Cancer Research in Switzerland - Krebsliga Schweiz

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126 Benhattar Jean | Identification of biomarkers for early cancer detection in Barrett’s esophagus patients using methylation profiles and the Wnt pathway (OCS 01638-02-2005) Barrett’s oesophagus (BE) is a lesion resulting from chronic gastro-oesophageal reflux disease, in which the stratified squamous epithelium of the oesophagus is replaced by metaplastic columnar epithelium that predisposes to the development of oesophageal adenocarcinoma. Barrett’s oesophageal adenocarcinoma is characterized by one of the most rapidly increasing incidence rates of any cancer in the Western world. Despite advances in staging and treatment, this malignancy is highly lethal, with a 5-year survival rate of less than 10 %. Early detection represents one of the most promising approaches to reducing the growing cancer number, as already demonstrated in other malignancies such as cervical and breast cancer. Early detection research has recently been revitalized by the advent of novel molecular technologies that can identify cellular changes at the genome level. These molecular technologies offer many new opportunities for developing biomarker-based tests that could be used in addition to or in substitution for some of the existing screening tests. A variety of molecular genetic and epigenetic events appear to coincide in the progression of BE to adenocarcinoma. Our research activities are focused on the detection and the development of epigenetic biomarkers that can predict the likelihood of the neoplastic progression in Barrett’s patients. To increase knowledge on methylation changes, a Methylation Ligation-dependent Macroarray (MLM) has been generated. This array-based DNA methylation profiling allows the screening of 45 promoter genes on 20 samples at the same time. This technology can be used: 1) in clinical trials to identify methylation profiles for appropriate drug delivery; 2) to distinguish pathologies with or without potential progressive evolution; 3) for metastases prognosis; and 4) for diagnosis. In oesophageal adenocarcinoma, aberrant methylation of promoter regions occurs with a high frequency not only in advanced cancer but also in BE. Hypermethylation of a subset of tumour suppressor gene promoters strongly predicts progression to high-grade dysplasia or cancer in patients with BE. On the other hand, rare occurrence of tumour suppressor gene hypermethylation is associated with a benign course in BE. Our research also focuses on the aberrant activation of the Wnt signalling pathway, which is a key feature of many cancers. While mutations in APC or b-catenin are exceptional in Barrett’s adenocarcinomas, alterations of upstream components, such as overexpression of Wnt2 ligand or downregulation by promoter methylation of several Wnt antagonists, may play dominant roles in the activation of the Wnt pathway. Our data suggest that inhibiting the Wnt pathway could become a new targeted therapy for the treatment of cancers and could therefore be promising for the prevention and cure of oesophageal adenocarcinoma. Furthermore, methylation biomarker-based panel to predict neoplastic progression in BE has potential clinical value in improving both the efficiency of surveillance endoscopy and the early detection of neoplasia. Project coordinator Dr Jean Benhattar Institut universitaire de pathologie de Lausanne (IUP) Centre hospitalier universitaire vaudois (CHUV) Rue du Bugnon 25 CH-1011 Lausanne Phone +41 (0)21 314 71 53 Fax +41 (0)21 314 71 15 jean.benhattar@chuv.ch Bertoni Francesco | Evaluation of the tyrosine kinase SYK as a possible therapeutic target in lymphomas (KLS 01835-02-2006) SYK is a non-receptor tyrosine kinase involved in the B-cell receptor (BCR) signalling pathway. When activated, it leads to intracellular calcium mobilization, activation of AKT, mitogen-activated protein kinases (MAPKs) and NFkB. Inhibition of SYK had been proposed as a new promising therapeutic approach for lymphoid neoplasms. In this project we evaluated the efficacy of a series of SYK