2. Carbono 14
2.3. La muestra; procesado y métodos de medida
Heim Markus Hermann | KLS 02522-02-2010 | CHF 218,300.–
Klinik für Gastroenterologie und Hepatologie, Universitätsspital Basel, Basel
102
Clinical research
List of approved research projects in 2012
Total funds allocated: CHF 4,145,600.–
Ammann Roland A. | KFS 02933-02-2012 | CHF 63,300.–
Abteilung für Hämatologie /Onkologie, Universitätsklinik für Kinderheilkunde, Inselspital, Universitätsspital Bern, Bern
The impact of lowering fever limits on the rate of fever in chemotherapy induced neutropenia (FN): a prospective single-centre observational study in children and adolescents with cancer (Paediatric FN Definition 2012 Bern)
Bach Cuadra Meritxell | KFS 02937-02-2012 | CHF 157,500.–
Département de radiologie, Centre hospitalier universitaire vaudois (CHUV), Université de Lausanne, Lausanne
Towards robust and highly accurate computer assisted treatment planning for intraocular tumours: advanced image processing in a multi-modal framework
Beck Popovic Maja | KFS 02886-02-2012 | CHF 176,800.–
Service et laboratoire d’hématologie, Centre hospitalier universitaire vaudois (CHUV), Lausanne
SPOG-RB-2011: treatment of recurrent or progressive intraocular retinoblastoma. A national phase II study of the Swiss Paediatric Oncology Group
Beerenwinkel Niko | KLS 02892-02-2012 | CHF 263,000.–
Departement Biosysteme, ETH Zürich, Basel
Comparative sequencing of primary renal cell carcinoma: towards a quantitative understanding of tumour diversity and evolution
Bourquin Jean-Pierre | KFS 02920-02-2012 | CHF 248,300.–
Abteilung Onkologie, Kinderspital Zürich, Universitäts-Kinderkliniken, Zürich
Identification of critical determinants of the microenvironmental support for acute lymphoblastic leukaemia Brisken Cathrin | KLS 02907-02-2012 | CHF 339,200.–
Institut suisse de recherche expérimentale sur le cancer (ISREC), EPF de Lausanne, Lausanne
Mechanisms triggering cell proliferation in ER+ breast cancers in novel preclinical models Citi Sandra | KLS 02878-02-2012 | CHF 201,700.–
Département de biologie cellulaire, Université de Genève, Genève
The role of the new adherens junction protein PLEKHA7 in cancer and signalling Dotto Gian-Paolo | KLS 02922-02-2012 | CHF 202,500.–
Département de biochimie, Faculté de biologie et de médecine, Université de Lausanne, Epalinges
MicroRNAs as determinants of squamous cell carcinoma development in immune-suppressed patients Fey Martin F. | KFS 02919-02-2012 | CHF 274,700.–
Universitätsklinik für Medizinische Onkologie, Inselspital, Universitätsspital Bern, Bern
HOVON 102 AML /SAKK 30/09: randomized study with a run-in feasibility phase to assess the added value of clofarabine in combination with standard remission-induction chemotherapy in patients aged 18–65 years with previously untreated acute myeloid leukaemia (AML) or myelodysplasia (MDS)
Gautschi Oliver | KLS 02943-02-2012 | CHF 154,800.–
Medizinische Onkologie, Luzerner Kantonsspital, Luzern
SAKK 19 /09: bevacizumab, pemetrexed and cisplatin, or erlotinib and bevacizumab for advanced non-squamous NSCLC stratified by EGFR mutation status. A multicentre phase II trial including biopsy at progression (BIO-PRO trial)
Hegi Monika | KFS 02949-02-2012 | CHF 306,700.–
Laboratoire de biologie et génétique des tumeurs, Service de neurochirurgie, Centre hospitalier universitaire vaudois (CHUV), Lausanne
The methylome of low grade glioma: identification of novel therapeutic targets and biomarkers for response to treatment
Heinzelmann-Schwarz Viola | KFS 03013-08-2012 | CHF 200,600.–
Klinik für Operative Gynäkologie und Gynäkologische Onkologie, Universitätsspital Basel, Basel
Michalik Liliane | KFS 02900-02-2012 | CHF 202,500.–
Centre intégratif de génomique (CIG), Université de Lausanne, Lausanne
PPARg ligands: an emerging therapeutic strategy to treat malignant melanoma Nikolaev Sergey | KLS 02939-02-2012 | CHF 200,000.–
Département de médecine génétique et de développement, Université de Genève, Genève
