Bryan T Hennessy

Royal College of Surgeons in Ireland, Dublin, Leinster, Ireland

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Publications (125)874.81 Total impact

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    ABSTRACT: Because of advances in targeted therapies, the clinical evaluation of cutaneous melanoma is increasingly based on a combination of traditional histopathology and molecular pathology. Therefore, it is necessary to expand our knowledge of the molecular events that accompany the development and progression of melanoma to optimize clinical management. The central objective of this study was to increase our knowledge of the mutational events that complement melanoma progression. High-throughput genotyping was adapted to query 159 known single nucleotide mutations in 33 cancer-related genes across two melanoma cohorts from Ireland (n=94) and Belgium (n=60). Results were correlated with various clinicopathological characteristics. A total of 23 mutations in 12 genes were identified, that is - BRAF, NRAS, MET, PHLPP2, PIK3R1, IDH1, KIT, STK11, CTNNB1, JAK2, ALK, and GNAS. Unexpectedly, we discovered significant differences in BRAF, MET, and PIK3R1 mutations between the cohorts. That is, cases from Ireland showed significantly lower (P<0.001) BRAF mutation rates (19%) compared with the mutation frequency observed in Belgian patients (43%). Moreover, MET mutations were detected in 12% of Irish cases, whereas none of the Belgian patients harbored these mutations, and Irish patients significantly more often (P=0.027) had PIK3R1-mutant (33%) melanoma versus 17% of Belgian cases. The low incidence of BRAF-mutant melanoma among Irish patients was confirmed in five independent Irish cohorts, and in total, only 165 of 689 (24%) Irish cases carried mutant BRAF. Together, our data show that melanoma-driving mutations vary by demographic area, which has important implications for the clinical management of this disease.
    Melanoma Research 03/2015; DOI:10.1097/CMR.0000000000000149 · 2.10 Impact Factor
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    ABSTRACT: Inflammatory myofibroblastic tumours (IMTs) are rare sarcomas that were first described in the lung. They are composed of myofibroblastic mesenchymal spindle cells accompanied by an inflammatory infiltrate of plasma cells. Complete resection is the treatment of choice. There is currently no standard treatment for inoperable or recurrent disease. Expression of ALK protein triggered by ALK gene rearrangement at chromosome 2p23 has been found in 36%-60% of IMTs. We report a rapid early response to crizotinib as neoadjuvant therapy, enabling surgical excision of a large ALK-translocated IMT, which resulted in complete disease clearance. To the best of our knowledge, this is the first case in the literature of a patient with IMT in whom crizotinib was used successfully in the neoadjuvant or curative setting.
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    ABSTRACT: Approximately 20 % of human breast cancers (BC) overexpress HER2 protein, and HER2-positivity is associated with a worse prognosis. Although HER2-targeted therapies have significantly improved outcomes for HER2-positive BC patients, resistance to trastuzumab-based therapy remains a clinical problem. In order to better understand resistance to HER2-targeted therapies in HER2-positive BC, it is necessary to examine HER family signalling as a whole. An extensive literature search was carried out to critically assess the current knowledge of HER family signalling in HER2-positive BC and response to HER2-targeted therapy. Known mechanisms of trastuzumab resistance include reduced receptor-antibody binding (MUC4, p95HER2), increased signalling through alternative HER family receptor tyrosine kinases (RTK), altered intracellular signalling involving loss of PTEN, reduced p27kip1, or increased PI3K/AKT activity and altered signalling via non-HER family RTKs such as IGF1R. Emerging strategies to circumvent resistance to HER2-targeted therapies in HER2-positive BC include co-targeting HER2/PI3K, pan-HER family inhibition, and novel therapies such as T-DM1. There is evidence that immunity plays a key role in the efficacy of HER-targeted therapy, and efforts are being made to exploit the immune system in order to improve the efficacy of current anti-HER therapies. With our rapidly expanding understanding of HER2 signalling mechanisms along with the repertoire of HER family and other targeted therapies, it is likely that the near future holds further dramatic improvements to the prognosis of women with HER2-positive BC.
