Cellular and Molecular Oncology

Head of the group: Prof. Evangelia Patsavoudi

Email: epatsavoudi@pasteur.gr, epatsavoudi@teiath.gr

Tel. +30 2106478871

 

About

Our research is mainly focused on the biology of molecular chaperones and in particular on the study of the heat shock protein 90 (HSP90).

Despite being induced following heat shock, HSP90 is one of the most abundant proteins in unstressed cells under normal conditions (1-2% of cytosolic protein) where it performs housekeeping functions, controlling the stability, maturation, activation, intracellular deposition and proteolytic turn-over of numerous  proteins, including kinases, steroid receptors and transcription factors. Most of the HSP90-regulated proteins are involved in signal transduction and consequently, HSP90 by controlling their activity plays a pivotal role in multiple cellular processes such as proliferation, apoptosis, differentiation and cell migration.

Over the past years it has been shown that many of the HSP90 substrates, are often activated, mutated, or over-expressed in cancer cells, and therefore, HSP90 is viewed as a key player in the acquisition of the malignant phenotype. HSP90 inhibitors, such as geldanamycin (GA) and 17-allyl-aminogeldanamycin (17-AAG) cause the destabilization and eventual degradation of HSP90 client proteins. Moreover these inhibitors have shown promising anti-tumor activity in preclinical model systems.

We have produced a monoclonal antibody named mAb 4C5 which specifically recognizes HSP90. Previous studies have shown that (a) mAb 4C5 positively immunostains human metastatic tumors, (b) mAb 4C5 reduces the invasive capacity of human cancer cells in vitro by selectively inhibiting the function of surface HSP90, (c) mab 4C5 inhibits the metastatic deposition of melanoma cells in vivo and (d) HSP90 is localized on the surface of cancer cells where it interacts with the growth factor receptor HER-2 which is known to be involved in the development of human breast cancer. Through this functional interaction with the extracellular domain of the receptor, HSP90 is assumed to contribute in the invasive potential of these cells.

Taking the above into consideration our research activities are focused in two main directions:

 

1. Study and understanding of the mechanisms underlying thefunction of surface HSP90 using in vitro and in vivo models of tumour growth

Structure of HSP90

Structure of HSP90


More specifically, mAb 4C5 in combination with several human cancer cell lines of diverse origin are used in order to explore the mechanisms of HSP90 function, including possible interactions and subsequent signal transduction activation, during invasion and metastasis of cancer cells. The presence and role of co-chaperones such as cdc37 on the cell surface is also examined in this context.

 

2. Investigation of the possibility of using mAb 4C5 as a therapeutic agent for the treatment of metastatic cancer

The analysis of the function of the partially humanized recombinant chimeric antibody ch4C5is carried out in in vitro and in vivo models of cancer cell invasion and metastasis, respectively. Next and in order to confirm that the chimeric antibody selectively targets cancer cells and does not affect normal cells, we will perform a comparative study of the binding of the antibody on cancer and

 

3. Study of HSP90 in Cancer Stem Cells and investigation of the possibility to use mAb4C5 as a marker for these cells and ultimately as a therapeutic agent Presense of HSP90 in cancer stem cells is investigated. This is performed in situ using sections of human cancers and also in human cancer cell lines. Moreover, analysis of the invasive behavior of cancer stem cells in in vitro systems will be studied as well as the effect of mAb 4C5 in the invasive capacity of these cells.

Research programs

Research Programs

 

The main objectives of our research activities are a) the understanding and the in depth knowledge of the mode of action and the involvement of extracellular HSP90 in metastatic cancer and b) the investigation of the possibility to use a partially humanized antibody against HSP90, the chimera 4C5, for the treatment of a broad spectrum of metastatic cancers. Ιn this context our research programs are the following:

 

1. Study of the molecular mechanisms underlying the function of extracellular HSP90 in in vitro and in vivo experimental models of cancer cell invasion and metastasis respectively with the use of monoclonal antibody mAb4C5.

 

 

ΜΑb4C5 inhibits melanoma metastasis into the lungs of mice

 

2. Partial humanization of mouse mAb 4C5 and functional study of the specificity of the chimeric antibody in in vitro and in vivo models of cancer cell invasion and metastasis.

 

3. Epitope mapping of mAb4C5 and humanized ch4C5 .

 

4. Study of HSP90 in cancer stem cells with the use of mAb4C5

Members

Members


Groupleader

E. Patsavoudi, Professor

Εmail: epatsavoudi@pasteur.gr, epatsavoudi@teiath.gr

 

Post-doctoral Research Fellows

Katerina Sidera sidera@pasteur.gr

Panagiota Stamou stamou@pasteur.gr

 

Post-graduate student

Katia Sesele ksesele@pasteur.gr

 

Past members of the group (2000-2010)

E. Yfanti, K. Dimas, D. Stellas, E. Mathioudaki, Avraam el Hamidie

 

Publications

Publications

2011-2013

Sidera K and Patsavoudi E(2013) HSP90 Inhibitors: Current Development and Potential in Cancer Therapy. Recent Pat. Anti-Cancer Drug Discov. [Epub ahead of print]

El Hamidieh A, Grammatikakis N, PatsavoudiE (2012) Cell surface Cdc37 participates in extracellular HSP90 mediated cancer cell invasion. PLoS One. 2012;7(8):e42722.

