Principal Investigators

Principal-Investigators

Karin Vanderkerken


Karin Vanderkerken is professor of Hematology at the Vrije Universiteit Brussel, Brussels. She is heading a research group of 3 post-doctoral researchers, 6 PhD students and 2 technicians.   Our research is focussing on the pathobiology of multiple myeloma and has started more than 30 years ago. More recently (2009) the Myeloma Center Brussels (www.myeloma.be) was created for a better integration of research and clinic activities, both contributing to research (also translational) and patients. The research group was integrated in the Oncology Research center (http://orc.vub.ac.be).

Tasks in the project

Karin Vanderkerken will coordinate OVER-MyR and be the leader of WP3 (The role of the bone marrow microenvironment in developing drug resistance). The VUB team will participate to the selection and molecular characterization of drug resistant human and murine myeloma cell lines (WP2); they will define the role of Syndecan-1 and HSMEs, Osteoblasts and Osteoclasts, Endothelial Cells and Fibroblasts, and Immune Cells in drug resistance (WP3) and achieve rapid translation of OVER-MyR results into finding compounds able to revert drug resistance in in vitro and in vivo models (WP4).


Team members

Els Van Valckenborgh PhD,Susanne Lub and Nathan De Beule PhD students, Kim De Veirman, Carine Seynave and Marie Joos de ter Beerst technicians.


5 relevant publications

1. Deleu S, Lemaire M, Arts J, Menu E, Van Valckenborgh E, King P, Vande Broek I, De Raeve H, Van Camp B, Croucher P, Vanderkerken K.  The effects of JNJ-26481585, a novel hydroxamate-based histone deacetylase inhibitor, on the development of multiple myeloma in the 5T2MM and 5T33MM murine models. Leukemia. 2009 Oct;23(10):1894-903.

2. De Bruyne E, Bos TJ, Schuit F, Van Valckenborgh E, Menu E, Thorrez L, Atadja P, Jernberg-Wiklund H, Vanderkerken K. IGF-1 suppresses Bim expression in multiple myeloma via epigenetic and posttranslational mechanisms. Blood. 2010 Mar 25;115(12):2430-40.

3. Hu J, Handisides DR, Van Valckenborgh E, De Raeve H, Menu E, Vande Broek I, Liu Q, Sun JD, Van Camp B, Hart CP, Vanderkerken K. Targeting the multiple myeloma hypoxic niche with TH-302, a hypoxia-activated prodrug. Blood. 2010 Sep 2;116(9):1524-7.

4. Tumor-initiating capacity of CD138- and CD138+ tumor cells in the 5T33 multiple myeloma model. Van Valckenborgh E, Matsui W, Agarwal P, Lub S, Dehui X, De Bruyne E, Menu E, Empsen C, van Grunsven L, Agarwal J, Wang Q, Jernberg-Wiklund H, Vanderkerken K. Leukemia 2012 published on line Jan 6.

5. Activation of ATF4 mediates unwanted Mcl-1 accumulation by proteasome inhibition. Hu J, Dang N, Menu E, De Bryune E, Xu D, Van Camp B, Van Valckenborgh E, Vanderkerken K. Blood. 2012 Jan 19;119(3):826-37.

 


 

 

Principal-Investigators2

Bernard Klein


Bernard Klein is the director of the Institute for Research in Biotherapy (IRB, http://irb.chu-montpellier.fr/) located at INSERM-University Montpellier I. IRB gathers 130 people working in fundamental and translational research laboratories, around common technical platforms. Partner 2 is working on Multiple Myeloma cell (MMC) plasticity, stem cells and niche. Bernard Klein had 243 peer-reviewed articles and a Hirsh factor of 55. For 2005-2009, partner 2 published 2 top 1% and 15 top 10% publications.