    Breast Cancer Research and Treatment 12/2014; 149(1). DOI:10.1007/s10549-014-3250-x · 4.20 Impact Factor
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    ABSTRACT: The PI3K pathway is a key mechanism of trastuzumab resistance, but early attempts to indirectly target this pathway with mTOR inhibitors have had limited success. We present the results of a preclinical study of the selective alpha/delta isoform dominant PI3K inhibitor BAY 80-6946 tested alone and in combination with HER2-targeted therapies in HER2-positive cell lines, including models with acquired resistance to trastuzumab and/or lapatinib. A panel of HER2-positive breast cancer cells were profiled for their mutational status using Sequenom MassARRAY, PTEN status by Western blot, and anti-proliferative response to BAY 80-6946 alone and in combination with the HER2-targeted therapies trastuzumab, lapatinib and afatinib. Reverse phase protein array was used to determine the effect of BAY 80-6946 on expression and phosphorylation of 68 proteins including members of the PI3K and MAPK pathways. The Boyden chamber method was used to determine if BAY 80-6946 affected cellular invasion and migration. BAY 80-6946 has anti-proliferative and anti-invasive effects when used alone in our panel of cell lines (IC50s 3.9–29.4 nM). BAY 80-6946 inhibited PI3K signalling and was effective in cells regardless of their PI3K, P53 or PTEN status. The combination of HER2-targeted therapies and BAY 80-6946 inhibited growth more effectively than either therapy used alone (with clear synergism in many cases), and can restore sensitivity to trastuzumab and lapatinib in cells with acquired resistance to either trastuzumab and/or lapatinib. The addition of BAY 80-6946 to HER2-targeted therapy could represent an improved treatment strategy for patients with refractory metastatic HER2-positive breast cancer, and should be considered for clinical trial evaluation.
    Breast Cancer Research and Treatment 12/2014; 149(2). DOI:10.1007/s10549-014-3239-5 · 4.20 Impact Factor
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    ABSTRACT: In locally advanced rectal cancer, neoadjuvant chemoradiotherapy is performed prior to surgery to downstage the tumour. Thirty to 40 % of patients do not respond. Defects in apoptotic machinery lead to therapy resistance; however, to date, no study quantitatively assessed whether B cell lymphoma 2 (BCL2)-dependent regulation of mitochondrial apoptosis, effector caspase activation downstream of mitochondria or a combination of both predicts patient responses. In a cohort of 20 rectal cancer patients, we performed protein profiling of tumour tissue and employed validated ordinary differential equation-based systems models of apoptosis signalling to calculate the ability of cancer cells to undergo apoptosis. Model outputs were compared to clinical responses. Systems modelling of BCL2-signalling predicted patients in the poor response group (p = 0.0049). Systems modelling also demonstrated that rectal cancers depended on BCL2 rather than B cell lymphoma-extra large (BCL(X)L) or myeloid cell leukemia 1 (MCL1) for survival, suggesting that poor responders may benefit from therapy with selective BCL2 antagonists. Dynamic modelling of effector caspase activation could not stratify patients with poor response and did not further improve predictive power. We deliver a powerful patient stratification tool identifying patients who will likely not benefit from neoadjuvant chemoradiotherapy and should be prioritised for surgical resection or treatment with BCL2 antagonists.
    Journal of Molecular Medicine 11/2014; 93(3). DOI:10.1007/s00109-014-1221-7 · 4.74 Impact Factor
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    ABSTRACT: Angiogenesis or new vessel formation is essential for tumour growth and progression. Therefore, targeting angiogenesis has been an attractive strategy in the treatment ofcancer. Bevacizumab is a recombinant humanized monoclonal IgG1 antibody thattargets vascular endothelial growth factor-A (VEGF-A) - a key molecular player inangiogenesis. Bevacizumumab has shown clinical efficacy in phase III clinical trials inseveral advanced solid malignancies. The clinical efficacy of bevacizumumab isprimarily due to its antiangiogenic effects; however, there are direct antitumor effectsand immunomodulatory effects. Enhancing the immune system to restore itsantitumour activity has been utilized successfully in clinical setting. In this article we willdiscuss the possible immunomodulatory effects of the most clinically usedantiangiogenic agent; bevacizumumab.