Stellas D and Patsavoudi E. (2012) Inhibiting matrix metalloproteinases , an old story with new potentials for cancer treatment. Anticancer Agents Med Chem. 12(7):707-17

 2000-2010

Stellas D., El Hamidieh A. and Patsavoudi E. (2010) Monoclonal antibody 4C5 prevents activation of MMP2 and MMP9 by disrupting their interaction with extracellular HSP90 and inhibits formation of metastatic breast cancer cell deposits. BMC Cell Biol 11:51

 Sidera K. and Patsavoudi E. (2009) Extracellular HSP90: An emerging target for cancer therapy. Current Signal Transduction Therapy .4: 51-58

 Katerina Sidera, Maria Gaitanou, D. Stellas, Rebecca Matsasand Evangelia Patsavoudi  (2008) A critical role for surface HSP90 in cancer cell invasion involves extracellular interaction with HER-2  J Biol Chem. 283:2031-2041

Sidera K, Patsavoudi E. (2008) Extracellular HSP90: conquering the cell surface. Cell Cycle. 7:1564

Casado JG, Delgado E, Patsavoudi E, Durán E, Sanchez-Correa B, Morgado S, Solana R, Tarazona R. (2008) Functional Implications of HNK-1 Expression on Invasive Behaviour of Melanoma Cells. Tumour Biol. 29:304-310.

D. Stellas, A. Karameris, and E. Patsavoudi  (2007)  MAb 4C5, a monoclonal antibody against HSP90, immunostains human melanomas and inhibits melanoma cell invasion and metastasis ”  Clinical Cancer Res 13 : 1831-1838

 K.  Sidera , M. Samiotaki , E. Yfanti , G. Panayotou  and E. Patsavoudi (2004)Involvement of cell surface HSP90 in cell migration reveals a novel role in the developing nervous system J Biol. Chem. 279: 45379-45388

Y. Koutmani, C. Hurel, E. Patsavoudi, M. Haeck, M. Gotz, D. Thomaidou, and R. Matsas (2004) BM88 is a marker of proliferating neuroblasts that will differentiate into the neuronal lineage. Eur. J Neurosci. 20: 2509-2523

Kontodimopoulos N, Cavouras D, Kandarakis I, Spyropoulos ,Patsavoudi E., Ventouras E. (2004) Upgrading the biomedical engineering undergraduate curriculum based on current trends in higher education. Conf Proc IEEE Eng Med Biol Soc. 2004

E. Yfanti,K. Sidera, L. Margaritis and E. Patsavoudi (2004)  “The 4C5 antigen is associated with Schwann cell migration in vitro” Glia 45: 89-53

 1990-1999

E. Patsavoudi, C. Hurel and R. Matsas. (1991) Purification and characterization of a neuron-specific surface antigen defined by monoclonal antibody BM88. J. of Neurochem., 56, p. 782-788.

D. Thomaidou and E. Patsavoudi. (1993) Identification of a novel neuron specific surface antigen in the developing nervous system by monoclonal antibody 4C5. Neuroscience 53, p. 813-827.

L. Probert, J. Keffer, P. Corbella, H. Cazlaris, E. Patsavoudi, S. Stephens, E. Kaslaris, D. Kioussis and G. Kollias. (1993) Wasting ischaemia and lymphoid abnormalities in mice eexpressing T cell-tergeted human tumour necrosis factor transgenes. J. of Immunol. 151, p. 1894-1906.

E. Patsavoudi, E. Merkouri, D. Thomaidou, F. Sandillon, G. Alonso and R. Matsas (1995) Biochemical characterization and immunocytochemical localization of the BM88 antigen in the developing and adult rat brain. J. Neurosci. Res. 40, 506-518

D. Thomaidou, I. Dori and E. Patsavoudi. (1995) Developmental expression and functional characterization of the 4C5 antigen in the post-natal cerebellar cortex. J. Neurochem. 64, p. 1937-1944

A. Mamalaki, E. Boutou, C. Hurel, E. Patsavoudi, S. Tzartos and R. Matsas. (1995)  The BM88 antigen, a novel neuron specific molecule, enhances the differentiation of mouse neuroblastoma cells. J. Biol. Chem. 270, p. 14201-14208

D. Thomaidou, E. Yfanti and E. Patsavoudi. (1996) Expression of the 4C5 antigen during development and after injury of the rat sciatic nerve. J. Neurosci. Res. 46:24-33.

