients will be resistant to first-line agents and the prognosis for these patients is particularly poor. At present there are no reliable methods to determine or predict platinum resistance. T-box 2 (TBX2) is widely expressed in cancer cells and is involved in embryonic development and cell cycle regulation. TBX2 enables cells to bypass senescence through its ability to repress the cell cycle regulators p21 and p14ARF; silencing TBX2 induces senescence...
March 2018: Oncology Letters
Yanxiu Guo, Haoxia Zeng, Xiaohong Chang, Chaohua Wang, Heng Cui
BACKGROUND: Side-effects have been considered as the limitation of the chemotherapy agents' administration and life quality in patients with ovarian cancers. In order to explore the influence of the chemotherapy agents commonly used in ovarian cancer patients on the blood glucose metabolism in rat models, we conducted this study which simulated the conditions of clinical protocols. METHODS: Eighty clean-grade female Wistar rats were randomized into 8 groups: Group 1 (Negative control), Group 1' (Dexamethasone), Group 2 (Carboplatin), Group 2' (Carboplatin-plus-dexamethasone), Group 3 (Paclitaxel), Group 3' (Paclitaxel-plus-dexamethasone), Group 4 (Combined therapy), Group 4' (Combined-therapy-plus-dexamethasone)...
January 16, 2018: BMC Cancer
S Pignata, S C Cecere, A Du Bois, P Harter, F Heitz
Despite optimal surgery and appropriate first-line chemotherapy, ∼70%-80% of patients with epithelial ovarian cancer will develop disease relapse. The same modalities as used primarily are available for treatment of recurrent ovarian cancer (ROC). The rationale for repetitive surgery in ROC was based on a stable body of retrospective data; however, prospective data were missing. Now, preliminary data from the prospective AGO-DESKTOP III give evidence that surgery for ROC seems to be of benefit for selected patients with platinum-sensitive relapse undergoing complete resection...
November 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Fang Fang, Horacio Cardenas, Hao Huang, Guanglong Jiang, Susan M Perkins, Chi Zhang, Harold N Keer, Yunlong Liu, Kenneth P Nephew, Daniela Matei
DNA methylation aberrations have been implicated in acquired resistance to platinum drugs in ovarian cancer. In this study, we elucidated an epigenetic signature associated with platinum drug resensitization that may offer utility in predicting the outcomes of patients who are coadministered a DNA methyltransferase inhibitor. The ovarian cancer specimens we analyzed were derived from a recent clinical trial that compared the responses of patients with recurrent platinum-resistant ovarian cancer who received carboplatin plus the DNA methyltransferase inhibitor guadecitabine or a standard-of-care chemotherapy regimen selected by the treating physician...
February 1, 2018: Cancer Research
Verena Schneider, Selim Chaib, Claudia Spanier, Mandy Knapp, Violeta Moscvin, Laura Scordovillo, Alessandra Ewertz, Ulrich Jaehde, Ganna V Kalayda
Combining the multikinase inhibitor sorafenib with the platinum-based chemotherapy of solid tumors was expected to improve treatment outcome. However, in many clinical trials, no benefit from sorafenib addition to the platinum-containing regimen could be demonstrated. Moreover, in some studies, decreased survival of ovarian cancer patients as well as non-small cell lung cancer patients with squamous cell histology was observed. The aim of this study was to investigate the cellular mechanisms of the pharmacological interaction between platinum drugs and sorafenib in different cancer cell lines...
November 30, 2017: AAPS Journal
May Thuu Mon, Supachai Yodkeeree, Wanisa Punfa, Sonthaya Umsumarng, Suree Lekwanavijit, Sumalee Siriaunkgul, Prapaporn Suprasert, Pornngarm Limtrakul
Objective: Our goal was to determine the ex-vivo drug resistance assay, as well as the cytokine production, in response to platinum-based chemotherapy treatment in primary culture cells established from the tumor tissue of ovarian or fallopian tube carcinoma patients, and to predict the clinical responses to chemotherapy. Methods: Sensitivity to the platinum-based drug was analyzed in two ovarian cancer cell lines and 19 tumor samples using the primary cell culture obtained from 19 patients having ovarian or fallopian tube cancer that had undergone surgery from 2014 to 2017...
