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J. Creaney



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    MO19 - Lung Cancer Immunobiology (ID 91)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO19.06 - The role of fibroblast growth factor-9 in the regulation of the tumour-specific immune response in malignant mesothelioma (ID 3237)

      10:30 - 12:00  |  Author(s): J. Creaney

      • Abstract
      • Presentation
      • Slides

      Background
      Identifying key molecules in the pathobiology of malignant mesothelioma is needed to develop new therapies and biomarkers. Fibroblast growth factor-9 (FGF-9) is an exciting and novel target uncovered from our global gene profiling of human MPM samples. Recently FGF-9 has been implicated in cancer development and neoplastic transformation of embryonic fibroblasts. We have verified over-expression of FGF-9 in MPM over other cancers and benign pleuritis in five separate cohorts of human pleural tissues and effusions. Our preliminary in vitro work demonstrated that FGF-9 induces mesothelioma cell proliferation and matrix invasion. We therefore hypothesised that antagonising FGF-9 may reduce tumour aggressiveness, growth and induce tumour regression in vivo.

      Methods
      To study the ‘necessity’ of FGF-9 in MPM development in vivo we transfected the mouse MM cell line, AB1, with shRNA directed against murine FGF-9 (or control vector expressing a scrambled sequence). For the heterotopic model murine AB1-FGF-9 knock-down cells (or controls) were injected (5x10[5 ]cells) subcutaneously into the flank of Balb/c mice. Tumour dimensions were measured thrice weekly and animals sacrificed when tumours reached 100mm[2] and tumour tissues harvested. FGF-9 expression in tumour tissue was determined by immunohistochemistry. For orthotopic experiments, Balb/c mice received a single intraperitoneal injection of 5x10[5 ]AB1-FGF-9 knock-down cells (or controls). At day 13, animals were sacrificed and the number of peritoneal tumour nodules enumerated by blinded investigators. To determine whether the immune system plays a role in the regulation of AB1 MM tumour growth, 5x10[5 ]AB1-FGF-9 knock-down cells (or controls) were injected subcutaneously into nude mice. To elucidate the immune cells involved in AB1 MM tumour growth regulation, T cells were depleted in Balb/c tumour bearing mice using specific antibodies to CD4 and CD8 and tumour growth monitored. T cell depletion was confirmed using flow cytometry.

      Results
      Heterotopic tumour growth was significantly retarded in mice inoculated with AB1-FGF-9 knockdown cells compared to the scrambled vector and parent MM cells (p<0.001). A significant reduction in the number, and hence tumour burden, of tumour nodules was also observed for AB1-FGF-9 knockdown tumours in the orthotopic peritoneal model compared to controls (p<0.001). When grown in nude mice, which lack a functional T cell repertoire, AB1-FGF-9 knockdown tumours grew at a similar rate to that of the parent and vector controls which was suggestive of a role of the immune response in the regulation of MM tumours lacking FGF-9. AB1-FGF-9 knockdown tumours demonstrated significantly greater tumour burden in mice depleted of CD4+ and CD8+ T cells, either alone or in combination, when compared to saline controls which is highly suggestive of a T cell-mediated immune response to these tumours. These results also suggest that FGF-9 inhibits the tumour-specific immune response in MM.

      Conclusion
      In combination with our previous in vitro data which clearly demonstrated the proliferative and invasive properties of FGF-9, we suggest that FGF-9 has an important role in the pathobiological characteristics of MM in vivo and represents a novel therapeutic target.

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    MS24 - Mesothelioma Biology and Biomarkers (ID 41)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Mesothelioma
    • Presentations: 1
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      MS24.4 - New Biomarker Research in Mesothelioma (ID 577)

