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124 Clinical research Presentation of completed research projects from July 2008 to December 2010 Aebersold Daniel M. | The role of activating point mutations in the met receptor tyrosine kinase in tumor radioresistance (OCS 1681-02-2005) The growth factor receptor Met activates various pathways and corresponding biological functions that are implicated in the development of malignant tumours, including critical roles in tumour progression and metastasis. Moreover, it was demonstrated that the activation of this receptor can adversely affect the response of malignant tumour cells to chemotherapy and radiotherapy. Consequently, Met is considered to be a promising molecular target for the development of new cancer drugs. Various mechanisms that can lead to excessive activation of the Met receptor in tumours have been described. In this regard, Met receptor overexpression and the occurrence of activating point mutations are the most prevalent. The aim of this research project was to investigate in more detail the importance of activating Met mutations, from both the biological and clinical point of view. For this purpose, the following sub-projects were pursued: 1) The clinical study focused on the potential role of the MET variant Y1253D, for which we previously suggested a role in tumour response to radiation therapy, in metastatic head and neck squamous cells carcinoma. This work – performed on biopsy samples from a prospective randomised trial combining radiotherapy and chemotherapy – confirmed a role for an activating MET mutation in metastasis of these tumours. 2) The scope of this sub-study was to perform a characterization of the response of four MET mutated variants, all of clinical significance, to the small molecule inhibitor SU11274 before a combination treatment with IR could be performed. The data obtained suggest that although all four mutants are responsive to SU11274, considerable differences in IC50 were observed on various MET-dependent biochemical and biological endpoints. Those response differences would have to be taken into consideration once SU11274 is combined with IR. 3) This study focused on mechanistic aspects that underlie the molecular cross-talk between MET and the DNA damage response in cells harbouring both overexpression of MET and MET mutations. The work shows that MET inhibition results in reduced clonogenic survival of cells to IR, which is accompanied by increased apoptosis. The work also shows that MET inhibition cooperates with DNA damaging agents to induce double strand DNA breaks (DSBs) in a synergistic manner, and one of the reasons for this synergism is the fact the MET inhibition alone results in high levels of DSBs. The study also shows that Met inhibition results in blocking of a major checkpoint signalling pathway, the ATR-CHK1-CDC25, which results in disruption of a post-damage S-phase associated cell cycle arrest, which could eventually lead to mitotic entry of cells that harbour high levels of unrepaired DSBs. 4) In this study we further explored previous findings, published in 2008, coupling MET to effectors of DSBs repair via homologous recombination. In that respect, by using the DR-GFP homologous recombination (HR) assay, we show that MET inhibition results in attenuation of HR in a dose-dependent manner in cells harbouring MET overexpression and MET mutants. Moreover, mechanistically the study shows that this MET-dependent inhibition of HR is coupled to a reduction of nuclear RAD51 and a disruption of the physical association between RAD51 and BRCA2, which is crucial for successful HR. The overall objective of the research project was to pave the way for the implementation of genetic and mechanistic evidence related to the growth factor receptor Met in clinical research protocols to test the combination of Met inhibition with conventional radiotherapy or chemotherapy. Project coordinator Prof. Dr. Daniel M. Aebersold Universitätsklinik für Radio-Onkologie Inselspital/Universität Bern Freiburgstrasse CH-3010 Bern Phone +41 (0)31 632 24 31 Fax +41 (0)31 382 23 42 daniel.aebersold@insel.ch Baege Astrid | The role of adult stem cells in HPV- associated carcinogenesis: Identification of the HPV target cell capable of driving viral persistence (KLS 02220-02-2008) Objective Cervical cancer is still the second most common malignancy-related cause of death worldwide. Persistent infection with high risk human papillomavirus (HPV) is necessary for the emergence of cervical cancer, but the crucial factors determining persistence are largely unknown. The overall goal is to identify stem cells within the human cervical epithelium to further investigate their role during HPV-transmission, establishment of persistent infection and HPV-induced transformation. Methods Epithelial cells are isolated from fresh human cervical tissue and fractionated by FACS sorting. Subpopulations of putative stem cells, transit amplifying cells and differentiating cells are sequentially subjected to microarray analysis to compare gene expression pattern. Recruited stem cell markers will be used to localize stem cells within the cervical epithelium. Advanced organotypic cervical explant models will be infected with fluorescent high risk HPV pseudoviruses, and the course of infection will be monitored to identify the HPV target cell capable of maintaining the viral DNA over a course of time.
