Cancer Research in Switzerland - Krebsliga Schweiz

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166 (> 50.000/patient). For their analysis, the Swiss Group for Clinical Cancer Research (SAKK) obtained the assistance of the Swiss Institute of Bioinformatics (SIB), which is specialized in the analysis of this type of biological data, with the financial support of the Swiss Cancer League. Project coordinator Dr Arnaud Roth Unité d’oncochirurgie Hôpitaux universitaires de Genève (HUG) 4, rue Gabrielle-Perret-Gentil 1211 Genève 14 Phone +41 (0)22 372 77 44 Fax +41 (0)22 372 98 50 arnaud.roth@hcuge.ch Rothermundt Christian | Metformin in castration resistant prostate cancer. A multicenter phase II trial of the SAKK (Swiss Group for Clinical Cancer Research) (SAKK08/09) (KFS 02641-08-2010) Duration: 01.01.2011– 01.07.2012 Patients with prostate cancer receiving androgen deprivation therapy (orchiectomy or GnRH analogue) develop hyperglycaemia and hyperinsulinaemia. There is a suggestion that high insulin concentrations promote progression of prostate cancer. Metformin is a biguanide and is being used in the treatment for diabetes. Metformin can potentially revert the above-mentioned negative effects of androgen deprivation in patients with metastatic prostate cancer. Additionally, metformin has an inhibitory effect on cell proliferation. We conduct a multicenter phase II trial with metformin in patients with slowly progressing castration resistant prostate cancer. The research question is whether metformin can stabilize the disease with tolerable side effects. We also measure metabolic changes due to metformin, and we aim to identify pharmacogenetic markers for a favourable treatment response. Project coordinator Dr. Christian Rothermundt Fachbereich Onkologie/Hämatologie Kantonsspital St. Gallen CH-9007 St. Gallen Phone +41 (0)71 494 11 63 christian.rothermundt@kssg.ch Rufer Nathalie | Structural and functional studies of T-cell receptors specific for tumor antigens: Implications for immunotherapy of cancer patients (KLS 02635-08-2010) Duration: 01.04.2011– 01.04.2013 Although tumour-reactive T lymphocytes can be detected in cancer patients, these immune responses often fail to control or eliminate the disease. Adoptive transfer of Tcells engineered with T-cell receptors (TCRs) has been recently developed with the aim to induce immune reactivity towards defined tumour-associated antigens to which the endogenous T-cell repertoire is non-responsive. An attractive approach to improve this strategy is to optimize the TCR sequence to increase its affinity for cognate tumour antigen. We recently generated tumour-specific T lymphocytes expressing sequence-optimized TCRs, and we showed that T-cell immune responses against cancer cells could be specifically improved. However, our study also revealed the presence of an affinity window for optimal T-cell function. The objectives of our current project are to characterize some of the parameters involved in regulation of TCR function. Identifying rationally optimized TCRs and expressing such tumour-specific receptors in T lymphocytes represents one of the most promising approaches to improving adoptive T-cell therapy against cancer. Project coordinator Dr Nathalie Rufer Centre Ludwig de recherche sur le cancer Université de Lausanne c/o CHUV HO 05/1532 Avenue Pierre-Decker 4 CH-1011 Lausanne Phone +41 (0)21 314 01 99 nathalie.rufer@unil.ch Schwaller Jürg | Exploring new molecular therapeutic targets in MLL-X acute leukemia (OCS 02357-02-2009) Duration: 01.07.2009 – 01.07.2011 Expression of mixed lineage leukaemia/lymphoma fusions (MLL-X) is a hallmark for a significant group of paediatric, adult and therapy-related acute leukaemias with a poor prognosis. Previous work suggested that the MLL fusion is essential to induce and probably maintain the disease. Genetic studies identified potential functional co-factors as well as downstream effectors of MLL-X leukaemogenesis including protein kinases like PIM1. We propose to: 1) address the role of PIM kinases as biomarkers and therapeutic targets in haematological malignancies including MLL leukaemia; 2) search for potentially druggable novel protein kinases by performing an RNA interference screen in cells from conditional transgenic MLL models; and 3) to explore possibilities to block MLL leukaemia by targeting the fusion or critical co-factors of the MLL-X complex. Our project will provide important insights for potential molecular targeting, setting new landmarks for future therapeutic intervention. Project coordinator Prof. Dr. Jürg Schwaller Forschungsgruppe Kinder-Leukämie Departement Biomedizin Universitätsspital Basel Hebelstrasse 20 CH-4031 Basel Phone +41 (0)61 265 35 04 Fax +41 (0)61 265 23 50 j.schwaller@unibas.ch