      14:00 - 15:30  |  Author(s): J. Creaney

      • Abstract
      • Presentation
      • Slides

      Abstract
      Malignant mesothelioma (MM) represents a significant clinical challenge. Not only can this tumour be difficult to diagnose but treatment options are limited. There is a desperate clinical need for biomarkers that can aid the diagnosis of MM, and/or predict survival and measure disease response to treatment. MM diagnosis is challenging as phenotypic differentiation of malignant mesothelial cells from benign reactive ones is notoriously difficult. No immunohistochemical marker(s) can uniformly define the cancer either. Invasive pleural tissue sampling for MM is more frequently negative than in any other cancer type [1]. A reliable diagnostic marker will present a major aid to clinicians. The median survival for the MM population is less than 12 months, however about 5% of patients live for several years and unusually long survivals of over 10 years have also been seen. But no reliable prognostic algorithm exists to predict survival in individual cases – a question of utmost concern for patients and their families. There is no cure for MM. Chemotherapy may improve survival, but only 30 to 40% of patients respond [2]. Thus finding a biomarker that may reflect disease burden and response to therapy, and hence prognosis, will be a significant advance. It has been nearly a decade since mesothelin [3] and MPF [4,5]were reported as candidate biomarkers for MM, both providing similar diagnostic accuracy [6]. A recent meta-analysis of serum mesothelin in the diagnosis of MM determined that having a sensitivity of 32% at a 95% specificity was too low for diagnostic use and highlighted the need for ongoing research for better biomarker(s) [7]. However, studies world-wide on a range of soluble markers including osteopontin, hyaluronic acid, CA125, CA15-3 and others have failed to improve upon diagnostic accuracy. More potential biomarkers such as fibulin-3 and the SOMamer panel have recently been identified [8,9]and the search to discover novel biomarker(s) for this disease using a variety of genomic, proteomic and immunologic approaches continues. For these candidate MM biomarkers to attain their professed clinical potential, independent externally validated studies with large, representative patient cohorts will be required. The next stage will then need studies to determine how to integrate promising markers into clinical diagnostic and/or management algorithms, a process essential to improve outcomes for MM patients. 1 Davies, H. E. et al. Outcome of patients with nonspecific pleuritis/fibrosis on thoracoscopic pleural biopsies. Eur J Cardiothorac Surg 38, 472-477, (2010). 2 Nowak, A. & Bydder, S. Management of malignant pleural mesothelioma: a review. Asia Pacific J clin Oncol (2007). 3 Robinson, B. W. et al. Mesothelin-family proteins and diagnosis of mesothelioma. Lancet 362, 4 Onda, M. et al. Megakaryocyte potentiation factor cleaved from mesothelin precursor is a useful tumor marker in the serum of patients with mesothelioma. Clin Cancer Res 12, 4225-4231 (2006). 5 Shiomi, K. et al. Novel ELISA system for detection of N-ERC/mesothelin in the sera of mesothelioma patients. Cancer Sci 97, 928-932 (2006). 6 Hollevoet, K. et al. Diagnostic performance of soluble mesothelin and megakaryocyte potentiating factor in mesothelioma. Am J Respir Crit Care Med 181, 620-625, (2010). 7 Hollevoet, K. et al. Serum mesothelin for diagnosing malignant pleural mesothelioma: an individual patient data meta-analysis. J Clin Oncol 30, 1541-1549, (2012). 8 Ostroff, R. M. et al. Early detection of malignant pleural mesothelioma in asbestos-exposed individuals with a noninvasive proteomics-based surveillance tool. PLoS One 7, e46091, (2012). 9 Pass, H. I. et al. Fibulin-3 as a blood and effusion biomarker for pleural mesothelioma. N Engl J Med 367, 1417-1427, (2012).

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    P1.05 - Poster Session 1 - Preclinical Models of Therapeutics/Imaging (ID 156)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.05-020 - Identifying therapeutic targets for mesothelioma using siRNA (ID 3200)

      09:30 - 16:30  |  Author(s): J. Creaney

      • Abstract

      Background
      Mesothelioma is essentially incurable and new drugs to effectively treat it are urgently needed. Our strategy to achieve this aim was to identify candidate mouse and human genes that may have a role in mesothelioma growth and to inhibit their expression in fully transformed mesothelioma cell lines using siRNA.

      Methods
      The initial selection of candidate genes was made on the basis of their differential expression in transcriptome or CGH analyses when comparing malignant to normal mesothelial cells. This was combined with known functional information relevant to tumorigenesis. We also selected a small number of candidates from other published studies. A second set of candidates was chosen from expressed kinases with the idea that these genes are more likely to represent druggable targets given the broad range of kinase inhibitors that are widely available. Where possible, we identified mouse and human homologues of the 40 candidates and then generated both mouse and human siRNA libraries. We tested the effect of gene knockdown on the growth of mouse and human mesothelioma cell lines in vitro.

      Results
      We found knockdown was efficient and inhibition of a subset of the selected genes slowed cell growth significantly across a range of cell lines in both mouse and human systems. There was not complete concordance between the mouse and human: Incenp, Plk1 and Tpx2 were important pathways for murine cellular proliferation; whereas, AURKA, TPX2 and BIRC5 were relevant for human cellular proliferation only. KIF11 was identified in both studies.

      Conclusion
      These genes all have a function in chromosome positioning, centrosome separation and spindle assembly during cell mitosis. Our data show that targeting these gene products in mesothelioma cell line causes growth inhibition both in vitro and in vivo. These studies could provide new leads for drug development.