    Cancer Microenvironment 10/2014; DOI:10.1007/s12307-014-0160-8
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    ABSTRACT: Peroxiredoxin-1 (PRDX1) is a multifunctional protein, acting as a hydrogen peroxide (H2O2) scavenger, molecular chaperone and immune modulator. Although differential PRDX1 expression has been described in many tumors, the potential role of PRDX1 in breast cancer remains highly ambiguous. Using a comprehensive antibody-based proteomics approach, we interrogated PRDX1 protein as a putative biomarker in estrogen receptor (ER)-positive breast cancer.
    Breast cancer research: BCR 07/2014; 16(4):R79. DOI:10.1186/bcr3691 · 5.88 Impact Factor
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    ABSTRACT: The prognosis of epithelial ovarian cancer is poor in part due to the high frequency of chemoresistance. Recent evidence points to the Toll-like receptor-4 (TLR4), and particularly its adaptor protein MyD88, as one potential mediator of this resistance. This study aims to provide further evidence that MyD88 positive cancer cells are clinically significant, stem-like and reproducibly detectable for the purposes of prognostic stratification. Expression of TLR4 and MyD88 was assessed immunohistochemically in 198 paraffin-embedded ovarian tissues and in an embryonal carcinoma model of cancer stemness. In parallel, expression of TLR4 and MyD88 mRNA and regulatory microRNAs (miR-21 and miR-146a) was assessed, as well as in a series of chemosensitive and resistant cancer cells lines. Functional analysis of the pathway was assessed in chemoresistant SKOV-3 ovarian cancer cells. TLR4 and MyD88 expression can be reproducibly assessed via immunohistochemistry using a semi-quantitative scoring system. TLR4 expression was present in all ovarian epithelium (normal and neoplastic), whereas MyD88 was restricted to neoplastic cells, independent of tumour grade and associated with reduced progression-free and overall survival, in an immunohistological specific subset of serous carcinomas, p<0.05. MiR-21 and miR-146a expression was significantly increased in MyD88 negative cancers (p<0.05), indicating their participation in regulation. Significant alterations in MyD88 mRNA expression were observed between chemosensitive and chemoresistant cells and tissue. Knockdown of TLR4 in SKOV-3 ovarian cells recovered chemosensitivity. Knockdown of MyD88 alone did not. MyD88 expression was down-regulated in differentiated embryonal carcinoma (NTera2) cells, supporting the MyD88+ cancer stem cell hypothesis. Our findings demonstrate that expression of MyD88 is associated with significantly reduced patient survival and altered microRNA levels and suggest an intact/functioning TLR4/MyD88 pathway is required for acquisition of the chemoresistant phenotype. Ex vivo manipulation of ovarian cancer stem cell (CSC) differentiation can decrease MyD88 expression, providing a potentially valuable CSC model for ovarian cancer.
    PLoS ONE 06/2014; 9(6):e100816. DOI:10.1371/journal.pone.0100816 · 3.53 Impact Factor
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    ABSTRACT: The cytotoxicity of PARP inhibitors olaparib, veliparib, and CEP-8983 were investigated in two P-glycoprotein (P-gp) overexpressing drug-resistant cell models (IGROVCDDP and KB-8-5-11). IGROVCDDP and KB-8-5-11 were both resistant to olaparib and resistance was reversible with the P-gp inhibitors elacridar, zosuquidar, and valspodar. In contrast, the P-gp overexpressing models were not resistant to veliparib or CEP-8983. Olaparib and veliparib did not induce protein expression of P-gp in IGROVCDDP or KB-8-5-11 at doses that successfully inhibit PARP. Olaparib therefore appears to be a P-gp substrate. Veliparib and CEP-8983 do not appear to be substrates. Veliparib and CEP-8983 may therefore be more useful in combined chemotherapy regimens with P-gp substrates and may be active in platinum and taxane-resistant ovarian cancer. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci
    Journal of Pharmaceutical Sciences 06/2014; 103(6). DOI:10.1002/jps.23952 · 3.01 Impact Factor
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    ABSTRACT: Locally advanced rectal cancer (LARC: T3/4 and/or node-positive) is treated with preoperative/neoadjuvant chemoradiotherapy (CRT), but responses are not uniform. The phosphatidylinositol 3-kinase (PI3K), MAP kinase (MAPK), and related pathways are implicated in rectal cancer tumorigenesis. Here, we investigated the association between genetic mutations in these pathways and LARC clinical outcomes. We genotyped 234 potentially clinically relevant nonsynonymous mutations in 33 PI3K and MAPK pathway-related genes, including PIK3CA, PIK3R1, AKT, STK11, KRAS, BRAF, MEK, CTNNB1, EGFR, MET, and NRAS, using the Sequenom platform. DNA samples were extracted from pretreatment LARC biopsy samples taken from 201 patients who were then treated with long-course neoadjuvant CRT followed by surgical resection. Sixty-two mutations were detected in 15 genes, with the highest frequencies occurring in KRAS (47 %), PIK3CA (14 %), STK11 (6.5 %), and CTNNB1 (6 %). Mutations were detected in BRAF, NRAS, AKT1, PIK3R1, EGFR, GNAS, MEK1, PDGFRA, ALK, and TNK2, but at frequencies of <5 %. As expected, a pathologic complete response (pCR) was associated with improved 5-year recurrence-free survival (RFS; hazard ratio, 0.074; 95 % CI 0.01-0.54; p = 0.001). Mutations in PI3K pathway-related genes (odds ratio, 5.146; 95 % CI 1.17-22.58; p = 0.030), but not MAPK pathway-related genes (p = 0.911), were associated with absence of pCR after neoadjuvant CRT. In contrast, in patients who did not achieve pCR, mutations in PI3K pathway-related genes were not associated with recurrence-free survival (p = 0.987). However, in these patients, codon 12 (G12D/G12 V/G12S) and 13 mutations in KRAS were associated with poor recurrence-free survival (hazard ratio, 1.579; 95 % confidence ratio, 1.00-2.48; p = 0.048). Mutations in kinase signaling pathways modulate treatment responsiveness and clinical outcomes in LARC and may constitute rational targets for novel therapies.
    Annals of Surgical Oncology 04/2014; 21(8). DOI:10.1245/s10434-014-3658-x · 3.94 Impact Factor
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    ABSTRACT: Reverse-phase protein array (RPPA) analysis is a powerful, rel- atively new platform that allows for high-throughput, quantitative analysis of protein networks. One of the challenges that currently limit the potential of this technology is the lack of methods that al- low for accurate data modeling and identification of related networks and samples. Such models may improve the accuracy of biological sample classification based on patterns of protein network activation and provide insight into the distinct biological relationships underly- ing different types of cancer. Motivated by RPPA data, we propose a Bayesian sparse graphical modeling approach that uses selection priors on the conditional relationships in the presence of class infor- mation. The novelty of our Bayesian model lies in the ability to draw information from the network data as well as from the associated categorical outcome in a unified hierarchical model for classification. In addition, our method allows for intuitive integration of a priori network information directly in the model and allows for posterior inference on the network topologies both within and between classes. Applying our methodology to an RPPA data set generated from pan- els of human breast cancer and ovarian cancer cell lines, we demon- strate that the model is able to distinguish the different cancer cell types more accurately than several existing models and to identify differential regulation of components of a critical signaling network (the PI3K-AKT pathway) between these two types of cancer. This approach represents a powerful new tool that can be used to improve our understanding of protein networks in cancer.