Basal cell carcinoma: an integrative approach to detect somatically acquired sequence variants that identify genes involved in carcinogenesis
Rentsch Cyrill A. | KFS 03059-08-2012 | CHF 230,600.–
Urologische Klinik, Universitätsspital Basel, Basel
Identification of genomic correlates of cancer immunoediting in responders and non-responders to Bacillus Calmette-Guérin immunotherapy in bladder cancer
Rimoldi Donata | KFS 03056-08-2012 | CHF 209,900.–
Centre Ludwig de l’Université de Lausanne pour la recherche sur le cancer, Université de Lausanne, Epalinges
Investigating somatic variants in cutaneous melanoma Romero Pedro | KFS 03064-08-2012 | CHF 204,600.–
Centre Ludwig de l’Université de Lausanne pour la recherche sur le cancer, Université de Lausanne, Epalinges
104
Soltermann Alex | KFS 02984-08-2012 | CHF 185,800.–
Institut für Klinische Pathologie, Universitätsspital Zürich, Zürich
Desmoplastic stroma of lung squamous cell carcinoma – relevance for targeted therapy and drug resistance Stern Martin | KFS 03030-08-2012 | CHF 120,600.–
Klinik für Hämatologie, Universitätsspital Basel, Basel
Role of activating killer cell immunoglobulin-like receptors in natural killer cell cytotoxicity against leukaemic cells
Wolfer Anita | KFS 02935-02-2012 | CHF 202,500.–
Centre pluridisciplinaire d’oncologie (CePo), Centre hospitalier universitaire vaudois (CHUV), Lausanne
The role of MYC in cancer cell invasion and metastasis
Approved bursaries in 2012 Total funds allocated: CHF 472,150.–
Böhm Steffen | BIL KLS 02883-02-2012 | CHF 58,400.–
The inflammatory cytokine Interleukin-6 as a therapeutic target in ovarian cancer
Destination: Centre for Cancer & Inflammation, Queen Mary University, London, United Kingdom
Gamondi Claudia | BIL KLS 02942-02-2012 | CHF 38,750.–
Extended visit to the international observatory on end of life care
Destination: Division of Health Research, Faculty of Health & Medicine, Lancaster University, Lancaster, United Kingdom
Hermanns Thomas | BIL KFS 03036-08-2012 | CHF 136,000.–
A non-invasive personalized urinary biomarker panel for the early diagnosis of bladder cancer
Destination: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada
Kollár Attila | BIL KFS 02989-08-2012 | CHF 57,200.–
Translational study of pre-operative pazopanib in patients with resectable soft tissue sarcomas
Destination: Institute of Cancer Research, Royal Marsden Hospital, Sutton, United Kingdom
Meyer Sara Christina | BIL KFS 03005-08-2012 | CHF 47,100.–
Genetic and functional insights into the pathogenesis of myeloproliferative neoplasms
Destination: Memorial Sloan-Kettering Cancer Center, New York, USA
Morand Grégoire | BIL KFS 03002-08-2012 | CHF 41,400.–
Clinicopathological implications of EMT relevant genes in oral cancer
Destination: Segal Cancer Center, Jewish General Hospital, McGill University, Montreal, Canada
Volorio Angela | BIL KFS 02995-08-2012 | CHF 93,300.–
Transcriptomic-, proteomic-, and genomic-based prognostic and treatment-predictive biomarker discovery in the TEACH clinical trial
Destination: Center for Cancer Research, Harvard Medical School, Massachusetts General Hospital, Charlestown, USA
105
Clinical research
Presentation of approved research projects in 2012
Ammann Roland A. | The impact of lowering fever limits on the rate of fever in chemotherapy induced neutropenia (FN): a prospective single-centre observational study in children and adolescents with cancer (Paediatric FN Definition 2012 Bern)
(KFS 02933-02-2012)
Duration: 01. 07. 2012 – 31. 12. 2013
Fever in neutropenia (FN) (deficiency of white blood cells) is the most frequent potentially lethal side effect of chemo therapy for cancer. Thanks to emergency hospital- ization and immediate start of intravenous broad-band antibiotics, today less than 1 % of children with FN die. But bacterial infections are detected in only one-quarter of FN. Thus, three-quarters of FN are overtreated, im- plying – strictly speaking – unnecessary hospitalizations, antibiotics, and high costs. One way to reduce this over- treatment is to restrict making the diagnosis of FN by in- creasing the fever limit applied.