Tasks in the project

Bernard Klein will lead the WP2 (Modeling drug resistance using human or murine cell lines in vitro and in vivo). In WP1, the INSERM team will participate to patients’ samples collection and molecular characterization. In WP2, they will obtain subclones of human myeloma cell lines, which are resistant to major drugs inMM and make an extensive molecular and phenotypic characterization of these drug resistant subclones and immortalized primary myeloma cells harvested from patients at different disease stages. In WP4, the team will investigate whether the synthetic compounds produced by the CellZ company could induce block in cell cycle or induce apoptosis in the drug resistant human MM cell lines (MCLs) or in immortalized primary MMCs.


Team members

Thierry REME, PhD, MD with expertise in bioinformatic analysis


5 relevant publications

1. Kassambara A, Hose D, Moreaux J, Walker BA, Protopopov A, Reme T, Pellestor F, Pantesco V, Jauch A, Morgan G, Goldschmidt H, Klein B. Genes with a spike expression are clustered in chromosome (sub)bands and spike (sub)bands have a powerful prognostic value in patients with multiple myeloma. Haematologica. 2011 Nov 18. [Epub ahead of print]


2. Moreaux J, Hose D, Kassambara A, Reme T, Moine P, Requirand G, Goldschmidt H, Klein B. Osteoclast-gene expression profiling reveals osteoclast-derived CCR2 chemokines promoting myeloma cell migration. Blood. 2011 Jan 27;117(4):1280-90.


3. Mahtouk K, Moreaux J, Hose D, Rème T, Meissner T, Jourdan M, Rossi JF, Pals ST, Goldschmidt H, Klein B. Growth factors in multiple myeloma: a comprehensive analysis of their expression in tumor cells and bone marrow environment using Affymetrix microarrays. BMC Cancer. 2010 May 13;10:198


4. Moreaux J, Klein B, Bataille R, Descamps G, Maïga S, Hose D, Goldschmidt H, Jauch A, Rème T, Jourdan M, Amiot M, Pellat-Deceunynck C. A high-risk signature for patients with multiple myeloma established from the molecular classification of human myeloma cell lines. Haematologica. 2011 Apr;96(4):574-82.


5. Moreaux J, Hose D, Kassambara A, Reme T, Moine P, Requirand G, Goldschmidt H, Klein B. Osteoclast-gene expression profiling reveals osteoclast-derived CCR2 chemokines promoting myeloma cell migration. Blood. 2011 Jan 27;117(4):1280-90.

 


 

 

Principal-Investigators3

Dirk Hose


Partner 3 is the head of the MM Research Laboratory (MMRL) of the Sektion Multiples Myeloma (University Hospital Heidelberg and National Centre for Tumour Diseases, headed by Prof. H. Goldschmidt), Ruprecht Karls University Heidelberg (#43 (Biomedicine) at Top 100 World Universities). The Sektion MM with approximately 150 autologous transplantations per year is the largest specialised centre for the treatment of MM in Europe. Its head leads the German Speaking Myeloma Multicenter Group (GMMG) and has initiated several multicente  trials (e.g. GMMG-HD4, GMMG-MM5) and experimental phase I/II trials. The MMRL as part of the Sektion has longstanding experience performing molecular analyses and preparation of phase I/II clinical trials.


Tasks in the project

Dirk Hose will lead the WP1 (Molecular determinants of clinical relapse). Moreover, in WP1, the UKL HD group will investigate clinical determinants of relapse and refractority in terms of interpatient heterogeneity, intra-patient heterogeneity and chromosomal instability by high throughput techniques in jointly with partner 2 (including GEP, miRNA-profiling, aCGH, iFISH, and WGS) in purified samples of MM patients. In WP2, they will analysis jointly with partner 2 molecular changes between the parental cell lines and their refractory subclone and analyse this on the background of the clinical determinants of relapse (WP1). In WP3, the group will take part in investigating the role of osteoblasts, osteoclasts and endothelial cells in drug resistance. And in WP4, they will, in analogy to our previous joint research participate in the analysis of the mechanism of action the screening compounds, transmission of molecular data from WP1-3 into the development of these compounds, and design of a respective trial protocol.


