Publications
331 results found
Gungor H, Saleem A, Babar S, et al., 2015, Dose-finding quantitative F-18-FDG PET imaging study with the oral pan-AKT inhibitor GSK2141795 in patients with gynecologic malignancies, Journal of Nuclear Medicine, Vol: 56, Pages: 1828-1835, ISSN: 1535-5667
AKT (a serine/threonine-specific protein kinase) regulates many cellular processes contributing to cytotoxic drug resistance. This study’s primary objective examined the relationship between GSK2141795, an oral, pan-AKT inhibitor, and 18F-FDG PET markers of glucose metabolism in tumor tissue to determine whether 18F-FDG PET could be used to guide personalized dosing of GSK2141795. Biomarker analysis of biopsies was also undertaken. Methods: Twelve patients were enrolled in 3 cohorts; all underwent dynamic 18F-FDG PET scans and serial pharmacokinetic sampling at baseline, week 2, and week 4 with tumor biopsies before treatment and at week 4. Response was evaluated by RECIST v1.1 and Gynecologic Cancer Intergroup criteria. Biopsy samples were analyzed for mutations and protein expression. Results: GSK2141795 did not significantly influence blood glucose levels. No dose–response relationship was observed between GSK2141795 pharmacokinetics and 18F-FDG PET pharmacodynamic measures; however, an exposure–response relationship was seen between maximum drug concentrations and maximal decrease in 18F-FDG uptake in the best-responding tumor. This relationship also held for pharmacokinetic parameters of exposure and 1,5-anhydroglucitol (a systemic measure of glucose metabolism). Phospho-AKT upregulation at week 4 in biopsies confirmed AKT inhibition by GSK2141795. Single-agent activity was observed with a clinical benefit rate of 27% (3/11) and 30% (3/10) CA125 response in the study’s platinum-resistant ovarian patients. AKT pathway activation by PIK3CA/PIK3R1 mutation did not correlate with clinical activity, whereas RAS/RAF pathway mutations did segregate with resistance to AKT inhibition. Conclusion: GSK2141795 demonstrated an exposure–response relationship with decreased 18F-FDG uptake and is active and tolerable. This study’s design integrating 18F-FDG PET, pharmacokinetics, and biomarker analyses demonstrates the potential for clinical
Gourley C, Gabra H, Vergote I, et al., 2015, EUTROC PISARRO: PRELIMINARY RESULTS OF PHASE IB STUDY COMBINING APR-246 WITH CHEMOTHERAPY IN PLATINUM SENSITIVE RELAPSED HIGH GRADE SEROUS OVARIAN CARCINOMA(HGSOC), Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 1368-1368, ISSN: 1048-891X
Nasser S, Lazaridis A, Jones B, et al., 2015, CORRELATION OF PRE-OPERATIVE CT FINDINGS WITH SURGICAL & HISTOLOGICAL TUMOR DISSEMINATION PATTERNS AT CYTOREDUCTION FOR ADVANCED OVARIAN CANCER: A RETROSPECTIVE EVALUATION, INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, Vol: 25, Pages: 502-502, ISSN: 1048-891X
Antony J, Tan TZ, Paterson A, et al., 2015, The receptor tyrosine kinase AXL modulates oncogenic signaling and epithelial mesenchymal transition in epithelial ovarian cancer, 10th Biennial Ovarian Cancer Research Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 1078-0432
Curry E, Cheraghchi-Bashi-Astaneh A, Chen M, et al., 2015, DNA-PKcs is amplified in high grade serous ovarian cancer (HGSC), correlates with poor outcome and drives resistance to platinum therapy via the AKT signaling pathway, 10th Biennial Ovarian Cancer Research Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 1078-0432
von Euler M, Wiman KG, Gabra H, et al., 2015, Preliminary results from PiSARRO, a phase Ib/II study of APR-246, a mutant p53 reactivating small molecule, in combination with standard chemotherapy in platinum-sensitive ovarian cancer, 106th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: American Association for Cancer Research, ISSN: 1538-7445
Matsuo K, Hasegawa K, Yoshino K, et al., 2015, Venous thromboembolism, interleukin-6 and survival outcomes in patients with advanced ovarian clear cell carcinoma, European Journal of Cancer, Vol: 51, Pages: 1978-1988, ISSN: 1879-0852
Background:We compared survival outcomes and risk of venous thromboembolism (VTE) among patients with advanced and early-stage ovarian clear cell carcinoma (OCCC) and serous ovarian carcinoma (SOC), as well as potential links with interleukin-6 (IL-6) levels.Methods:A multicenter case-control study was conducted in 370 patients with OCCC and 938 with SOC. In a subset of 200 cases, pretreatment plasma IL-6 levels were examined.Findings:Patients with advanced OCCC had the highest 2-year cumulative VTE rates (advanced OCCC 43.1%, advanced SOC 16.2%, early-stage OCCC 11.9% and early-stage SOC 6.4%, P < 0.0001) and the highest median levels of IL-6 (advanced OCCC 17.8 pg/mL, advanced SOC 9.0 pg/mL, early-stage OCCC 4.2 pg/mL and early-stage SOC 5.0 pg/mL, P = 0.006). Advanced OCCC (hazard ratio [HR] 3.38, P < 0.0001), thrombocytosis (HR 1.42, P = 0.032) and elevated IL-6 (HR 8.90, P = 0.046) were independent predictors of VTE. In multivariate analysis, patients with advanced OCCC had significantly poorer 5-year progression-free and overall survival rates than those with advanced SOC (P < 0.01), and thrombocytosis was an independent predictor of decreased survival outcomes (P < 0.01). Elevated IL-6 levels led to poorer 2-year progression-free survival rates in patients with OCCC (50% versus 87.5%, HR 4.89, P = 0.016) than in those with SOC (24.9% versus 40.8%, HR 1.40, P = 0.07).Interpretation:Advanced OCCC is associated with an increased incidence of VTE and decreased survival outcomes, which has major implications for clinical management of OCCC.