This limit currently varies in paediatric oncology from 37.5 °C to 39.0 °C. For higher fever limits, both the effi- cacy (reduction of the number of FN diagnoses made) and the safety (risk of complications because of delayed diag- nosis and start of therapy) are not known. In Bern, the highest fever limit of ≥ 39.0 °C is used. This allows us to study the influence of hypothetically lowering the fever limit on the frequency of FN diagnoses, without changing diagnosis and therapy of FN in reality. This purely obser- vational study can thus assess the efficacy of a higher fe- ver limit. The results will also allow us to refine the design of a future interventional study assessing also the safety of a high fever limit.
Project coordinator
Prof. Dr. med. Roland A. Ammann Abteilung für Hämatologie/Onkologie Universitätsklinik für Kinderheilkunde Inselspital, Universitätsspital Bern CH-3010 Bern
Bach Cuadra Meritxell | Towards robust and highly accurate computer assisted treatment planning for intraocular tumours: advanced image processing in a multi-modal framework (KFS 02937-02-2012)
Duration: 01. 01. 2013 – 31. 12. 2015
The eye is one of the most important sensory organs. Un- desirable side effects or failure of radiotherapy treatments of ocular tumours could be fatal for the vision of the pa- tient and consequently lead to life-threatening situations. Treatment planning for the eye needs to be very precise to accurately target the tumour while preserving surround- ing healthy tissues (to prevent the development of sec- ondary tumours). Nowadays, treatment planning is done based on different medical imaging methods such as com- puted tomography, fundus photography, ultrasound, or magnetic resonance imaging. However, these images are
observed independently of each other and are combined mentally by the radiation oncologists to obtain an overall vision of the tumour and its location.
In this project, advanced image processing algorithms will help to produce a comprehensive and objective picture of the tumour and its surrounding healthy tissues. We will develop a virtual eye model that will be adapted to the different imaging modalities and thus to the patient anat- omy. This patient-specific eye model will allow all existing image modalities to be efficiently fused, will help to plan the therapy in a reproducible manner, and will allow calculation of the exact position of the eye relative to the treatment unit.
Project coordinator Dr. Meritxell Bach Cuadra Département de radiologie
Centre hospitalier universitaire vaudois (CHUV) CH-1011 Lausanne
Beerenwinkel Niko | Comparative sequencing of primary renal cell carcinoma: towards a quantitative understanding of tumour diversity and evolution (KLS 02892-02-2012)
Duration: 01. 07. 2012 – 30. 06. 2014
Carcinogenesis is a dynamic process characterized by tu- mour growth and the accumulation of mutations in the tumour cell population. Tumour progression is a somatic evolutionary process that can be modelled by evolution- ary theory. The genetic diversity of tumours is extremely high, both among histologically identical tumours from different patients and within single tumours. The latter intra-tumour genetic diversity is largely responsible for drug resistance development. We analyse genomic varia- tion in renal cell carcinoma using modern high-through- put sequencing technology. Our goal is to identify the mutations responsible for the progression of the primary tumour and the formation of metastases. We will se- quence the cancer genomes of tumour biopsies and ana- lyse the resulting huge amounts of DNA data using spe- cific statistical and bioinformatics methods. The results of these investigations will allow derivation of a quantita- tive description of tumour evolution and a predictive model of cancer development. These insights on the di- versity and progression dynamics of tumours will provide the basis for improved tumour diagnostics and (eventu- ally) treatment.