Team members

A Seckinger PhD, MD; T Meißner PhD and G Hoock Technician.


5 relevant publications

1. Hose D, Moreaux J, Meissner T, Seckinger A, Goldschmidt H, Benner A, Mahtouk K, Hillengass J, Rème T, De Vos J, Hundemer M, Condomines M, Bertsch U, Rossi JF, Jauch A, Klein B, Möhler T. Induction of angiogenesis by normal and malignant plasma cells. Blood 2009 114: 128-143.


2. Seckinger A, Meissner T, Moreaux J, Goldschmidt H, Fuhler GM, Benner A, Hundemer M, Rème T, Shaughnessy JD Jr, Barlogie B, Bertsch U, Hillengass J, Ho AD, Pantesco V, Jauch A, De Vos J, Rossi JF, Möhler T, Klein B, Hose D. Bone morphogenic protein 6: a member of a novel class of prognostic factors expressed by normal and malignant plasma cells inhibiting proliferation and angiogenesis. Oncogene 2009. 28: 3866-3879.


3. Caers J, Hose D, Kuipers I, Bos TJ, Van Valckenborgh E, Menu E, De Bruyne E, Goldschmidt H, Van Camp B, Klein B, Vanderkerken K. Thymosin β4 has tumor suppressive effects and its decreased expression results in poor prognosis and decreased survival in multiple myeloma. Haematologica. 2010 Jan;95(1):163-7.


4. Meissner T, Seckinger A, Rème T, Hielscher T, Möhler T, Neben K, Goldschmidt H, Klein B, Hose D. Gene expression profiling in multiple myeloma--reporting of entities, risk, and targets in clinical routine. Clin Cancer Res. 2011 Dec 1;17(23):7240-7.


5. Hose D et al. Proliferation is a central independent prognostic factor and target for personalized and risk-adapted treatment in multiple myeloma. Haematologica 2011. 96: 87-95.

 

 


 

Principal-Investigators4

Surinder Sahota


Surinder Sahota is a faculty member in the University of Southampton based in the Cancer Sciences Division (CSD) in The Faculty of Medicine. Partner 4’s expertise is in immunogenetics, cancer immunology and immunotherapy (DNA vaccines). Partner 4 was Principal Investigator in a recent FP6-2005-LIFESCIHEALTH-6 EU Award (2006-10) for the EMN ‘MSCNET’ network investigating the MM stem cell. Partner 4’s group has also developed the R2gC ‘Hu-xen’ to examine MM progenitor cells, and role for stroma in tumor engraftment to bypass constraints of a xenogeneic microenvironment.


Tasks in the project

 In WP1, Partner 4 will link closely with Partners 2 and 3 to investigate the MM genome using WGS in both presentation and relapsed disease. This analysis should provide fundamental data on understanding drug resistance in MM. In WP3, Partner 4 will evaluate the role of specific immune cells in the development of drug resistance in MM, in particular, tumor infiltrating macrophages which have now emerged as an important component of the tumor:niche interaction.


Team members

Prof. A. Collins PhD, N Weston-Bell PhD, D Joseph-Pietras PhD, G Babbage M Phil.


5 relevant publications

1. Pfeifer S, Perez-Andres M, Ludwig H, Sahota SS, Zojer N. Evaluating the clonal hierarchy in light-chain multiple myeloma: implications against the myeloma stem cell hypothesis. Leukemia. 2011 Jul;25(7):1213-6.


2. Joseph-Pietras D, Gao Y, Zojer N, Ait-Tahar K, Banham AH, Pulford K, Rice J, Savelyeva N, Sahota SS. DNA vaccines to target the cancer testis antigen PASD1 in human multiple myeloma. Leukemia (2010) 24:1951-1959.


3. Weston-Bell N, Townsend M, Di Genova G, Forconi F, Sahota SS. (2009). Defining origins of malignant B-cells: a new circulating normal human IgM+D+ B-cell subset lacking CD27 expression and displaying somatically mutated IGVH genes as a relevant memory population. Leukemia (2009) 23:2075-80.