Curry E, Cheraghchi-Bashi-Astaneh A, Chen M, et al., 2015, DNA-PKcs is amplified in high-grade serous ovarian cancer (HGSC), correlates with poor outcome and drives resistance to platinum therapy via the AKT signaling pathway, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 1535-7163
Openshaw MR, Fotopoulou C, Blagden S, et al., 2015, The next steps in improving the outcomes of advanced ovarian cancer, Women's Health, Vol: 11, Pages: 355-367, ISSN: 1745-5057
Worldwide ovarian cancer affects over 200,000 women per year. Overall survival rates are poor due to two predominate reasons. First, the majority of patients present with advanced disease creating significant difficulty with effecting disease eradication. Second, acquisition of chemotherapy resistance results in untreatable progressive disease. Advances in treatment of advanced ovarian cancer involve a spectrum of interventions including improvements in frontline debulking surgery and combination chemotherapy. Anti-angiogenic factors have been shown to have activity in frontline and recurrent disease while novel chemotherapeutic agents and targeted treatments are in development particularly for disease that is resistant to platinum-based chemotherapy. These developments aim to improve the progression-free and overall survival of women with advanced ovarian cancer.
Patch A-M, Christie EL, Etemadmoghadam D, et al., 2015, Whole-genome characterization of chemoresistant ovarian cancer, Nature, Vol: 521, Pages: 489-494, ISSN: 0028-0836
Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.
Fotopoulou C, Cunnea P, Rama NR, et al., 2015, Characterising phenotypically relevant intratumoural heterogeneity in high grade serous ovarian cancer., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) / Clinical Science Symposium on Predicting and Improving Adverse Outcomes in Older Adults with Cancer, Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Brown R, Timms K, Paul J, et al., 2015, Homologous recombination (HR) deficiency, tumor BRCA1/2 mutations (tmBRCA) and association with response and outcome following platinum monotherapy in high grade serous ovarian cancer (HGSOC)., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) / Clinical Science Symposium on Predicting and Improving Adverse Outcomes in Older Adults with Cancer, Publisher: American Society of Clinical Oncology, ISSN: 0732-183X
Blagden SP, Rizzuto I, Stavraka C, et al., 2015, Final results of ProGem1, the first in-human phase I/II study of NUC-1031 in patients with solid malignancies, Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: American Society of Clinical Oncology, ISSN: 0732-183X
Blagden SP, Rizzuto I, Stavraka C, et al., 2015, A first in human Phase I/II study of NUC-1031 in patients with advanced gynecological cancers, Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: American Society of Clinical Oncology, ISSN: 0732-183X
Gourley C, Gabra H, Vergote I, et al., 2015, EUTROC PiSARRO: A phase Ib study combining APR-246 with standard chemotherapy in platinum sensitive relapsed high grade serous ovarian carcinoma (HGSOC)., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) / Clinical Science Symposium on Predicting and Improving Adverse Outcomes in Older Adults with Cancer, Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
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Stronach EA, Cunnea P, Turner C, et al., 2015, The role of interleukin-8 (IL-8) and IL-8 receptors in platinum response in high grade serous ovarian carcinoma, Oncotarget, Vol: 6, Pages: 31593-31603, ISSN: 1949-2553
Platinum based drugs are the cornerstone of chemotherapy for ovarian cancer, however the development of chemoresistance hinders its success. IL-8 is involved in regulating several pro-survival pathways in cancer. We studied the expression of IL-8 and IL-8 receptors in platinum sensitive and resistant cell lines. Using qRT-PCR and immunohistochemistry, both platinum sensitive (PEA1, PEO14) and resistant (PEA2, PEO23) show increased expression of IL-8 and IL-8 receptors. IL-8RA shows nuclear and cytoplasmic expression, whilst IL-8RB is present solely in the cytoplasm. Knockdown of IL-8 increased sensitivity to cisplatin in platinum sensitive and reversed platinum resistance in resistant cell lines, decreased the expression of anti-apoptotic Bcl-2 and decreased inhibitory phosphorylation of pro-apoptotic Bad. IL-8 receptor antagonist treatment also enhanced platinum sensitivity. Nuclear localisation of IL-8RA was only detected in platinum resistant tumours. Inhibition of IL-8 signalling can enhance response in platinum sensitive and resistant disease. Nuclear IL-8RA may have potential as a biomarker of resistant disease.
