Cancer Research in Switzerland - Krebsliga Schweiz

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90 To address these questions, we are combining detailed analysis of cells and tissues from patients with MPD with mouse models of MPD. Our studies in patients revealed that JAK2V617F may be preceded by as yet unknown mutations. To follow up on this observation, we studied patients with MPD that in addition to JAK2V617F have deletions of chromosome 20q (del20q) or carry mutations in a gene called TET2, and we determined the temporal order in which these mutations were acquired. Our studies showed that there is no fixed order of events, and some patients acquire JAK2V617F first, followed by del20q or TET2 mutations, whereas in other patients with MPD the inverse order can be observed. Thus, deletions of chromosome 20 and mutations in TET2 are unlikely to represent predisposing events for JAK2V617F, and we are examining other candidate genes for such a function in familial forms of MPD. A second question that we are addressing is why the JAK2V617F mutation can cause 3 different subtypes of MPD, namely, essential thrombocythemia (ET) with elevated platelet levels, polycythemia vera (PV) with increased numbers of red cells and in some cases primary myelofibrosis (PMF) with fibrosis of the bone marrow and blood formation in the spleen and liver. We generated a mouse model of MPD that expresses the mutant JAK2 V617F and displays all 3 types of MPD. We found that ET develops when the mutant human JAK2V617F is expressed at lower levels, while at higher levels PV phenotype can be observed. Myelofibrosis occurred later in these mice and appears to correlate with the platelet counts. Interestingly, when we made a mutation in a different position in JAK2 that is associated with a pure red cell phenotype in patients (JAK2 exon 12 mutation), we observed a pure red cell elevation in the mice, i.e. the same phenotype as in patients. Thus, in addition to expression levels, the different JAK2 mutations may also cause different quality of signals that favour the expansion of specific blood cell types. Finally, inhibitors have been developed that can reduce the enzymatic activity of JAK2 and are undergoing clinical trials in patients with MPD. Our mouse models have proven to be valuable in testing such compounds. Our projects on JAK2 have contributed to changing the diagnostic and therapeutic approach to patients with MPD. We are now examining how other known gene mutations collaborate with JAK2 mutations and are searching for as yet unknown new gene mutations in MPD. Project coordinator Prof. Dr. Radek C. Skoda Forschungsgruppe experimentelle Hämatologie Departement Biomedizin Universitätsspital Basel Hebelstrasse 20 4031 Basel Phone +41 (0)61 265 22 72 Fax +41 (0)61 265 32 72 radek.skoda@unibas.ch Suter Beat | Control of the cell cycle function of Xpd and Cdk7 (OCS 01834022006) The Xpd gene aids our body in different ways to prevent cells from turning into tumour cells. Many patients with a genetic defect in the Xpd gene have a one to two thousandfold increase in cancer risk. Whereas skin cancer is the most prevalent form, other tissues can be affected as well. It was known for some time that one of the functions of this XPD is to repair the genetic material once it gets damaged in certain ways. However, it was also known that the reduced repair capacity alone does not necessarily lead to this very high cancer incidence in patients. We tried to elucidate novel functions of Xpd, and we wanted to find out whether these functions could play important roles in preventing tumour formation. To be able to identify additional novel functions of XPD and to analyze them, we developed a model system in which the previously known activities of XPD are not required. We were able to develop such a model in an intact organism by using the embryo of the fruit fly Drosophila. Using this model we found that the XPD protein is a truly multifunctional protein that helps to organize the division of cells and that coordinates this process with other cellular processes. If it fails to function properly, the genetic material is not distributed equally to the ensuing daughter cells. As a consequence, daughter cells arise that lack pieces of chromosomes or even entire chromosomes. This instability of the genome is a decisive step in tumour formation. Identifying the need for XPD to prevent this instability in our model system was a big step forward in finding out the causes of this devastating disease. The diverse functions of XPD make it a truly fascinating multifunctional protein. It performs diverse cellular functions and acts through several different cellular processes. The cells need to tightly coordinate these diverse processes for the body to function properly. In the course of our experimental work we realized that XPD is able to coordinate these processes by acting as a dispatcher for another protein complex named CAK. XPD sends CAK at the correct time to the appropriate place in the cell, where it can act on the local target substrates. At the same time, the localization to a new region terminates CAK activity towards a previous target that should no longer be activated at this point. Therefore, by sending CAK to the right place at the right time, the dispatcher controls and coordinates these different cellular processes. As described at the beginning, malfunctioning of this XPD in human patients can lead to highly elevated cancer risk in Xpd patients. Combining our own studies with earlier studies we came to the conclusion that the very strongly elevated cancer risk arises most likely in Xpd patients in which the failure to repair the genetic material combines with defective Xpd activity in organizing and controlling the cell division. It seems likely that as long as one of the two functions is still active, the cancer risk is only moder