4. Frøyland M, Thompson KM, Thorpe SJ, Sahota SS, Gedde-Dahl T, Bogen B. (2007). A VH4-34+ myeloma protein with weak autoreactivity. Haematologica 92(5):690-3.


5. Sahota SS, Goonewardena CM, Cooper CD, Liggins AP, Ait-Tahar K, Zojer N, Stevenson FK, Banham AH, Pulford K. (2006). PASD1 is a potential multiple myeloma associated antigen. Blood. 108(12):3953-3955.

 

 


 

steven
 Stevens T Pals


Prof. Steven T. Pals is the head of the Department of Pathology of the Academic Medical Center (AMC), University of Amsterdam (UVA). Partner 5 has a long-standing expertise in the fields of B cell development, lymphomagenesis, and cell migration/tumor metastasis. The group has recently elucidated the signaling mechanisms connecting the chemokine CXCL12 (SDF-1) to B-cell migration and migration of myeloma plasma cells.


Tasks in the project

In WP3, the group will define the role of Syndecan-1 and HSMEs in drug resistance. In WP3, they will provide the consortium with a newly developed xenotransplant model in RAG2-/- IL2R¬c-/- immunodeficient mice, which allows study of the homing, proliferation and survival of human MMCs in vivo.


Team members

Marcel Spaargaren MD, PhD co-project leader; Sander Joosten MSc research technician; Annemieke Kuil BSc reseach technician; Marie Jose Kersten MD, PhD, advisor. 


5 relevant publications

 1. de Gorter DJ, Beuling EA, Kersseboom R, Middendorp S, van Gils JM, Hendriks RW, Pals ST, Spaargaren M. (2007). Bruton’s tyrosine kinase and Phospholipase Cgamma2 mediate chemokine-controlled B cell migration and homing. Immunity 26:93-10.


2. de Gorter DJ, Reijmers RM, Beuling EA, Naber HP, Kuil A, Kersten MJ, Pals ST, Spaargaren M. (2008) The small GTPase Ral mediates SDF-1-induced migration of B cells and multiple myeloma cells. Blood 111:3364-72.


3. Reijmers RM, Groen RW, Rozemuller H, Kuil A, de Haan-Kramer A, Csikós T, Martens AC, Spaargaren M, Pals ST. (2010) Targeting EXT1 reveals a crucial role for heparan sulfate in the growth of multiple myeloma. Blood 115: 601-4.


4. Mahtouk K, Tjin EP, Spaargaren M, Pals ST. (2010) The HGF/MET pathway as target for the treatment of multiple myeloma and B-cell lymphomas. Biochim Biophys Acta 1806: 208-16.


5. Groen RW, de Rooij MF, Kocemba KA, Reijmers RM, de Haan-Kramer A, Overdijk MB, Aalders L, Rozemuller H, Martens AC, Bergsagel PL, Kersten MJ, Pals ST, Spaargaren M. (2011) N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation. Haematologica 96(11):1653-61.

 


 

 

Principal-Investigators5

Peter Croucher


Tasks in the project

In WP3, the group will be responsible for evaluating the role of osteoclasts and osteoblasts in the development of drug resistance. This will be determined using both in vitro and in vivo models of osteclast and osteoblast/tumour interactions and by studying these cells in the myeloma niche using multi-photon microscopy The emphasis will be on the use of the 5TMM series of murine models in which partner 6 has extensive experience.


Team members

Jennifer Down HNC, senior research technician


5 relevant publications

1. Croucher, P.I., Shipman, C.M., Lippitt, J., Perry, M., Asosingh, K., Hijzen, A., Brabbs, A.C., van Beek, E.J.R., Holen, I., Skerry, T.M., Dunstan, C.R., Russell, R.G.G. Russell, Van Camp, B., Vanderkerken, K. (2001) Osteoprotegerin inhibits the development of osteolytic bone disease in multiple myeloma. Blood, 98:3534-3540.