Rizzuto I, Stavraka C, Chatterjee J, et al., 2015, Risk of Ovarian Cancer Relapse Score A Prognostic Algorithm to Predict Relapse Following Treatment for Advanced Ovarian Cancer, International Journal of Gynecological Cancer, Vol: 25, Pages: 416-422, ISSN: 1525-1438
Objective: The aim of this study was to construct a prognostic index that predicts risk ofrelapse in women who have completed first-line treatment for ovarian cancer (OC).Methods: A database of OC cases from 2000 to 2010 was interrogated for InternationalFederation of Gynecology and Obstetrics stage, grade and histological subtype of cancer,preoperative and posttreatment CA-125 level, presence or absence of residual disease aftercytoreductive surgery and on postchemotherapy computed tomography scan, and time toprogression and death. The strongest predictors of relapse were included into an algorithm,the Risk of Ovarian Cancer Relapse (ROVAR) score.Results: Three hundred fifty-four cases of OC were analyzed to generate the ROVARscore. Factors selected were preoperative serum CA-125, International Federation ofGynecology and Obstetrics stage and grade of cancer, and presence of residual disease atposttreatment computed tomography scan. In the validation data set, the ROVAR score had asensitivity and specificity of 94% and 61%, respectively. The concordance index for thevalidation data set was 0.91 (95% confidence interval, 0.85-0.96). The score allows patientstratification into low (G0.33), intermediate (0.34Y0.67), and high (90.67) probability ofrelapse.Conclusions: The ROVAR score stratifies patients according to their risk of relapsefollowing first-line treatment for OC. This can broadly facilitate the appropriate tailoring ofposttreatment care and support.
Hopkins TG, Stavraka C, Gabra H, et al., 2015, Sexual activity and functioning in ovarian cancer survivors: an internet-based evaluation, CLIMACTERIC, Vol: 18, Pages: 94-98, ISSN: 1369-7137
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- Citations: 24
Wu W, Vitharana K, Gorgy T, et al., 2015, A Method for Voltage Measurements of Cancerous vs Non-cancerous Omentum, 37th Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society (EMBC), Publisher: IEEE, Pages: 7514-7517, ISSN: 1557-170X
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Mura M, Hopkins TG, Michael T, et al., 2014, LARP1 post-transcriptionally regulates mTOR and contributes to cancer progression, Oncogene, Vol: 34, Pages: 5025-5036, ISSN: 1476-5594
RNA-binding proteins (RBPs) bind to and post-transcriptionally regulate the stability of mRNAs. La-related protein 1 (LARP1) is a conserved RBP that interacts with poly-A-binding protein and is known to regulate 5′-terminal oligopyrimidine tract (TOP) mRNA translation. Here, we show that LARP1 is complexed to 3000 mRNAs enriched for cancer pathways. A prominent member of the LARP1 interactome is mTOR whose mRNA transcript is stabilized by LARP1. At a functional level, we show that LARP1 promotes cell migration, invasion, anchorage-independent growth and in vivo tumorigenesis. Furthermore, we show that LARP1 expression is elevated in epithelial cancers such as cervical and non-small cell lung cancers, where its expression correlates with disease progression and adverse prognosis, respectively. We therefore conclude that, through the post-transcriptional regulation of genes such as mTOR within cancer pathways, LARP1 contributes to cancer progression.