inhibitors in lymphoma cell lines and primary cells and studied the pattern of SYK expression in mature B-cell lymphomas. Material and methods We exposed cell lines of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and primary cells of a variety of lymphomas to increasing doses of different SYK inhibitors. SYK expression was evaluated on a series of 303 lymphoma biopsies by immunohistochemistry. Results We first evaluated the potentiality of SYK inhibition (Rinaldi et al., Hematological Oncology 2011). Based on our previous data on MCL cell lines (Rinaldi et al., British Journal of Haematology 2006), we first treated six DLBCL cell lines with increasing doses of the SYK inhibitor piceatannol. The cell line that was the most sensitive and that showed a clear dose response had the highest level of SYK, and it presented an extra copy of the locus containing SYK. Three of the 6 DLBCL cell lines and 4 MCL cell lines were then exposed to increasing doses of a potent SYK/ZAP70 inhibitor, NVP, for 72 h. Only the two cell lines expressing high levels of SYK showed an IC50 at a dose suggestive of a SYK-mediated cytotoxic effect. Due to the suggested capacity of the BCR-ABL inhibitor imatinib to bind SYK, MCL and DLBCL cell lines were exposed to the BCR-ABL inhibitors imatinib and nilotinib, which are already in clinical use. No cell line responded to doses of imatinib lower than the concentration clinically achievable and used for chronic myeloid leukemia and other sensitive neoplasms. Still, the two cell lines with
constitutively high SYK levels showed progressive inhibition of cell proliferation, indicating a possible dose-dependent cytotoxic effect. To obtain further data on the relevance of SYK inhibition in lymphoma, we treated 5 lymphoma primary cells derived from DLBCL and 3 from leukemic MALT lymphomas with increasing doses of NVP and piceatannol and with nilotinib at the clinically reachable dose. The data obtained on lymphoma primary cells confirmed the cytotoxic activity of tyrosine kinase inhibitors in lymphoma primary cells, but the heterogeneous pattern of response suggested that the effect could be due to inhibition of molecules other than SYK and contributing to the constitutive BCR signaling. Regarding protein expression in clinical specimens, four patterns of SYK localization were shown to have a peculiar distribution among different types of lymphoma and lymphoid tissues analyzed (Ponzoni et al., Leukemia Re- search 2011). SYK was statistically significantly more frequently detected mainly or exclusively in the cytoplasm in DLBCLs, splenic marginal zone lymphomas and reactive spleens. The kinase was statistically significantly found mainly or exclusively in the nucleus in MCL. Conclusions Our functional characterization of SYK in lymphoma cell lines and lymphoma primary cells support the design of prospective trials testing different molecules targeting SYK. Our extensive immunohistochemical characterization pointed towards divergent SYK localization in different lymphoma subtypes, suggesting different functions in the different subtypes. Project coordinator Dr. Francesco Bertoni Laboratorio di oncologia sperimentale Istituto oncologico della Svizzera italiana (IOSI) Via Vincenzo Vela 6 CH-6500 Bellinzona Phone +41 (0)91 8200 367 Fax +41 91 8200 397 frbertoni@mac.com
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Cancer Research in Switzerland A pu
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Cancer Research in Switzerland
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Basic biomedical research 55 Cancer
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policy work and was in charge of de
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The main focus of the research fund
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gramme research funding decreased b
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Table 2 Distribution of funds for i
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Funding patient-centred research Pa
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value was not clearly discernible.
