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  • Journal article
    Gungor H, Saleem A, Babar S, Dina R, El-Bahrawy MA, Curry E, Rama N, Chen M, Pickford E, Agarwal R, Blagden S, Carme S, Salinas C, Madison S, Krachey E, Santiago-Walker A, Smith DA, Morris SR, Stronach EA, Gabra Het 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

  • Journal article
    Curry E, Green I, Chapman-Rothe N, Shamsaei E, Kandil S, Cherblanc F, Payne L, Bell E, Ganesh T, Srimongkolpithak N, Caron J, Li F, Uren AG, Snyder JP, Vedadi M, Fuchter MJ, Brown Ret al., 2015,

    Dual EZH2 and EHMT2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells

    , Clinical Epigenetics, Vol: 7, ISSN: 1868-7083

    Background: Many cancers show aberrant silencing of gene expression andoverexpression of histone methyltransferases. The histone methyltransferases (HKMT)EZH2 and EHMT2 maintain the repressive chromatin histone marks H3K27 and H3K9methylation respectively, which are associated with transcriptional silencing. Althoughselective HKMT inhibitors reduce levels of individual repressive marks, removal ofH3K27me3 by specific EZH2 inhibitors, for instance, may not be sufficient for inducingexpression of genes with multiple repressive marks.Results: We report that gene expression and inhibition of triple negative breast cancer cellgrowth (MDA-MB-231) are markedly increased when targeting both EZH2 and EHMT2,either by siRNA knockdown or pharmacological inhibition, rather than independently. Indeed,expression of certain genes is only induced upon dual inhibition. We sought to identifycompounds which showed evidence of dual EZH2 and EHMT2 inhibition. Using a cell-basedassay, based on the substrate-competitive EHMT2 inhibitor BIX01294, we have identifiedproof-of-concept compounds that induce re-expression of a subset of genes consistent withdual HKMT inhibition. Chromatin immunoprecipitation verified a decrease in silencing marksand an increase in permissive marks at the promoter and transcription start site of reexpressedgenes, while Western analysis showed reduction in global levels of H3K27me3and H3K9me3. The compounds inhibit growth in a panel of breast cancer and lymphoma celllines with low to sub-micromolar IC50s. Biochemically, the compounds are substratecompetitive inhibitors against both EZH2 and EHMT1/2.Conclusions: We have demonstrated that dual inhibition of EZH2 and EHMT2 is moreeffective at eliciting biological responses of gene transcription and cancer cell growthinhibition compared to inhibition of single HKMTs, and we report the first dual EZH2-EHMT1/2 substrate competitive inhibitors that are functional in cells.

  • Conference paper
    Curry E, Cheraghchi-Bashi-Astaneh A, Chen M, Cunnea P, De Sousa C, Maginn E, Dai Y, Liu E, Wasan H, Mills G, Bowtell D, Gabra H, Stronach EAet 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
  • Journal article
    Matsuo K, Hasegawa K, Yoshino K, Murakami R, Hisamatsu T, Stone RL, Previs RA, Hansen JM, Ikeda Y, Miyara A, Hiramatsu K, Enomoto T, Fujiwara K, Matsumura N, Konishi I, Roman LD, Gabra H, Fotopoulou C, Sood AKet 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.

  • Journal article
    He YJ, Winham SJ, Hoskins JM, Glass S, Paul J, Brown R, Motsinger-Reif A, McLeod HLet al., 2015,

    Carboplatin/taxane-induced gastrointestinal toxicity: a pharmacogenomics study on the SCOTROC1 trial

    , Pharmacogenomics Journal, Vol: 16, Pages: 243-248, ISSN: 1473-1150
  • Conference paper
    Curry E, Cheraghchi-Bashi-Astaneh A, Chen M, Cunnea P, Camila DS, Maginn E, Dai Y, Liu E, Wasan H, Mills GB, Bowtell D, Gabra H, Stronach EAet 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
  • Journal article
    Teo PY, Yang C, Whilding LM, Parente-Pereira AC, Maher J, George AJT, Hedrick JL, Yang YY, Ghaem-Maghami Set al., 2015,

    Ovarian Cancer Immunotherapy Using PD-L1 siRNA Targeted Delivery from Folic Acid-Functionalized Polyethylenimine: Strategies to Enhance T Cell Killing

    , ADVANCED HEALTHCARE MATERIALS, Vol: 4, Pages: 1180-1189, ISSN: 2192-2640
  • Journal article
    Openshaw MR, Fotopoulou C, Blagden S, Gabra Het 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.

  • Journal article
    Patch A-M, Christie EL, Etemadmoghadam D, Garsed DW, George J, Fereday S, Nones K, Cowin P, Alsop K, Bailey PJ, Kassahn KS, Newell F, Quinn MCJ, Kazakoff S, Quek K, Wilhelm-Benartzi C, Curry E, Leong HS, Hamilton A, Mileshkin L, Au-Yeung G, Kennedy C, Hung J, Chiew Y-E, Harnett P, Friedlander M, Quinn M, Pyman J, Cordner S, O'Brien P, Leditschke J, Young G, Strachan K, Waring P, Azar W, Mitchell C, Traficante N, Hendley J, Thorne H, Shackleton M, Miller DK, Arnau GM, Tothill RW, Holloway TP, Semple T, Harliwong I, Nourse C, Nourbakhsh E, Manning S, Idrisoglu S, Bruxner TJC, Christ AN, Poudel B, Holmes O, Anderson M, Leonard C, Lonie A, Hall N, Wood S, Taylor DF, Xu Q, Fink JL, Waddell N, Drapkin R, Stronach E, Gabra H, Brown R, Jewell A, Nagaraj SH, Markham E, Wilson PJ, Ellul J, McNally O, Doyle MA, Vedururu R, Stewart C, Lengyel E, Pearson JV, Waddell N, deFazio A, Grimmond SM, Bowtell DDLet 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.

  • Conference paper
    Brown R, Timms K, Paul J, Hughes E, El-Bahrawy M, Steel JH, Kalva S, Liu X, Wang Y, Rama NR, Wilhelm-Benartzi C, Gutin A, Lewsley L-A, Siddiqui N, Patel N, Lanchbury JS, Gabra H, Stronach EAet 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

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