Cancer Research in Switzerland - Krebsliga Schweiz

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134 new drugs that specifically target KRAS and that are now entering clinical trials. As a corollary, KRAS testing decreases the cost of the management of these patients. Project coordinator Dr. Milo Frattini Laboratorio di diagnostica molecolare Istituto cantonale di patologia (ICP) Via in selva 24 CH-6600 Locarno Phone +41 (0)91 816 08 05 Fax +41 (0)91 816 07 19 milo.frattini@ti.ch Gautschi Oliver | Regulation of lD1 expression by Src in cancer: Clinical implications (KLS 02164-02-2008) Invasion and metastasis are important hallmarks of cancer, but only few drugs are currently available that target these mechanisms in patients. Most anticancer drugs target cell proliferation and survival. Members of the Src family of non-receptor tyrosine kinases are part of the focal adhesion complex, which mediates migration and invasion in normal and cancer cells. Src is frequently activated in human cancer by growth factor and cytokine receptors. Therefore, Src is a promising cancer drug target, and several Src kinase inhibitors are currently in clinical trials. Although preliminary results indicate that these agents have clinical activity against solid tumours including lung cancer, the activity appears to be limited to a group of patients. As for many other molecular targeted agents, predictive factors for Src inhibitors remain to be identified. The aim of our project is to better understand the Src signalling pathway in human lung cancer, which may lead to a rational development of Src inhibitors in oncology. Using pharmacological small-molecule Src kinase inhibitors, viral vectors carrying Src mutant constructs and gene expression microarrays, we previously identified inhibitor of differentiation 1 (ID1) as a new and functionally relevant target gene of Src kinase in human lung cancer cells. The ID1 gene mediates stem cell function and is a potent regulator of cancer cell invasion. More recently, using an established lung cancer biobank, we demonstrated that Src and ID1 are frequently and strongly co-expressed in primary human lung cancer, compared with matched lung tissue. ID1 expression correlated with poor tumour differentiation and with expression of matrix metalloproteinase 9 (MMP9). Interestingly, ID1 was also overexpressed in pre-invasive lung lesions. In lung cancer cell lines, forced expression of ID1 enhanced Matrigel invasion and caused resistance to Src kinase inhibitors, which was supported by preliminary animal experiments. Using Src inhibitors and microarrays, we identified two microRNAs that target ID1 expression. Manipulation of these microRNAs in lung cancer cell lines again changed the effect of Src kinase inhibitors on migration and invasion. Tumour microRNA expression in patient samples inversely correlated with ID1 expression and with patient survival. These results suggest that ID1 and microRNAs are dysregulated in lung cancer and can modulate and predict the activity of Src kinase inhibitors. As a consequence, ongoing work includes further experiments to confirm the predictive value of ID1 and microR- NAs for Src inhibitors in preclinical models of metastatic lung cancer. Further efforts are focused on the pharmacological targeting of microRNAs to develop rational drug combinations with Src inhibitors and other targeted agents. Project coordinator Dr. Oliver Gautschi Departement für klinische Forschung Universität Bern Inselspital Murtenstrasse 35 CH-3010 Bern Phone +41 (0)31 632 25 18 Fax +41 (0)31 632 09 46 oliver.gautschi@onkologie.ch Heim Markus Hermann | Hepatocarcinogenesis in chronic hepatitis C (OCS 02192-02-2008) Background Chronic hepatitis C (CHC) is a major cause of liver disease worldwide and a risk factor for cirrhosis and hepatocellular carcinoma (HCC). Regardless of its aetiology, cirrhosis is a major clinical risk factor for HCC, and indeed, hepatitis C virus (HCV) associated HCC generally develops in patients with cirrhosis. There is also evidence for HCV specific tumourigenic pathways, mainly involving HCV core and NS5A proteins. However, the molecular pathways responsible for HCV induced hepatocarcinogenesis have not yet been characterized. A potential tumourigenic pathway could involve protein phosphatase 2A (PP2A) and protein arginine methyltransferase 1 (PRMT1), since both enzymes are dysregulated in chronic hepatitis C and both enzymes have been involved in chromatin remodelling and DNA damage repair. Aim The aim of the studies was to elucidate the role of PP2A overexpression and of PRMT1 inhibition for carcinogenesis. Methods We used cell lines that allow the inducible expression of hepatitis C virus proteins (UHCV57.3) and of the catalytic subunit of PP2A (UPP2A-C8) as well as Huh7.5 cells infected with recombinant cell culture-derived HCV (HCVcc) to study epigenetic histone modifications and DNA damage repair. We also investigated if the methyl group donor S-adenosyl-L-methionine (SAMe) could reverse the HCV induced changes. Results The induction of viral proteins, the overexpression of PP2Ac or the infection of Huh7.5 cells with HCVcc resulted in an inhibition of histone H4 methylation/acetylation and histone H2AX phosphorylation in a significantly changed expression of genes important for hepatocarcinogenesis and inhibited DNA damage repair. These changes were partially reversed by the treatment of cells with the methyl-group donor S-adenosyl-L-methionine (SAMe).
Conclusion The correction of defective histone modifications by Sadenosyl-L-methionine makes this drug a candidate for chemo-preventive therapies in patients with chronic hepatitis C who are at risk for developing hepatocellular carcinoma. Project coordinator Prof. Dr. Markus Hermann Heim Klinik für Gastroenterologie und Hepatologie Universitätsspital Basel Petersgraben 4 CH-4031 Basel Phone +41 (0)61 265 51 74 markus.heim@unibas.ch Heinzelmann-Schwarz Viola | Detection of anti-glycan autoantibodies as biomarkers of high stage serous ovarian cancer; acronym: GOS-study (OCS 02115-08-2007) Serous ovarian cancer (SOC) is the most common subtype of ovarian cancers in the Western world, contributing to its high overall mortality rate. It is known that altered glycosylation of cell-surface proteins and lipids as well as extracellular proteins are associated with transformation into a cancer, producing specific tumour-associated antigens. Utilizing a printed glycan array (PGA), we aimed to identify abnormal patterns in serum samples of healthy controls and patients with SOC in order to develop a new generation of tumour markers for the early detection of ovarian cancer. Serum samples were collected from healthy control patients with known negative intra-operative findings (n=26) and patients with advanced SOC (n=16) at University Hospital Zurich and Limmattal Hospital following ethical approval. The printed glycan array incorporates 211 carbohydrate structures, which are printed on glass
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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
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76 Methods and experimental approac
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78 of cMyc and/or NMyc and demo
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80 In summary, this work improves o
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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 128 and 129: 126 Benhattar Jean | Identification
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 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
Page 178 and 179: 176 National Strategy for Palliativ
Page 180 and 181: 178 Psychosocial research List of c
Page 182 and 183: 180 Within the patient group, level
Page 184 and 185: 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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