    The Annals of Applied Statistics 03/2014; 8(3). DOI:10.1214/14-AOAS722 · 1.69 Impact Factor
  • Cancer Research 03/2014; 73(24 Supplement):P4-12-25-P4-12-25. DOI:10.1158/0008-5472.SABCS13-P4-12-25 · 9.28 Impact Factor
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    ABSTRACT: Ovarian cancer is now recognized as a number of distinct diseases primarily defined by histological subtype. Both clear cell ovarian carcinomas (CCC) and ovarian endometrioid carcinomas (EC) may arise from endometriosis and frequently harbor mutations in the ARID1A tumor suppressor gene. We studied the influence of histological subtype on protein expression with reverse phase protein array (RPPA) and assessed proteomic changes associated with ARID1A mutation/BAF250a expression in EC and CCC. Immunohistochemistry (IHC) for BAF250a expression was performed on 127 chemotherapy-naive ovarian carcinomas (33 CCC, 29 EC, and 65 high-grade serous ovarian carcinomas (HGSC)). Whole tumor lysates were prepared from frozen banked tumor samples and profiled by RPPA using 116 antibodies. ARID1A mutations were identified by exome sequencing, and PIK3CA mutations were characterized by MALDI-TOF mass spectrometry. SAM (Significance Analysis of Microarrays) was performed to determine differential protein expression by histological subtype and ARID1A mutation status. Multivariate logistic regression was used to assess the impact of ARID1A mutation status/BAF250a expression on AKT phosphorylation (pAKT). PIK3CA mutation type and PTEN expression were included in the model. BAF250a knockdown was performed in 3 clear cell lines using siRNA to ARID1A. Marked differences in protein expression were observed that are driven by histotype. Compared to HGSC, SAM identified over 50 proteins that are differentially expressed in CCC and EC. These included PI3K/AKT pathway proteins, those regulating the cell cycle, apoptosis, transcription, and other signaling pathways including steroid hormone signaling. Multivariate models showed that tumors with loss of BAF250a expression showed significantly higher levels of AKT-Thr308 and AKT-Ser 473 phosphorylation (p < 0.05). In 31 CCC cases, pAKT was similarly significantly increased in tumors with BAF250a loss on IHC. Knockdown of BAF250a by siRNA in three CCC cell lines wild type for ARID1A showed no increase in either pAKT-Thr308 or pAKT-S473 suggesting that pAKT in tumor tissues is indirectly regulated by BAF250a expression. Proteomic assessment of CCC and EC demonstrates remarkable differences in protein expression that are dependent on histotype, thereby further characterizing these cancers. AKT phosphorylation is associated with ARID1A/BAF250a deficient tumors, however in ovarian cancers the mechanism remains to be elucidated.
    BMC Cancer 02/2014; 14(1):120. DOI:10.1186/1471-2407-14-120 · 3.32 Impact Factor
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    ABSTRACT: Treatment with tyrosine kinase inhibitors (TKIs) including trastuzumab has revolutionized the management of HER2-positive breast cancer. Recent evaluation of clinical trial data suggests that a subset of HER2/ER double-positive cancers may not receive significant benefit from the TKI therapy. Here we investigate the cross talk between HER2 and ER in breast cancer and monitor the effect of trastuzumab on the tyrosine kinase effector transcription factor Myc. In HER2-positive breast cancer patients treated with neoadjuvant trastuzumab, steroid receptor-negative status (ER and PR negative) of pre-treatment biopsies predicted pathological complete response (pCR) (n=31 patients, P=0.0486), whereas elevated Myc protein inversely associated with pCR (P=0.0446). Liquid chromatography mass spectrometry identified the corepressor SMRT as a novel Myc-interacting protein. Trastuzumab treatment enhanced Myc-SMRT interactions in HER2-overexpressing breast cancer cells (LCC1) and inhibited expression of the Myc target gene survivin. In HER2-low, ER-positive steroid-dominant cells (MCF7), trastuzumab therapy repressed Myc-SMRT interactions and upregulated survivin expression. Trastuzumab treatment induced ER-CBP interactions, enhanced ER transcriptional activity and upregulated expression of the ER target gene pS2. The absence of pS2 expression in pre-treatment biopsies predicted pCR to neoadjuvant trastuzumab in breast cancer patients (n=25, P=0.0089) and pS2 expression associated with residual cancer burden (P=0.0196). Furthermore, metastatic tissues from patients who had failed trastuzumab therapy were pS2 positive. In HER2-overexpressing cells, trastuzumab treatment can repress Myc transcriptional activity and clinical response is favorable. However, with co-expression of the steroid pathway, this inhibition is lost and response to treatment is often poor.Oncogene advance online publication, 27 January 2014; doi:10.1038/onc.2013.586.