Skoda Radek C. | The pathogenesis of myeloproliferative disorders (KLS 02398-02-2009) Duration: 01.10.2009 – 01.10.2012 Myeloproliferative disorders (MPD) are chronic blood diseases characterized by overproduction of blood cell precursors in the bone marrow. Patients with MPD bear an increased risk (5–20 %) to develop an acute leukaemia after a variable latency. Therefore, MPD is often considered a “pre-leukaemia“. We found that in about 70–80 % of MPD patients, the blood stem cells carry a mutation in the gene “Janus kinase 2” (JAK2). JAK2 is an enzyme that transmits signals coming from the outside into the cell and the mutation (JAK2-V617) amplifies the growth-promoting effect of these signals, so that more blood cells are formed. The aim of our studies is to better understand how the JAK2-V617F mutation causes MPD, with which partner genes it collaborates in this process and what the predisposing events are that can favour the acquisition of MPD. 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 JAK2-V617F may be preceded by as yet unknown mutations. To follow up on this observation, we studied patients with MPD that in addition to JAK2-V617F 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 JAK2-V617F 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 pre-disposing events for JAK2-V617F, 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 JAK2-V617F 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 JAK2-V617F 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 Biochemie Universitätsspital Basel Hebelstrasse 20 4031 Basel Phone +41 (0)61 265 22 72 Fax +41 (0)61 265 32 72 radek.skoda@unibas.ch Stenner-Liewen Frank | Establishment of GOLPH2 as a serum marker in hepatocellular carcinoma (within the SAKK 77/08 trial) and in bile duct cancer for routine clinical use (KFS 02423-04-2009) Duration: 01.11.2009 – 01.11.2011 Malignant tumours of the liver are often detected in advanced stages, thus having a poor prognosis. Strategies for detection and surveillance of hepatocellular carcinoma (HCC) are urgently warranted. We recently described a novel marker GOLPH2 in HCC and bile duct cancer (BDC). Validation of our data and meanwhile other conformational data will be validated prospectively within the setting of a randomised clinical trial. Purpose Within the HCC trial SAKK 77/08 serial GOLPH2 measurements will be performed to investigate the prognostic and predictive value of this tumour marker. Methods Serum-GOLPH2 will be quantified using a sandwich ELISA, or enzyme-linked immunosorbent assay. Specific antibodies against GOLPH2 and purified GOLPH2 will be employed. Further, by screening phage libraries novel antibodies for therapeutic and testing purposes will be defined. Descriptive statistical analysis will be performed correlating GOLPH2 values with disease progression and overall survival. Benefit for patients A new marker for diagnostics and monitoring of HCC and BDC could be established. This has the potential to simplify clinical routine and clinical trials. Project coordinator PD Dr. Frank Stenner-Liewen Medizinische Onkologie UniversitätsSpital Zürich Rämistrasse 100 CH-8091 Zürich Phone +41 (0)44 255 22 14 Fax +41 (0)44 255 45 48 frank.stenner@usz.ch 167
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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
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84 Renner Christoph | Selective inh
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86 Goal Here we build on these obse
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88 by TDG prevents efficient downst
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90 To address these questions, we a
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92 Translational relevance The resu
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94 Grünberg Jürgen | KFS 025460
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96 Tschan Mario P. | KFS 0248608
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98 Boyman Onur | Preclinical testin
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100 Constam Daniel | Role of activi
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102 this study we will examine the
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104 Janscak Pavel | Study of the ro
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106 Müller Anne | The molecular pa
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108 Radtke Freddy | The role of Not
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110 Schär Primo | DNA repair, epig
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112 In this project we will investi
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114
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
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 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
Page 186 and 187: 184 It is in this context that the
Page 188 and 189: 186 Recommendation Female spouses o
Page 190 and 191: 188 Psychosocial research Presentat
Page 192 and 193: 190 rates communication skills rema
Page 195 and 196: Epidemiological research Epidemiolo
Page 197 and 198: data from cancer registries. In the
Page 199 and 200: The importance of cancer registries
Page 201 and 202: Ess Silvia | Patterns of care and s
Page 203 and 204: Epidemiological research List of ap
Page 205 and 206: Impact This work will serve as the
Page 207 and 208: Thürlimann Beat | Management of br
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