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    P2.14 - Poster Session 2 - Mesothelioma (ID 196)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
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      P2.14-004 - EORTC and CALGB prognostic models, but not neutrophil-to-lymphocyte ratio, are prognostic in unselected patients with newly diagnosed malignant mesothelioma (ID 1259)

      09:30 - 16:30  |  Author(s): J. Creaney

      • Abstract

      Background
      Neutrophil-to-lymphocyte ratio (NLR), a marker of systemic inflammation, was proposed as a prognostic biomarker in a number of malignancies, including malignant pleural mesothelioma (MPM). We examined baseline variables predictive of overall survival (OS) in patients with newly diagnosed MPM, including NLR and the established EORTC and CALGB prognostic models.

      Methods
      Consecutive patients with newly diagnosed MPM between 1[st] January 2005 and 31[st] December 2010 at Sir Charles Gairdner Hospital, Western Australia were included in this retrospective study. Eligible patients had a confirmed diagnosis of MPM, neutrophil and lymphocyte count within 90 days of diagnosis, no concurrent haematological malignancy, and follow-up more than 90 days from diagnosis. Any subsequent treatment, including supportive care alone, was allowed. Variables to be analysed and cut-off determination was predetermined according to previous reports. Multiple imputation was performed for missing values, and univariate analyses and multivariate Cox models were calculated for OS.

      Results
      274 of 369 patients screened met the eligibility criteria and were included in this retrospective study. 159 received systemic chemotherapy, 10 underwent tri-modality therapy; 2 underwent surgery only, and 103 received supportive care alone. Prognostic factors predictive of shorter survival in univariate analysis were: age ≥ 65 years, non-epithelioid histology, sarcomatous histology, AJCC stage III-IV, ECOG performance status (PS) 2-3, weight loss, chest pain, low haemoglobin and high platelet count. An NLR ≥ 5 at diagnosis did not predict for shorter OS (hazard ratio (HR) 1.25; p=0.122). On multivariate analysis, age, histology, PS, weight loss, chest pain, and platelet count remained significant. The EORTC and CALGB prognostic groups were highly statistically significant as predictors for OS (HR 1.62; p<0.001 and HR 1.65; p<0.001, respectively). On preplanned subgroup analyses, baseline NLR was not prognostic in chemotherapy-treated or non-chemotherapy treated patients.

      Univariate and multivariate analyses of association of prognostic factors with overall survival
      Univariate analysis Multivariate analysis
      Baseline prognostic factor HR (95% CI) P-value HR (95% CI) P-value
      Baseline NLR <5* vs. ≥5 1.25 (0.94-1.66) 0.122 1.02 (0.76-1.37) 0.893
      Age <65* vs. ≥65 years 1.64 (1.24-2.17) <0.001 1.41 (1.05-1.90) 0.023
      Female* vs. Male 1.23 (0.86-1.77) 0.262 1.24 (0.85-1.81) 0.269
      Epithelioid* vs. non-epilthelioid 1.40 (1.08-1.80) 0.009 1.38 (1.05-1.82) 0.023
      Non-sarcomatous* vs. sarc. 2.37 (1.62-3.48) <0.001 1.86 (1.22-2.84) 0.004
      AJCC Stage I-II* vs. III-IV 1.52 (1.17-1.97) 0.002 1.27 (0.97-1.66) 0.087
      ECOG PS 0-1* vs. 2-3 2.35 (1.59-3.46) <0.001 1.81 (1.21-2.70) 0.004
      Weight loss absent* vs. present 2.11 (1.62-2.74) <0.001 1.62 (1.22-2.15) <0.001
      Chest pain absent* vs. present 1.58 (1.21-2.07) <0.001 1.34 (1.02-1.76) 0.038
      Hb difference <10* vs. >10 1.87 (1.41-2.49) <0.001 1.32 (0.96-1.80) 0.087
      WCC (x 10[9]/L) ≤8.30* vs. >8.30 1.22 (0.96-1.57) 0.110 0.95 (0.73-1.25) 0.745
      PLT (x 10[9]/L) ≤400* vs. >400 1.96 (1.49-2.58) <0.001 1.71 (1.26-2.33) <0.001
      Abbreviations: *=referent; AJCC=American Joint Committee on Cancer Staging System; ECOG= Eastern Cooperative Oncology Group, WCC=White cell count; NLR=Neutrophil-to-lymphocyte ratio

      Conclusion
      Our findings validate established baseline prognostic variables as well as the EORTC and CALGB models, but not baseline NLR in unselected patients with newly diagnosed MPM. In guiding treatment decisions for patients at time of diagnosis, multiple variables should be considered that jointly predict survival