    Oncogene 01/2014; 34(4). DOI:10.1038/onc.2013.586 · 8.56 Impact Factor
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    ABSTRACT: Ovarian cancer has the lowest survival rate of all gynaecologic cancers and is characterised by a lack of early symptoms and frequent late stage diagnosis. There is a paucity of robust molecular markers that are independent of and complementary to clinical parameters such as disease stage and tumour grade.
    Molecular Cancer 01/2014; 13(1):241. DOI:10.1186/1476-4598-13-241 · 5.40 Impact Factor
  • Lung Cancer 01/2014; 83:S2. DOI:10.1016/S0169-5002(14)70004-2 · 3.74 Impact Factor
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    Lung Cancer 01/2014; 83:S4. DOI:10.1016/S0169-5002(14)70010-8 · 3.74 Impact Factor
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    ABSTRACT: To date, there is no uniform consensus whether tumour regression grade (TRG) is predictive of outcome in rectal cancer. Furthermore, the lack of standardization of TRG grading is a major source of variability in published studies. The aim of this study was to evaluate the prognostic impact of TRG in a cohort of patients with locally advanced rectal cancer treated with neoadjuvant chemoradiation therapy (CRT). In addition to Mandard TRG, we utilized four TRG systems modified from the Mandard TRG system and applied them to the cohort to assess which TRG system is most informative. 153 patients with a T3/T4 and/or a node positive rectal cancer underwent neoadjuvant 5-fluorouracil-based CRT followed by surgical resection. Thirty-six (23.5%) patients achieving complete pathologic response (ypCR) had a 5-year disease-free survival (DFS) of 100% vs. 74% for 117 (76.5%) patients without ypCR (P=0.003). The Royal College of Pathologists (RCPath) TRG best condenses the Mandard 5-point TRG by stratifying patients into three groups with distinct 5-year DFS rates of 100%, 86% and 67%, respectively (P=0.001). In multivariate analysis, pathological nodal status and circumferential resection margin (CRM) status, but not TRG, remained significant predictors of DFS (P=0.002, 0.035, 0.310, respectively). Our findings support the notion that ypCR status, nodal status after neoadjuvant CRT and CRM status but not TRG are predictors of long-term survival in patients with locally advanced rectal cancer. This article is protected by copyright. All rights reserved.
    Colorectal Disease 10/2013; 16(1). DOI:10.1111/codi.12439 · 2.02 Impact Factor
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    ABSTRACT: Background: The phosphoinositide-3 kinase (PI3K) pathway is commonly activated in cancer, including endometrial cancer (EC) due to mutations at multiple nodes, for example PIK3CA, or loss of expression of PTEN. Additionally, we and others have shown that, in EC, mutations in the RAS/RAF/MEK/MAPK pathway and the PI3K pathway frequently co-exist. Here, we examined the hypothesis that interaction between PI3K and RAS/RAF/MEK/MAPK pathway mutations is important in determining responsiveness of EC to therapies targeted to these pathways. Methods: We used a large panel of genetically defined EC cell lines (n=16, with diverse genetic backgrounds) to identify the anti-tumour effects (using IC50 values derived from viability assays) of a PI3K inhibitor GDC0941, a MEK inhibitor GDC0973 and a dual PI3K/mTOR inhibitor GDC0980 as single agents and in combination. We subdivided 16 endometrial cancer cell lines into 4 groups according to the mutational status of PIK3CA, PTEN, and KRAS: group 1 (n= 2), cell lines with PIK3CA mutations only; group 2 (n=9), cell lines with PTEN mutations (+/-PIK3CA mutations) and wild type for KRAS; group 3 (n= 3) all cell lines with KRAS mutations; group 4 (n= 2), cell lines wild type for PIK3CA, PTEN and KRAS. Results: We observed that the cell lines in groups 1 (p=0.02) and 2 (p=0.04) but not group 4 (p=0.77) are significantly more sensitive to GDC0941 than cell lines in group 3. Group 2 cell lines with PTEN mutations without KRAS mutations and group 4 cell lines are significantly more resistant to the MEK inhibitor GDC0973 than cell lines in either group 1 (p=0.0007, 0.008, respectively) or group 3 (p<0.0001, =0.002, respectively) (surprisingly, IC50 values for GDC0973 were not significantly different between cell lines in