Project coordinator Prof. Dr. Niko Beerenwinkel Departement Biosysteme ETH Zürich
CH-4058 Basel
106
Bourquin Jean-Pierre | Identification of critical deter- minants of the microenvironmental support for acute lymphoblastic leukaemia (KFS 02920-02-2012)
Duration: 01. 01. 2013 – 31. 12. 2014
Despite impressive progress in the treatment of patients with acute lymphoblastic leukaemia over the last decades, many relapses occur. For these, new treatment approaches are needed. Leukaemia cells are critically dependent upon interactions with the microenvironment in the bone mar- row, which may provide new opportunities for therapeu- tic intervention. In the bone marrow, acute lymphoblastic leukaemia (ALL) cells were shown to displace normal haematopoietic stem cells (HSC) from their niche, indicat- ing that similar components constitute a niche for both normal and leukaemia stem cells. Given the diversity of genetic lesions in ALL and based on preliminary data, we postulate that different patterns of interactions between ALL cells exist that may have therapeutic implications. Here we propose to take advantage of an in vitro co- culture model of human primary ALL cells with bone mar- row stromal cells to identify interactions that are critical for leukaemia survival and to determine common and distinct features for the protection of ALL selected from genetically and clinically distinct ALL subgroups.
In serum-free conditions most primary leukaemia cells can be maintained on hTERT-immortalized mesenchymal stro- mal cells (MSC) in vitro. In contrast, in most cases these xenografts do not survive longer than one week in cell sus- pension cultures. This constituted the basis for a focused candidate gene siRNA approach using our newly estab- lished automated microscopy-based platform. Among 100 genes that were selected based on their expression on MSC, the existence of predicted interaction partners on ALL cells, and /or reported experimental evidence for a haematopoietic niche function in other models, we identi- fied 16 genes that contribute to ALL cell survival. Here we propose to further characterize these candidates function- ally. It will be important to evaluate if given signals are im- portant only for a subset of cases or if it will be possible to identify general survival mechanisms. To investigate these protective signals in vivo, we will develop an animal model of the leukaemia niche. We expect to identify important signals from the bone marrow microenvironment that sup- port leukaemia survival; this will lead to a better under- standing of critical interactions between leukaemia cells and their microenvironment.
Project coordinator
PD Dr. med. et Dr. nat. Jean-Pierre Bourquin Abteilung Onkologie
Kinderspital Zürich Universitäts-Kinderkliniken CH-8032 Zürich
Brisken Cathrin | Mechanisms triggering cell prolifer- ation in ER+ breast cancers in novel preclinical
models (KLS 02907-02-2012)
Duration: 01. 09. 2012 – 31. 08. 2015
Two-thirds of breast cancers are oestrogen receptor posi- tive (ER+). The 5-year survival rate of patients with ER+
tumours is better than that of patients with oestrogen receptor-negative tumours, but one-third of ER+ tumours
become resistant to hormonal therapies and some will
recur decades later. We still do not understand this be- haviour and lack models that allow us to study this in vivo. We are developing novel models that mimic the human situation more closely and bear more clinical relevance. Specifically, we inject human ER+ breast cancer cells
through the nipple into the mouse milk duct system. The injected cells give rise to lesions that resemble human in
situ carcinomas and progress to invasive disease.
With this approach, we will study how oestrogen makes tumours grow. We propose that oestrogen tells ER+ tu-
mour cells to make and secrete various factors that stim- ulate the neighbouring cells. Such secreted factors are excellent targets for promising new drugs, humanized antibodies. For one of the factors we are studying, RANKL, such antibodies (denosumab) are already used in patients with bone disorders. Our work will help determine whether breast cancer patients might benefit from this drug and whether other factors should be targeted. The ability to interfere with what happens downstream of the activation of ER may benefit patients whose tumours have become resistant to hormonal therapy.