2. Croucher, P.I., De Raeve, H., Perry, M.J., Hijzen, A., Shipman, C.M., Lippitt, J., Green, J., Van Marck, E., Van Camp, B., Vanderkerken, K. (2003) Zoledronic acid prevents the development of osteolytic bone lesions and increases survival in the 5T2MM murine model of multiple myeloma. Journal of Bone and Mineral Research. 18:482-492.


3. Heath, D.J., Chantry, A.D., Buckle, C., Coulton, L., Shaughnessy Jr, J.D., Evans, H., Stover, D.R., Vanderkerken, K., Croucher, P.I. (2009) Inhibiting Dickkopf-1 (Dkk-1) prevents the development of osteolytic bone disease in multiple myeloma. Journal of Bone and Mineral Research, 24:425-436.


4. Chantry, A.D., Heath, D., Mulivor, A., Pearsall, R.S., Coulton, L., Evans, H., Abdul, N., Werner, E.D., Bouxsein,M.L., Key, M.L., Arnett, T.R., Seehra, J., Vanderkerken, K., Croucher P.I. (2010) Inhibiting activin-A signaling stimulates bone formation and prevents cancer induced bone destruction in vivo. Journal of Bone and Mineral Research, 25:2357-2370.


5. Lawson MA, Ashcroft J, Croucher PI. Bisphosphonate therapy in the treatment of multiple myeloma. Curr Pharm Des. 2010;16(27):3028-36.

 

 


 

Principal-Investigators6

Prof. Angelo Vacca, MD, PhD


Angelo Vacca was born in Bari, Italy, on February 16, 1956. He began medical studies in 1974 and was awarded M.D. degree on 1980. In 1983 he took the specialization in “Hematology”, and in 1993 the specialization in “Internal Medicine”. His present position is Full Professor of Internal Medicine at the University of Bari (IT) and Director of the Unit of Clinical Medicine and Oncology of the same University. Dr. Vacca’s research areas are: a) angiogenesis in patients with lymphoproliferative diseases, such as multiple myeloma and non-Hodgkin’s lymphomas; b) angiogenesis by inflammatory cells; c) TK inhibitors.


Tasks in the project

In WP3 the group will study: i) the role of HGF/c-MET signaling pathway in mediating drug resistance through fibroblasts and ECs; ii) the mechanisms related to progression and resistance-associated down-modulation of the angiogenic endogenous inhibitor Sema3A.


Team members

Mauro Coluccia MD, PhD; Federico Bussolino PhD ; G Mangialardi MD; Michele Moschetta MD


5 relevant publications

1. Moschetta M, Di Pietro G, Ria R, Gnoni A, Mangialardi G, Guarini A, Ditonno P, Musto P, D'Auria F, Ricciardi MR, Dammacco F, Ribatti D, Vacca A. (2010) Bortezomib and zoledronic acid on angiogenic and vasculogenic activities of bone marrow macrophages in patients with multiple myeloma Eur J Cancer. 46(2):420-9.


2. Ria R, Todoerti K, Berardi S, Coluccia AM, De Luisi A, Mattioli M, Ronchetti D, Morabito F, Guarini A, Petrucci MT, Dammacco F, Ribatti D, Neri A, Vacca A. (2009) Gene expression profiling of bone marrow endothelial cells in patients with multiple myeloma. Clin Cancer Res 15: 5369-78.


3. Coluccia AM, Cirulli T, Neri P, Mangieri D, Colanardi MC, Gnoni A, Di Renzo N, Dammacco F, Tassone P, Ribatti D, Gambacorti-Passerini C, Vacca A. (2008) Validation of PDGFRbeta and c-Src tyrosine kinases as tumor/vessel targets in patients with multiple myeloma: preclinical efficacy of the novel, orally available inhibitor dasatinib. Blood 112: 1346-56.


