Cancer Research in Switzerland - Krebsliga Schweiz

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104 Janscak Pavel | Study of the role of mismatch repair proteins in the cellular response to DNA double-strand breaks (KLS 02344022009) Duration: 01.07.2009 – 01.07.2011 DNA damage is a frequent event in the life of a cell. Failure to repair DNA damage can lead to cell death, and inaccurate DNA repair can give rise to genomic instability, which promotes the onset of cancer in mammals. The most deleterious form of DNA damage is DNA doublestrand break (DSB). In eukaryotic cells, two mechanistically distinct pathways are known to efficiently repair DSBs: nonhomologous end joining and homologous recombination. However, molecular mechanisms underlying these DNA repair pathways are not completely understood. Our recent experiments with human cells revealed that proteins involved in the initiation of postreplicative mismatch repair (MMR), such as MSH2, MSH3, MSH6 and MLH1, accumulate at sites of chromosomal DSBs generated by UVA laser. Ongoing research in our laboratory aims to gain insight into the function of MMR proteins at the sites of DNA damage in human cells. The project utilizes various cell biology methods in combination with laser microdissection technology and immunofluorescence microscopy. Using RNA interference, we intend to identify the DNA repair factors that are required for the recruitment of MMR proteins to the sites of DSBs. DNA repair capacity of cells depleted for the individual MMR proteins will be assessed using chromosomallybased reporters for specific DSB repair pathways and by testing sensitivity of depleted cells to DNA damaging agents. Our preliminary data indicate that the MMR proteins accumulate at DSBs in a manner dependent on MRE11 and CtIP, which are involved in the initiation homologous recombination. Germline mutations in the MLH1, MSH2 and MSH6 genes are the major cause of hereditary nonpolyposis colon cancer. It is anticipated that our study will advance understanding of the molecular events leading to this most common form of inherited colon cancer. Project coordinator Dr. Pavel Janscak Institut für molekulare Krebsforschung Universität Zürich Winterthurerstrasse 190 CH8057 Zürich Phone +41 (0)44 635 34 70 pjanscak@imcr.uzh.ch Krek Wilhelm | Roles of the URI oncoprotein in B-RAF-signaling and melanoma cancer cell proliferation (KFS 02690082010) Duration: 01.02.2011 – 01.02.2013 Malignant melanoma (“black skin cancer”) is one of the most aggressive cancers. Prognosis for advanced stages is dismal due to a lack of efficient systemic therapies, with classical cytotoxic chemotherapy being particularly inefficient. Elucidating the molecular and cell biological bases of melanomagenesis is therefore of prime importance and has already led to findings that have been translated successfully to the clinics. A central player in melanomagenesis is BRAF V600E , which is a constitutively active mutant form of the BRAF kinase, a component of the RAS/RAF/MEK/ ERKsignaling cascade. BRAF V600E is found in about 70 % of all melanomas, and mouse models demonstrated its oncogenic potential. Selective BRAF V600E inhibitors have been developed and their therapeutic efficiency in first clinical trials is promising. However, after some months clinical resistance develops, and therefore new therapeutic strategies are still very much needed. BRAF V600E provokes overactive RAS/RAF/MEK/ERKsignalling leading to un con trolled cellular proliferation. Several mechanisms regulate the activity of this pathway at multiple levels. Particularly important in the negative regulation of pathway activity are negative feedback systems mediated by phosphatases that dampen overactive signalling. That might also be one of the reasons why the BRAF V600E alone does not suffice for malignant transformation, but secondary changes (“second hits”) are a prerequisite. We recently discovered a novel phosphatase (PP)1dependent negative feedback system that acts to restrain S6K1 survival signalling in response to nutrient and growth factor stimulation. Moreover, PP1 is a target of oncogenic alterations that disable PP1mediated feedback inhibition on survival signalling in different human cancers. In this project we are testing whether this PP1dependent feedback system also acts on the RAS/RAF/MEK/ERK pathway and is oncogenically targeted in human melanoma. In this work we are combining human tissue microarrays (TMA), quantitative phosphoproteome analyses, RNA interference and mouse models of melanomagenesis. From these studies, we expect to discover novel regulatory mechanisms of oncogenic BRAF V600E signalling and of RAS/RAF/MEK/ERKsignalling in general. Project coordinator Prof. Dr. Wilhelm Krek Institut für Zellbiologie ETH Zürich HPM F42 Schafmattstrasse 18 CH8093 Zürich Phone +41 (0)44 633 34 47 Fax +41 (0)44 633 13 57 wilhelm.krek@cell.biol.ethz.ch
Martinou JeanClaude | Studies on the role of TRAIL as a tumor metastasis promoter (KLS 02370022009) Duration: 01.11.2009–01.11.2011 TRAIL is a protein that is able to trigger apoptosis of cancer cells but is inefficient in killing non tumour cells, hence its interest in cancer treatment. We noticed that TRAIL can induce apoptosis of various cancer cells but is unable to kill cells that display a dysfunctional mitochondrial pathway of apoptosis. In this case, TRAIL stimulates cell detachment from their substrate, which raises the possibility that administration of TRAIL for cancer treatment could lead to metastatic dissemination of the tumour. This is the hypothesis that we are currently testing using mice in which tumours are implanted and treated with TRAIL. Our results may have consequences for cancer treatment with TRAIL and may limit its administration to tumours with a functional apoptosis mitochondrial pathway. Project coordinator Prof. Dr JeanClaude Martinou Département de biologie cellulaire Faculté