 E. Yfanti, I. Nagata and  E. Patsavoudi. (1998) “Migration behavior of rodent granule neurons  the presence of antibody to the 4C5 antigen”, J. Neurochem. 71: 1381-1389

 

 

Funding

Funding 2000-2012

●R&D Franco-hellenique collaboration PLATON 2000-2002
Grant title: In vivo functional study of molecules involved in developmental events in  mammalian brain.

●EPEAEK II– Archimides 2003-2006
Grant title: Study of 4C5 antigen in primary and metastatic brain tumors.

●EPEAEK III-Archimides 2012-2014

Grant title: Study of  the heat shock protein HSP90 with the use of monoclonal antibody mAb4C5.

 Approved Patents: Compositions and methods for treating neoplasias

This application claims the benefit of U.S. Provisional Application No.: 61/386,764, filed September 27, 2010

 

 

 

 

 

 

 

ublications

2009

Sidera K. and Patsavoudi E. (2009) Extracellular HSP90: An emerging target for cancer therapy. Current Signal Transduction Therapy .4: 51-58

2008

Katerina Sidera, Maria Gaitanou, D. Stellas, Rebecca Matsasand Evangelia Patsavoudi(2008) A critical role for surface HSP90 in cancer cell invasion involves extracellular interaction with HER-2J Biol Chem. 283:2031-2041

Sidera K, Patsavoudi E. (2008)Extracellular HSP90: conquering the cell surface. Cell Cycle. 7:1564

Casado JG, Delgado E, Patsavoudi E, Durán E, Sanchez-Correa B, Morgado S, Solana R, Tarazona R. (2008) Functional Implications of HNK-1 Expression on Invasive Behaviour of Melanoma Cells. Tumour Biol. 29:304-310.

2007

D. Stellas, A. Karameris, and E. Patsavoudi(2007)MAb 4C5, a monoclonal antibody against HSP90, immunostains human melanomas and inhibits melanoma cell invasion and metastasis ” Clinical Cancer Res 13 : 1831-1838

2000-2006

K.Sidera , M. Samiotaki , E. Yfanti , G. Panayotou and E. Patsavoudi (2004)Involvement of cell surface HSP90 in cell migration reveals a novel role in the developing nervous system J Biol. Chem. 279: 45379-45388

Y. Koutmani, C. Hurel, E. Patsavoudi, M. Haeck, M. Gotz, D. Thomaidou, and R. Matsas (2004) BM88 is a marker of proliferating neuroblasts that will

differentiate into the neuronal lineage. Eur. J Neurosci. 20: 2509-2523

KontodimopoulosN, CavourasD, KandarakisI, Spyropoulos,PatsavoudiE., VentourasE. (2004)

Upgrading the biomedical engineering undergraduate curriculum based on current trends in higher education. Conf Proc IEEE Eng Med Biol Soc. 2004

E. Yfanti,K. Sidera, L. Margaritis and E. Patsavoudi (2004)“The 4C5 antigen is associated with Schwann cell migration in vitro” Glia 45: 89-53

1990-1999

E. Patsavoudi, C. Hurel and R. Matsas. (1991) Purification and characterization of a neuron-specific surface antigen defined by monoclonal antibody BM88. J. of Neurochem., 56, p. 782-788.

D. Thomaidou and E. Patsavoudi. (1993) Identification of a novel neuron specific surface antigen in the developing nervous system by monoclonal antibody 4C5. Neuroscience 53, p. 813-827.

L. Probert, J. Keffer, P. Corbella, H. Cazlaris, E. Patsavoudi, S. Stephens, E. Kaslaris, D. Kioussis and G. Kollias. (1993) Wasting ischaemia and lymphoid abnormalities in mice eexpressing T cell-tergeted human tumour necrosis factor transgenes. J. of Immunol. 151, p. 1894-1906.

E. Patsavoudi, E. Merkouri, D. Thomaidou, F. Sandillon, G. Alonso and R. Matsas (1995) Biochemical characterization and immunocytochemical localization of the BM88 antigen in the developing and adult rat brain. J. Neurosci. Res. 40, 506-518

D. Thomaidou, I. Dori and E. Patsavoudi. (1995) Developmental expression and functional characterization of the 4C5 antigen in the post-natal cerebellar cortex. J. Neurochem. 64, p. 1937-1944

A. Mamalaki, E. Boutou, C. Hurel, E. Patsavoudi, S. Tzartos and R. Matsas. (1995)The BM88 antigen, a novel neuron specific molecule, enhances the differentiation of mouse neuroblastoma cells. J. Biol. Chem. 270, p. 14201-14208

D. Thomaidou, E. Yfanti and E. Patsavoudi. (1996) Expression of the 4C5 antigen during development and after injury of the rat sciatic nerve. J. Neurosci. Res. 46:24-33.

E. Yfanti, I. Nagata and E. Patsavoudi. (1998) “Migration behavior of rodent granule neuronsthe presence of antibody to the 4C5 antigen”, J. Neurochem. 71: 1381-1389