ately elevated. In summary, Xpd protects our genetic material in different ways, and it therefore acts as a veritable bodyguard to our genetic material. Project coordinator Prof. Dr. Beat Suter Institut für Zellbiologie Universität Bern Baltzerstrasse 4 CH3012 Bern Phone: +41 (0)31 631 47 15 beat.suter@izb.unibe.ch Tschan Mario P. | Regulation of the DMP1-ARF-p53 tumor suppressor pathway in normal and leukemic hematopoiesis (OCS 01823022006) Cyclin D binding myblike protein 1 (DMP1) is a haploinsufficient tumour suppressor involved in positively modulating the alternative reading frame (ARF)p53 signalling pathway. This pathway is inactivated in most cancers, including leukaemias, and further understanding of its regulation might provide novel options for cancer treatment. DMP1 is a direct transcriptional activator of ARF and of CD13, a gene involved in myeloid differentiation. Using lentiviral vectors to express shRNA for gene knockdowns or transgenes as well as promoter reporter and proliferation assays, we identified novel transcriptional, posttranscriptional and posttranslational regulators of the DMP1 tumour suppressor. Moreover, we showed that a dominant negative splice variant of DMP1, DMP1 beta has oncogenic properties by inhibiting the fulllength DMP1 and promoting cellular proliferation. In addition, we found aberrant expression of this splice variant in acute myeloid leukaemia patients’ samples as compared to healthy controls. In summary, we discovered a variety of novel mechanisms to inactivate the DMP1 tumour suppressor in myeloid leukaemias, or other tumours, and propose the following DMP1 repression models: 1) enhanced expression of the dominant negative DMP1 beta splice variant leading to reduced ARF levels and thus aberrant proliferation; 2) altered expression of microRNAs, which target DMP1; and 3) inactivation of positive DMP1 regulators, such as the transcription factor OCT1 and or the kinase DAPK2. Project coordinator Dr. Mario P. Tschan Medizinische Onkologie/Hämatologie Departement für klinische Forschung Universität Bern MEM E829 Murtenstrasse 35 CH3010 Bern Phone +41 (0)31 632 87 80 mtschan@dkf.unibe.ch Walker Paul R. | Exploration of intracerebral immune responses in a spontaneous astrocytoma model and their exploitation in novel cancer therapies (OCS 1754082005) In this study we used a transgenic mouse model in which brain tumours spontaneously arise to understand the interactions of the immune system with the developing cancer. This is difficult to study in patients, because the limited tumour samples that are available for analysis are generally from advanced cancers, or after treatment. We studied mice before they developed any cancer related symptoms, and also when they became ill. We isolated immune cells from lymph nodes and spleen, as well as from the brain, to assess the leukocyte subsets present and their functions. We then tested a vaccination approach to improve the potential antitumour immune response. Objectives Immunotherapy for patients with malignant gliomas may be a useful future treatment option. However, it is not clear whether this should aim to reinforce or reprogram a preexisting immune response. By analyzing the spontaneous gliomas that arise in the brains of GFAPV 12 HAras transgenic mice, we aimed to determine whether brain tumours were detected by the immune system at an early stage, and whether antitumour immunity was functional at any stage, or could be induced or restored by vaccination. Methods In the GFAPV 12 HAras model, mice spontaneously form astrocytomas that develop progressively and gradually increase in malignancy. We sacrificed individual mice at fixed time points while they were still healthy (4, 8, and 12 weeks of age) and also once they became terminally ill. Immune cells were isolated from dissociated brain and lymphoid tissues and were stained with antibodies to identify all principle leucocyte subsets. We stained for cytokines and cytotoxic molecules important for anti tumour activity. Analysis was principally by flow cytometry. To augment the number of immune cells infiltrating the brain we used a vaccine comprised of a recombinant virus to induce immunity to brain tumour cells. Results There was an immune response induced by the tumour at early, nonmalignant stages of glioma development, before the mice developed symptoms. However, the immune cells that first infiltrated the brain included many regulatory T cells that are capable of suppressing cytotoxic T cells that could otherwise attack the glioma. Consistent with this, the CD8 T cells that coinfiltrated the brain had low or absent expression of the cytotoxic molecule granzyme B and cytokines useful in antitumour immunity (interferong, TNF and IL2). Peripheral vaccination with recombinant virus could augment interferong expression by CD8 T cells, but only direct intracranial stimulation could restore granzyme B expression. 91
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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.-
Page 41 and 42: Thurgau Cancer League Biotechnologi
Page 43 and 44: Weller Michael | 2010: CHF 65,828.-
Page 45 and 46: manageable funding of individual pr
Page 47 and 48: enhances breast cancer cell motilit
Page 49 and 50: Rüegg Curzio et al. | Tumor-mediat
Page 51 and 52: International Clinical Cancer Resea
Page 53 and 54: 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 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 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
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140 tions introduced to ARE motifs
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142 Müller Beatrice U. | The maste
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144 A novel method was developed fo
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146 (SAKK 35-98) the Swiss Group fo
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148 Timmermann Beate | Prospective
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150 recurrence of the disease, we a
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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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