des sciences Université de Genève 30, quai ErnestAnsermet CH1211 Genève 4 Phone +41 (0)22 379 64 43 Fax +41 (0)22 379 64 42 jeanclaude.martinou@unige.ch Meraldi Patrick | How does overexpression of the Aurora A oncogene override the spindle checkpoint? (KFS 02707082010) Duration: 01.06.2011–01.06.2013 Taxol is one of the most potent cancer drugs available. It is a spindle poison that perturbs orderly cell division. Cells possess a checkpoint that blocks cell division in the presence of such defects, which is why Taxol treatments block the uncontrolled growth of cancer cells. Unfortunately, many cancer patients are resistant to Taxol, as they overexpress the Aurora A protein, a condition that disrupts the cell division checkpoint. Although we have learned a lot about the functions of Aurora A in normal cells, we still do not understand how the cell division checkpoint is impaired by the pathological overexpression of Aurora A. Our goal is to understand this mechanism by identifying the proteins that interact specifically with overexpressed Aurora A. This knowledge will form the basis for new drugs that could prevent such pathological interactions with Aurora A and abolish Taxol resistance in cancer patients. Project coordinator Prof. Dr. Patrick Meraldi Institut für Biochemie ETH Zürich Schafmattstrasse 18 CH8093 Zürich Phone +41 (0)44 632 63 47 Fax +41 (0)44 632 15 91 patrick.meraldi@bc.biol.ethz.ch Merdes Gunter | Systems biology of tumor suppression and malignancy in the model system Drosophila (KFS 02695082010) Duration: 01.03.2011– 01.03.2014 To study the development of cancer, researchers use cells from patients and animals like the mouse or the fruit fly. At first sight, fruit flies seem inappropriate based on obvious differences between fruit flies and us. However, it was discovered not only that are we very similar even in the number of genes but also that important findings about the development of cancer are directly transferable from fruit flies to humans. Accordingly, we plan to identify all the genes involved in tumour suppression in the fruit fly by systematically switching on and off single genes and by studying the interconnectivity of the identified cancer genes. It is our longterm goal to recognize new therapeutic strategies in humans based on these results. Project coordinator Dr. Gunter Merdes Departement Biosysteme ETH Zürich Mattenstrasse 26 CH4058 Basel Phone +41 (0)61 387 31 24 Fax +41 (0)61 387 39 94 gunter.merdes@bsse.ethz.ch Michielin Olivier | Rational design of anti-MART-1 TCR sequences for adoptive transfer immunotherapies (KFS 02555022010) Duration: 01.03.2010 – 01.03.2013 Tcell receptors (TCRs) control the specificity and efficacy of the cellular specific immune system by recognizing foreign and abnormal antigens presented by the MHC molecules. However, their low affinity constitutes a critically limiting factor of tumour immunity. We therefore designed a new structurebased computational approach using free energy calculations to rationally design TCRs. By controlling the mutations’ structural and functional effect, the approach is likely to suggest TCRs with optimal activity and lower risk of crossreactivity. We engineered TCRs specific for NYESO1, a cancer testis antigen peptide expressed not only in melanoma but also in several other types of cancers. We obtained specific antigens with controlled affinities up to 160fold higher than that of the wild type TCR. Corresponding engineered Tcells exhibited improved killing of melanoma cell lines and better proliferative capacity, thus paving the road to clinical trials. We are now using this technique to design TCRs specifically recognizing the MART1 antigen, which is expressed by melanoma cells. Project coordinator Prof. Dr Olivier Michielin Molecular Modelling Group (MMG) Institut suisse de bioinformatique (ISB) Quartier Sorge – Bâtiment Génopode Chemin des Boveresses 155 CH1015 Lausanne Phone +41 (0)21 692 40 53 Olivier.michielin@unil.ch 105
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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
Page 55: Zucca Emanuele et al. | Internation
Page 58 and 59: 56 “hierarchical structure” of
Page 60 and 61: 58 the attempt should be made to st
Page 62 and 63: 60 Gönczy Pierre | KLS 0202402
Page 64 and 65: 62 Romero Pedro | OCS 020110220
Page 66 and 67: 64 Beermann Friedrich | In vivo scr
Page 68 and 69: 66 Christofori Gerhard | Podoplanin
Page 70 and 71: 68 Frei Christian | The function of
Page 72 and 73: 70 cell, this novel mechanism serve
Page 74 and 75: 72 Results The induction of viral p
Page 76 and 77: 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
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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 136 and 137: 134 new drugs that specifically tar
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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
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154 Heinimann Karl | KFS 02489-08-2
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156 Riggi Nicolò | BIL KFS 02717-0
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158 activity at the single cell lev
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160 Our research projects aim at un
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162 Körner Meike | In vitro evalua
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164 Nadal David | Is endemic Burkit
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166 (> 50.000/patient). For their a
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168 Zeller Rolf | Functional analys
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170
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172 area of health services researc
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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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