Results Transcriptional profiling of putative stem cells suggested an undifferentiated and slowly cycling phenotype. Genes, encoding transcripts involved in self-renewal of stem cells, negative regulation of proliferation via TGF-b signalling, organogenesis and inhibition of the WNT signalling pathway were overrepresented, whereas genes responsible for cell division and DNA replication and DNA repair were underrepresented. Markers for cervical stem cells were validated at the protein level, permitting localization of stem cells in a scattered pattern within the basal layer of the cervical epithelium. Isolation and characterization of these cells confirmed an undifferentiated, slowly cycling phenotype with high proliferative potential. We successfully optimized a cervical organ culture model developed in our laboratory, now maintaining original organ architecture, tissue heterogeneity and expression of cellular markers for up to 4 weeks. These cervical explants provided the basis for monitoring virus binding and the course of infection within the regenerating epithelium after exposure to HPV pseudoviruses. Long-term infection was detected in only a small number of cells within the basal cell layer. These cells possess characteristics and functional properties of stem cells, thus suggesting that stem cells are the targeted cell type to achieve viral persistence. Conclusion Our results permit the first time phenotypic and functional distinction of viable cervical stem cells, describe their localization within the human cervical epithelium and define their role in HPV-associated carcinogenesis. We describe the development of the first cervical organ culture system maintaining all cell types of squamous epithelium over a period of 4 weeks and permitting monitoring of high risk HPV infection. Data recruited from this model suggest that infection of stem cells within the cervical epithelium is indeed necessary to establish long-term infection. These findings represent an important step forward to thoroughly define the role of stem cells in HPVassociated carcinogenesis, not only within the cervix but also in other HPV-related malignancies, such as anal, vulvar and oropharyngeal cancers. Insights may be gained into the pathogenesis of cancers attributable to other oncogenic viruses, such as hepatocellular cancer and Burkitt lymphoma. Identification and characterization of tumour stem cells driving overall proliferation and malignant potential will be the key to developing effective treatments in the future. This project will continue until fall 2011. A follow-on project to translate results into an in vivo animal model is planned. Project coordinator Dr. Astrid Baege Klinik für Gynäkologie UniversitätsSpital Zürich Frauenklinikstrasse 10 CH-8091 Zürich Phone +41 (0)44 255 11 11 astrid.baege@usz.ch Ballmer Peter E. | Influence of a nutritional intervention on clinical course and quality of life in cancer patients (OCS 02000-02-2007) Involuntary loss of body weight is common in patients presenting with malignant tumours. The disease itself and various oncological treatments may further deteriorate the nutritional status. A deficient nutritional status potentially increases the side effects of the therapy and may increase the complication rate and length of hospital stay and decrease the effect of antitumoural therapies. In a pilot-study with undernourished hospitalized patients we showed that intensive nutritional counselling increased energy intake and protein intake as well as quality of life. The present study investigated the impact of nutritional intervention on energy and protein intake and quality of life in malnourished cancer patients in the ambulatory setting. The primary endpoints were improvement of the energy and protein intake and of quality of life. Methods Undernourished outpatients with cancer were randomised in two groups. One group was individually counselled by a professional dietician, and the other group received the usual oncological care without specific nutritional intervention. Study duration was 6 months. Patients in the counselled group were individually counselled and supported during the first 3 months. Study measurements were carried out at baseline and after 6 weeks, 3 and 6 months. Energy and protein intake was assessed at each study visit with dietary records, and quality of life was measured by standardized protocols (EORTC-QLQ-C30 and a visual analogue scale concerning dietary items). Results and Recommendations The study showed that the nutritional intervention significantly increased energy and protein intake. In contrast to our pilot study with hospitalized patients, there was no effect on quality of life. We hypothesize that the nutritional intervention may have been too late to result in a beneficial effect of the increased dietary intake on quality of life in these patients with already advanced cancer disease and deteriorated nutritional status. We therefore suggest that individual nutritional support be initiated at an early stage of the disease to avoid or delay nutritional deterioration; however, this hypothesis needs to be proven in a new clinical trial. Project coordinator Prof. Dr. Peter E. Ballmer Klinik für Innere Medizin Departement Medizin Kantonsspital Winterthur Brauerstrasse 15 CH-8401 Winterthur Phone +41 (0)52 266 23 01 Fax +41 (0)52 266 47 06 peter.ballmer@ksw.ch 125
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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
Page 76 and 77: 74 Hübscher Ulrich | Repair of oxi
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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 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 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
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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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