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New organization of the Foundation
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The board of the Foundation Cancer
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The president of the Scientific Com
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Prof. Martin Pruschy, PhD Departmen
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Swartz wants to find out how tumour
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The scientific and medical research
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3. The original order/sequence of t
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As a federation, the Cancer League
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List of funded research projects, i
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Zippelius Alfred | 2009: CHF 100,00
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Kridel Robert | 2010: CHF 100,000.-
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Thurgau Cancer League Biotechnologi
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Weller Michael | 2010: CHF 65,828.-
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manageable funding of individual pr
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enhances breast cancer cell motilit
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Rüegg Curzio et al. | Tumor-mediat
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International Clinical Cancer Resea
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in PHIV were shown for Hodgkin’s
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Zucca Emanuele et al. | Internation
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56 “hierarchical structure” of
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58 the attempt should be made to st
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60 Gönczy Pierre | KLS 0202402
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62 Romero Pedro | OCS 020110220
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64 Beermann Friedrich | In vivo scr
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66 Christofori Gerhard | Podoplanin
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68 Frei Christian | The function of
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70 cell, this novel mechanism serve
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72 Results The induction of viral p
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74 Hübscher Ulrich | Repair of oxi
Page 78 and 79: 76 Methods and experimental approac
Page 80 and 81: 78 of cMyc and/or NMyc and demo
Page 82 and 83: 80 In summary, this work improves o
Page 84 and 85: 82 Pruschy Martin | Microtubule int
Page 86 and 87: 84 Renner Christoph | Selective inh
Page 88 and 89: 86 Goal Here we build on these obse
Page 90 and 91: 88 by TDG prevents efficient downst
Page 92 and 93: 90 To address these questions, we a
Page 94 and 95: 92 Translational relevance The resu
Page 96 and 97: 94 Grünberg Jürgen | KFS 025460
Page 98 and 99: 96 Tschan Mario P. | KFS 0248608
Page 100 and 101: 98 Boyman Onur | Preclinical testin
Page 102 and 103: 100 Constam Daniel | Role of activi
Page 104 and 105: 102 this study we will examine the
Page 106 and 107: 104 Janscak Pavel | Study of the ro
Page 108 and 109: 106 Müller Anne | The molecular pa
Page 110 and 111: 108 Radtke Freddy | The role of Not
Page 112 and 113: 110 Schär Primo | DNA repair, epig
Page 114 and 115: 112 In this project we will investi
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Page 118 and 119: 116 and Research). Other financial
Page 120 and 121: 118 be totally unaffordable for aca
Page 122 and 123: 120 Clinical research List of compl
Page 124 and 125: 122 Hunger Robert E. | OCS 02262-08
Page 126 and 127: 124 Clinical research Presentation
Page 130 and 131: 128 Bertoni Francesco | Genome-wide
Page 132 and 133: 130 Interpretation ESA treatment in
Page 134 and 135: 132 Our results could pave the way
Page 136 and 137: 134 new drugs that specifically tar
Page 138 and 139: 136 slides in two different concent
Page 140 and 141: 138 Conclusions A strong network of
Page 142 and 143: 140 tions introduced to ARE motifs
Page 144 and 145: 142 Müller Beatrice U. | The maste
Page 146 and 147: 144 A novel method was developed fo
Page 148 and 149: 146 (SAKK 35-98) the Swiss Group fo
Page 150 and 151: 148 Timmermann Beate | Prospective
Page 152 and 153: 150 recurrence of the disease, we a
Page 154 and 155: 152 Zucca Emanuele | A prospective
Page 156 and 157: 154 Heinimann Karl | KFS 02489-08-2
Page 158 and 159: 156 Riggi Nicolò | BIL KFS 02717-0
Page 160 and 161: 158 activity at the single cell lev
Page 162 and 163: 160 Our research projects aim at un
Page 164 and 165: 162 Körner Meike | In vitro evalua
Page 166 and 167: 164 Nadal David | Is endemic Burkit
Page 168 and 169: 166 (> 50.000/patient). For their a
Page 170 and 171: 168 Zeller Rolf | Functional analys
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Page 174 and 175: 172 area of health services researc
Page 176 and 177: 174 The financing of palliative car
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176 National Strategy for Palliativ
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178 Psychosocial research List of c
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180 Within the patient group, level
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182 Further, the results suggest th
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184 It is in this context that the
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186 Recommendation Female spouses o
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188 Psychosocial research Presentat
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190 rates communication skills rema
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Epidemiological research Epidemiolo
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data from cancer registries. In the
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The importance of cancer registries
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Ess Silvia | Patterns of care and s
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Epidemiological research List of ap
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Impact This work will serve as the
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Thürlimann Beat | Management of br
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