November 26, 2017: Asian Pacific Journal of Cancer Prevention: APJCP
Xinxin Zhu, Jia Xu, Han Cai, Jinghe Lang
AIM: In advanced, platinum resistant or refractory ovarian cancer (OC), the therapeutic efficacy of carboplatin is controversial. Although anti-programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) pathway blockages show great potential in cancer treatment, the antitumor effect of single anti-PD-L1 pathway monoclonal antibody (mAb) is not obvious in advanced or some poorly immunogenic tumors, including OC. We compared the effects of single or combined carboplatin and anti-PD-L1 mAb treatments and explored the possible antitumor mechanisms in a murine ID8 OC model...
February 2018: Journal of Obstetrics and Gynaecology Research
Tran N Le, Rachel E Harvey, Christine K Kim, Jubilee Brown, Robert L Coleman, Judith A Smith
Background: While many of these agents have been compared in prospective clinical trials, the gemcitabine/platinumbased regimens have not been compared in a prospective, randomized clinical trial. While bothgemcitabine/carboplatin and gemcitabine/cisplatin have a similar ORR in separate clinical trials, the tworegimens have never been directly been compared. With overlapping dose-limiting toxicity of thrombocytopenia, the gemcitabine/carboplatin regimen has been challenging to employ in the clinical setting in previously treated ovarian cancer patients and is often associated with treatment delays and/or dose reductions...
2017: Gynecologic Oncology Research and Practice
Jinli Zhang, Xifeng Xiong, Xing Hua, Wenjuan Cao, Shengnan Qin, Libing Dai, Peihong Liang, Huiling Zhang, Zhihe Liu
Epithelial ovarian cancer (EOC) affects almost 25,000 women annually and is the fifth most common malignancy in women in North America. A combination of surgery and cytotoxic chemotherapy may produce a favorable clinical response. The platinum-paclitaxel combination regimen is the chemotherapy gold-standard for advanced ovarian cancer, and carboplatin is one of the agents in this combination therapy. However, the majority of patients eventually experience a relapse due to the development of platinum resistance...
November 2017: Oncology Letters
Silvia Carloni, Giulia Gallerani, Anna Tesei, Emanuela Scarpi, Giorgio Maria Verdecchia, Salvatore Virzì, Francesco Fabbri, Chiara Arienti
OBJECTIVE: We investigated the correlation between ploidy or S-phase fraction (SPF) and the clinical pathological characteristics of patients with peritoneal carcinomatosis from ovarian cancer. We also assessed their relation with the in vivo and in vitro response to several chemotherapeutic agents. PATIENTS AND METHODS: Fifty-three patients with peritoneal carcinomatosis from ovarian cancer were enrolled. Frozen tumor tissue was dissociated by a detergent-trypsin method, and the resulting cell suspension was stained with RNase A and propidium iodide...
2017: OncoTargets and Therapy
Young-Jae Lee, Yong-Man Kim, Shin-Wha Lee, Jeong-Yeol Park, Dae-Yeon Kim, Dae-Shik Suh, Jong-Hyeok Kim, Young-Tak Kim, Joo-Hyun Nam
OBJECTIVE: This study aimed to evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) with or without carboplatin in Korean patients with recurrent ovarian cancer (ROC), fallopian tube, or primary peritoneal cancer. METHODS: This retrospective study included 52 patients with ROC, fallopian tube, or primary peritoneal cancer who received PLD (50 mg/m2 ) between 1st December 2014 and 31th July 2016. RESULTS: The mean number of chemotherapy cycles was 3...
September 2017: Obstetrics & Gynecology Science
Tong Shu, Yi Li, Xiaowei Wu, Bin Li, Zhihua Liu
Resistance to platinum-based chemotherapy is a major cause of treatment failure in patients with epithelial ovarian cancer and predicts a poor prognosis. Previously, we found that HECTD3 confers cancer cell resistance to apoptosis. However, the significance of HECTD3 expression in ovarian cancer and its regulatory mechanisms were unknown. Here, we found that HECTD3 depletion promotes carboplatin-induced apoptosis in both an ovarian cancer cell model and a xenograft mouse model. Moreover, high HECTD3 expression is significantly associated with poor platinum response and prognosis in ovarian cancer patients...