4. Vacca A, Scavelli C, Serini G, Di Pietro G, Cirulli T, Merchionne F, Ribatti D, Bussolino F, Guidolin D, Piaggio G, Bacigalupo A, Dammacco F. (2006) Loss of inhibitory semaphorin 3A (SEMA3A) autocrine loops in bone marrow endothelial cells of patients with multiple myeloma. Blood 108: 1661-7.


5. Vacca A, Scavelli C, Montefusco V, Di Pietro G, Neri A, Mattioli M, Bicciato S, Nico B, Ribatti D, Dammacco F, Corradini P. Thalidomide downregulates angiogenic genes in bone marrow endothelial cells of patients with active multiple myeloma. J Clin Oncol (2005) 23: 5334-46.

 

 

 


 

Jan Hoflack

Jan Hoflack 


Dr. Jan Hoflack,,Ph.D. has been Chief Scientific Officer and Executive Vice President at Oncodesign Biotechnology in France since 2008. Dr. Hoflack has over 23 years of experience in the pharmaceutical industry, with previous employments at Marion Merrell Dow in France (now Sanofi-Aventis), Novartis in Switzerland, and AstraZeneca in Sweden. In 2000, he joined Johnson and Johnson in Belgium as Vice-President of Medicinal Chemistry and Biosciences for the European R&D operation. His experience is in drug discovery and development, building the translational research process, exploring new value creating entrepreneurial organizational models for R&D and developing partnerships with international pharmaceutical companies. He served as an External Director of GNI Group Ltd since June 2008. Dr. Hoflack holds a doctorate in Organic Chemistry from the State University Ghent, Belgium.


Tasks in the project

In WP4, ODS will achieve rapid translation of OVER-MyR results into tangible small molecules able to revert drug resistance in the consortium’s in vitro and in vivo models. ODS will first test a diversity set of Nanocyclix® compounds on resistant cell lines developed in WP2. Then, the company will evaluate analogs of active compounds or select new set of Nanocyclix® compounds known to target the pathways involved in the resistance mechanisms identified in the project. Finally, ODS will investigate whether synergy can be observed between the candidate drugs and standard of care drugs and evaluate whether this translates into animal models.


Team members

Cyril Berthet,PhD,Discovery Program Director

P. Blom, PhD; G.Serin, PhD; P.Benderitter, PhD


5 relevant publications

1. Julien et al. Characterization of a Large Panel of Patient-derived Tumor Xenografts Representing the Clinical Heterogeneity of Human Colorectal Cancer. Clinical Cancer Research 2012 Oct 1;18(19):5314-28.
2. Mignard et al. Characterization of CIEA NOG® mice reconstituted with human CD34+ stem cells (HSCs) or mature PBMCs. Poster at EORTC 2012.
3. Mirjolet et al. Oncodesign translational drug discovery process. . Poster at AACR 2010.

 

 


 

dahlia 

Dahlia Tsakiropoulos


Dahlia Tsakiropoulos holds a Master in Business law as well as the French Bar Exam. She joined Inserm Transfert’s Department of European and International affairs (DAEI) in 2004 and has a strong expertise in the management of European Projects, in particular on the financial rules and contractual aspects of the EU FP programmes.


Tasks in the project

In WP5, Inserm-Transfert SA will be responsible for the management of the OVER-MyR consortium and for the co-ordination of the dissemination and exploitation of foreground and management of Intellectual property. The main tasks can be summarized as follows:


• Ensure a professional driving of the project with adapted management internet based tools and in accordance with administrative, financial and legal issues defined by the EU contract;


• Provide the partners with adequate communication tools (website, logo, leaflet, press releases);


• Offer a logistic support for the organization of meetings and writing of minutes;


• Ensure a professional management of the IP of the project.


Team members

Denise Hirsch is the director of IP department at IT. She has 20 years of experience in IP management in the life science field both for private (Pfizer, Lavoix) and academic (INSERM); Sandrine Graff, Assistant; Laure Masson, legal counsel, Legal Departement – Consortium Agreement management.

 

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