Project coordinator Prof. Dr Cathrin Brisken
Institut suisse de recherche expérimentale sur le cancer (ISREC)
EPF de Lausanne CH-1015 Lausanne [email protected]
Citi Sandra | The role of the new adherens junction protein PLEKHA7 in cancer and signalling
(KLS 02878-02-2012)
Duration: 01. 07. 2012 – 30. 06. 2015
The majority of cancers derive from epithelial cells, which cover body cavities and surfaces and form glands. In can- cer, cells can lose their ability to adhere well to each other and acquire the ability to migrate and move within the body, which can lead to the formation of metastases. Specialized structures called “adherens junctions” control the adhesion between epithelial cells and are also impli- cated in the regulation of cell proliferation and migration. We are studying a new protein of adherens junctions, PLEKHA7, which links these junctions to the cytoskele- ton. The objective of our research is to understand how PLEKHA7 is implicated in the regulation of adhesion, pro- liferation, migration, and signalling pathways.
We will study the expression of PLEKHA7 in human can- cer, and we will artificially modify its expression levels in cultured cells to study the consequences of either the loss or overexpression of PLEKHA7 on proliferation, migration, gene expression, and epithelial barrier. This research pro- ject is particularly innovative, since PLEKHA7 was dis- covered very recently, and it will allow us to advance our knowledge about the cellular mechanisms underlying epithelial cancers.
Project coordinator Dr Sandra Citi
Département de biologie cellulaire Université de Genève
CH-1205 Genève [email protected]
107
erlands are being accrued into this international trial, with 176 patients registered in Switzerland since Septem- ber 2010. The protocol aims to prove whether the addi- tion of clofarabine to chemotherapy will improve disease- free survival and clearance of leukaemic cells from the bone marrow. The protocol was approved by the respec- tive ethical committees. Funding is necessary for data management and the study coordinator centre to ensure ongoing quality of research. In Switzerland, Prof. Thomas Pabst, MD, senior physician medical oncology, is the re- sponsible trial coordinator ([email protected]).
Project coordinator Prof. Dr. med. Martin F. Fey
Universitätsklinik für Medizinische Onkologie Inselspital, Universitätsspital Bern
CH-3010 Bern [email protected]
Hegi Monika | The methylome of low grade glioma: identification of novel therapeutic targets and biomar- kers for response to treatment (KFS 02949-02-2012)
Duration: 01. 08. 2012 – 31. 07. 2015
The treatment of low grade gliomas, a rare type of brain tumour that affects young adults, is difficult. Due to the invasive behaviour of these tumours, complete surgical resection is impossible, and tumours eventually recur within a few years. New insights suggest that epigenetic alterations are the major driver of this tumour type. Epige- netic alterations do not affect the sequence of the DNA bricks but involve modification of the DNA through the addition of methyl groups, which leads to deregulation of the affected genes.
The goal of this project is to analyse these tumour-specific alterations of DNA methylation – the low grade glioma “methylome” – in order to identify new targets for ther- apy. The idea is that some of these epigenetic alterations can be converted into the “Achilles heel” of the affected tumours upon treatment with certain classes of anti-can- cer agents. The methylome of a series of low grade glio- mas from patients treated homogenously within a large international clinical trial is being analysed genome-wide. Correlation of epigenetic alterations with clinical data, such as benefit from therapy, should allow identification of particularly cancer-relevant alterations that might be therapeutically targetable.
Project coordinator Prof. Dr. Monika Hegi
Laboratoire de biologie et génétique des tumeurs Service de neurochirurgie
Centre hospitalier universitaire vaudois (CHUV) CH-1011 Lausanne
Dotto Gian-Paolo | MicroRNAs as determinants of squamous cell carcinoma development in immune- suppressed patients (KLS 02922-02-2012)
Duration: 01. 10. 2012 – 30. 09. 2015
Skin cancer is frequent in the general population. Some groups are known for their even higher risk of this com- mon cancer. Organ transplant recipients nowadays live a long time with a donated organ such as heart, liver, or kid- ney. This success does not come without a cost, however, and relies on life-long immunosuppression through a combination of drugs. An important problem related to chronic immunosuppression is the increased occurrence of cancer at large and in particular, at the top of the list, of squamous cell carcinoma of the skin. We have improved our understanding of why this cancer in particular in- creases by an impressive 60- to 100-fold compared to the general population. Apparently, the immunosuppressive drugs also exert a direct effect on skin cells, resulting in increased formation of squamous cell carcinoma of the skin. Many questions remain unanswered, though. One of these open questions concerns the importance of micro- RNAs in the disease development. MicroRNAs are a newly