groups 1 and 3, p=0.1). Both the combination of the PI3K inhibitor GDC0941 with the MEK inhibitor GDC0973 (CI from 0.03 to 0.19) and the combination of the dual PI3K/mTOR inhibitor GDC0980 with the MEK inhibitor GDC0973 (CI from 0.13 to 0.30) demonstrated significant synergy in cell lines in groups 1 and 2. While both combinations also showed strong synergism in group 3 cell lines also possessing PIK3CA or PTEN mutations, group 3 cell lines with KRAS mutations only demonstrated strong antagonism (CI>10). Conclusions: Our data suggest that the mutational status of PIK3CA, PTEN and KRAS can be used as biomarkers to select patients for PI3K and RAS/RAF-targeted therapies. Further, the combinations of the PI3K inhibitors GDC0941 and GDC0980 with the MEK inhibitor GDC0973 are promising approaches for the treatment of patients with PIK3CA, PTEN and KRAS-mutated EC. Surprisingly, PIK3CA-mutated group 1 EC cell lines were as sensitive to the single agent MEK inhibitor GDC0973 as group 3 cell lines with KRAS mutations.
    17th ECCO / 38th ESMO / 32nd ESTRO European Cancer Congress on Reinforcing Multidisciplinarity, European Journal of Cancer; 09/2013; 09/2013
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    ABSTRACT: Background: An online database was needed for the Cochrane review “Taxanes for the treatment of platinum pre-treated epithelial ovarian cancer” for several reasons. Firstly, a large amount of clinical parameters were to be extracted from 68 identified studies and the data was to be subdivided into 16 different subgroups. Secondly, there were 6 authors performing data extraction for this Cochrane review, working at 4 different institutions. Therefore data could not be entered and stored centrally at one institution. Objectives: Development of a cloud computing database accessible online for all authors performing data extraction. Methods: The database utilises cloud computing, such that the information is stored online and can be accessed from anywhere and is populated through a web-based user interface. Results: Using an online database-as-a-service and cloud computing to query and compare data allows the elimination of transaction concurrency conflicts. That is, the 2 authors can simultaneously review the same study without breaking the database. In the data extraction phase the cloud computing model allows authors to all work remotely. Each study in our review must have the data extracted by 2 review authors. The database will crosscheck information entered by two authors and flag discrepancies that need to be resolved by discussion. In the analysis phase the database allows each relevant paper containing data for each subgroup to be easily identified amongst the identified studies. Data to be presented will include a demonstration of functionality of the database and excerpts of results highlighting the usefulness of the database in complex subgroup categorisation. Conclusions: The cloud computing database was invaluable for performing this Cochrane review as the subgroups overlapped in many publications. Many complex Cochrane reviews could benefit from this approach to data extraction which facilitates collaboration across multiple institutions.
    21st Cochrane Colloqium, Quebec City, Quebec, Canada; 09/2013

Publication Stats

6k Citations
874.81 Total Impact Points

Institutions

  • 2011–2014
    • Royal College of Surgeons in Ireland
      Dublin, Leinster, Ireland
  • 2010–2014
    • Beaumont Hospital
      Dublin, Leinster, Ireland
  • 2004–2014
    • University of Texas MD Anderson Cancer Center
      • • Department of Systems Biology
      • • Department of Molecular Therapeutics
      • • Department of Leukemia
      Houston, Texas, United States
  • 2013
    • Dublin City University
      • National Institute for Cellular Biotechnology (NICB)
      Dublin, Leinster, Ireland
    • Trinity College Dublin
      Dublin, Leinster, Ireland
  • 2012
    • Memorial Sloan-Kettering Cancer Center
      New York City, New York, United States
  • 2009
    • Rice University
      Houston, Texas, United States
  • 2006–2009
    • University of Houston
      Houston, Texas, United States
  • 2001–2004
    • St. James's Hospital
      Dublin, Leinster, Ireland
  • 2003
    • Cork University Hospital
      Corcaigh, Munster, Ireland