Gabra H, 2014, Introduction to managing patients with recurrent ovarian cancer, European Journal of Cancer, Supplement, Vol: 12, Pages: 2-6, ISSN: 1878-1217
Ovarian cancer is the 5th most common cancer found in women in the UK. It is the leading cause of death from gynaecological cancer, and is the 4th most common cause of cancer death among UK women. Similar to the majority of other cancers, relative survival rates for ovarian cancer are improving, although 5-year mortality rates remain stubbornly low. The stage of the disease at diagnosis is the single most important determinant of ovarian cancer survival, as many patients first present with advanced disease. Treatment of ovarian cancer involves a combination of 'upfront' primary surgery followed by chemotherapy. Platinum/taxane-based chemotherapy is the recommended standard-of-care first-line chemotherapy, but the majority of patients will relapse with drug-resistant disease within 3-5 years. However, not all patients can continue with platinum combination therapies due to loss of activity or toxicity-related issues, including hypersensitivity, neurotoxicity, alopecia and ototoxicity. Therefore the choice of second-line chemotherapy must take into account factors such as platinum-free treatment interval (PFI); patient's performance status; current symptoms; history of and likely future toxicities while on chemotherapy; dosing schedule requirement; and cost of treatment. A consensus in 2010 established 4 distinct subgroups within the ROC patient population based on the PFI: (platinum sensitive <12 months, partially platinum sensitive 6-12 months, platinum resistant <6 months, and refractory disease ≤4 weeks). Within patients with platinum sensitive disease, those with partially platinum sensitive disease remain the most clinically challenging to manage effectively. Non-platinum based combination therapies, in particular trabectedin with pegylated liposomal doxorubicin (PLD), offers new options together with a significant survival advantage relative to PLD alone for these patients.
Al Bakir M, Gabra H, 2014, The molecular genetics of hereditary and sporadic ovarian cancer: implications for the future, BRITISH MEDICAL BULLETIN, Vol: 112, Pages: 57-69, ISSN: 0007-1420
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- Citations: 15
Filipovic A, Lombardo Y, Faronato M, et al., 2014, Anti-nicastrin monoclonal antibodies elicit pleiotropic anti-tumour pharmacological effects in invasive breast cancer cells (vol 148, pg 455, 2014), BREAST CANCER RESEARCH AND TREATMENT, Vol: 148, Pages: 463-463, ISSN: 0167-6806
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- Citations: 1
Filipovic A, Lombardo Y, Fronato M, et al., 2014, Anti-nicastrin monoclonal antibodies elicit pleiotropic anti-tumour pharmacological effects in invasive breast cancer cells, BREAST CANCER RESEARCH AND TREATMENT, Vol: 148, Pages: 455-462, ISSN: 0167-6806
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- Citations: 16
Gorgy T, Paterson A, Vitharana K, et al., 2014, MOLECULAR PHYSIOLOGY MONITORING OF OVARIAN CANCER EX VIVO, INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, Vol: 24, Pages: 402-402, ISSN: 1048-891X
Blagden S, Hamilton A, Mileshkin L, et al., 2014, Afuresertib (GSK2110183), an oral AKT kinase inhibitor, in combination with carboplatin and paclitaxel in recurrent ovarian cancer, 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Publisher: ELSEVIER SCI LTD, Pages: 7-7, ISSN: 0959-8049
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- Citations: 5
Fotopoulou C, Cunnea P, Rama N, et al., 2014, CHARACTERISING PHENOTYPICALLY RELEVANT INTRATUMOURAL HETEROGENEITY IN HIGH GRADE SEROUS OVARIAN CANCER, INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, Vol: 24, Pages: 443-444, ISSN: 1048-891X
Gabra H, Oliver KE, Xiao N, et al., 2014, TUMOUR MOLECULAR PROFILE-DIRECTED TREATMENT IS ASSOCIATED WITH IMPROVED SURVIVAL IN RECURRENT EPITHELIAL OVARIAN CANCER, INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, Vol: 24, Pages: 27-27, ISSN: 1048-891X
Booth AEG, Tarafder AK, Hume AN, et al., 2014, A Role for Na+, K+-ATPase alpha 1 in Regulating Rab27a Localisation on Melanosomes, PLOS One, Vol: 9, ISSN: 1932-6203
The mechanism(s) by which Rab GTPases are specifically recruited to distinct intracellular membranes remains elusive. Herewe used Rab27a localisation onto melanosomes as a model to investigate Rab targeting. We identified the a1 subunit ofNa+,K+-ATPase (ATP1a1) as a novel Rab27a interacting protein in melanocytes and showed that this interaction is direct withthe intracellular M4M5 loop of ATP1a1 and independent of nucleotide bound status of the Rab. Knockdown studies inmelanocytes revealed that ATP1a1 plays an essential role in Rab27a-dependent melanosome transport. Specifically,expression of ATP1a1, like the Rab27a GDP/GTP exchange factor (Rab3GEP), is essential for targeting and activation ofRab27a to melanosomes. Finally, we showed that the ability of Rab27a mutants to target to melanosomes correlates withthe efficiency of their interaction with ATP1a1. Altogether these studies point to a new role for ATP1a1 as a regulator ofRab27a targeting and activation.
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