December 28, 2017: Cancer Letters
Xin Yu, Heyi Zheng, Matthew Tv Chan, William Kk Wu
Ovarian cancer accounts for the highest mortality among all gynecologic cancers. Cytoreductive surgery followed by chemotherapy with a platinum-based agent (cisplatin or carboplatin) plus paclitaxel is the first-line option for treatment of epithelial ovarian cancer. However, primary or acquired resistance to platinum-based agents is a major clinical challenge. MicroRNAs are a group of small non-coding RNAs that regulate gene expression post-transcriptionally and may function as oncogenes or tumor-suppressor genes through extensive crosstalk with intracellular signaling pathways...
2017: American Journal of Cancer Research
Yvonne Andersson, Synne Ihler Haavardtun, Ben Davidson, Anne Dørum, Karianne G Fleten, Øystein Fodstad, Kjersti Flatmark
Peritoneal metastasis (PM) is an important feature of epithelial ovarian cancer (EOC) and is a frequent site of drug resistant disease recurrence, identifying PM-EOC an important clinical challenge. The MOC31PE immunotoxin targets and kills tumor cells expressing the epithelial cell adhesion molecule (EpCAM), which is highly expressed in EOC, and MOC31PE is being investigated for use in treatment of PM-EOC. The efficacy of MOC31PE treatment alone and in combination with cytotoxic drugs was investigated in two human EpCAM expressing EOC cell lines, B76 and MDHA-2774, in vitro and in corresponding mouse models mimicking PM-EOC...
September 22, 2017: Oncotarget
Jie-Xue Pan, Fan Qu, Fang-Fang Wang, Jian Xu, Liang-Shan Mu, Long-Yun Ye, Jun-Jian Li
AIM: Resistance to platinum-based therapeutic agents is the major contributor to epithelial ovarian cancer (EOC) mortality. There is an urgent need to better understand the underlying mechanisms. Here we investigated the role of serpins in EOC chemoresistance and related mechanisms, and found that SERPINE1 played an important role in chemoresistance in A2780cp cells. MATERIALS AND METHODS: A2780cp and A2780s cells were used in our study. Microarray screening was used to identify the gene expression change under carboplatin treatment...
October 3, 2017: Archives of Gynecology and Obstetrics
Alberto Ballestrero, Davide Bedognetti, Domenico Ferraioli, Paola Franceschelli, Sana Intidhar Labidi-Galy, Elisabetta Leo, Junko Murai, Yves Pommier, Petros Tsantoulis, Valerio Gaetano Vellone, Gabriele Zoppoli
SLFN11 is a recently discovered protein with a putative DNA/RNA helicase function. First identified in association with the maturation of thymocytes, SLFN11 was later causally associated, by two independent groups, with the resistance to DNA damaging agents such as topoisomerase I and II inhibitors, platinum compounds, and other alkylators, making it an attractive molecule for biomarker development. Later, SLFN11 was linked to antiviral response in human cells and interferon production, establishing a potential bond between immunity and chemotherapy...
October 2, 2017: Journal of Translational Medicine
Yan Zhang, Qian Mei, Yang Liu, Xiang Li, Malcolm V Brock, Meixia Chen, Liang Dong, Lu Shi, Yao Wang, Mingzhou Guo, Jing Nie, Weidong Han
Purpose: DNA demethylating agents have shown clinical effectiveness in hematological and solid tumors. This trial tested the safety, efficacy, and treatment outcomes of decitabine-based chemotherapy or combined with immunotherapy in recurrent ovarian cancer patients. Patients and methods: Fifty-five patients with recurrent ovarian cancer were enrolled and 52 were assessable for clinical response and survival. Patients either received 5-d decitabine treatment, followed by reduced-dose of paclitaxel/carboplatin administration (DTC cohort), or the aforementioned regimen combined with cytokine-induced killer cells therapy (DTC+CIK cohort)...
2017: Oncoimmunology
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