Fondation MEDIC

www.fondation-medic.ch

Melanogenesis in melanoma progression and therapy
[13.09.2015]
Project leader – Ghanem Ghanem
Ghanem Ghanem

GHANEM Ghanem-Elias is a belgian citizen, born in 1953 married, two children. His main field of work is in cancer research, notbly in the field of melanoma. Ghanem earned aPhD after an MSc in Clinical Biology and a PharmD at the Free University of Brussels.

His present position is Director of the Laboratory of Oncology and Experimental Surgery at the Faculty of Medecine of the Cancer Center Institut J. Bordet and Professor of Radiopharmacy and Nuclear Medicine at the same University. He is President of the Scientific Committee of Institut J. Bordet, member of many international and national scientific associations, of which the most important are council member of the European Society of Pigment Cell Research and Editor of its official Bulletin and Council member and Treasurer of the Melanoma Group of the European Organization for Research and treatment of Cancer (EORTC). He is also president of the non profit «Association pour la lutte contre le mélanome malin» (Belgium).

L.O.C.E. – Institut J. Bordet
Rue Héger-Bordet 1
B-1000 Brussels

E-Mail: gghanem@ulb.ac.be

Group members
 

Isabelle Borsu

lab technician

Marie-Jeanne Gebski

lab technician

Petra El Hajj MSc

graduate student

Fabrice Journé PhD

senior scientist

Mohammad Krayem MSc

graduate student

Renato Morandini PhD

senior scientist

Murielle Wiedig MSc

senior scientist

Sebahat Yildirim

lab technician

Project description
 

Our group studies prognostic and predictive factors in melanoma based upon present understanding of melanoma biology. While prognostic parameters (Breslow thickness, Ulceration, Number of Mitosis, ...) are well defined on the melanoma primary lesion (Disease Stages I or II), only very few are used in clinical assessment at later stages.
We studied a melanosomal protein, Tyrp1, in metastatic tissue and found that high expression of the marker strongly correlated with a short survival. Interestingly, expression of the marker also correlated with Breslow thickness, the most important prognostic parameter in the primary lesion. This finding suggests a possibly important role of this protein in melanoma progression and aggressiveness and that it might be used as a target for therapy due to its contant expression regardless of the stage of disease. Studies of Tryp1 are further pursued.

About 50% of melanomas bear a mutated BRAF gene. BRAF mutated melanoma cells paradoxically exihibit a senescence-like phenotype and a low proliferation index compared to wild type. The consequence of such mutation is a constant activation of one of the major pathways in the melanocyte: the MAPK/MEK/ERK pathway. Specific inhibition of this pathway in these patients by newly designed drugs (e.g. Vemurafinib) resulted in a spectacular regression of the metastatic lesions in about half of the treated patients. However, the duration of the response is limited and resistance to the treatment appears in all cases. Contrasting with these important observations, we found in a panel of melanoma cell lines that BRAF mutations clearly drive a cell senescence-like phenotype (Fig.1) associated with low proliferation. Most interestingly, these characteristics can be reversed in some melanoma cell lines by inhibitors of mutated BRAF or MEK. These data suggest that these cells are less aggressive than the wild type ones and contrast with the status of “driver mutation” known in other tumors.

figure 1
In situ detection of β-galactosidase activity in wild type and V600EBRAF melanoma cells.

Mutated cKit has been an indication for the use of specific inhibitors in mucosal melanoma where this mutation is rather frequent. The frequent activation of SRC in melanoma has also been a target for therapy. Both strategies led to limited success.

We conducted a screening in a panel of cell lines with three important mutations known in melanoma (BRAF, NRAS and cKit) as to their sensitivity to cKit and SRC inhibitors. We found a group of lines extremely sensitive to the drug dasatinib with inhibitory concentrations (IC50) as low as 10-10M while other lines ranged from moderately sensitive to resistant (IC50=10-8-10-4M) (Table 1). We could identify common features explaining this high sensitivity: All highly sensitive cells are BRAF and NRAS wild type, they express high levels of cKit but no correlation with SRC expression. Dasatinib treatment resulted in a dramatically inhibition of cKit, SRC, ERK and AKT phosphorylation in sensitive cells, while it had no effect on the phosphorylation of both ERK and AKT in the mutated ones, suggesting a selective effect on proliferation/survival of cells with cKIT expression not harbouring NRAS/BRAF mutation.

This has an interesting clinical relevance since about 25% of metastatic melanoma patients (wild type for BRAF and NRAS) would potentially benefit from dasatinib treatment considering the wide therapeutic window of the drug in this particular group.

Publications
 
2013 / 10.3892/ijo.2013.2008
Aftimos PG, Wiedig M, Langouo Fontsa M, Awada A, Ghanem G, Journe F. Sequential use of protein kinase inhibitors potentiates their toxicity to melanoma cells: A rationale to combine targeted drugs based on protein expression inhibition profiles. Int J Oncol 2013;43:919-26
» PubMed
2013 / 10.1038/bjc.2013.115
El Hajj P, Journe F, Wiedig M, Laios I, Salès F, Galibert MD, Van Kempen LC, Spatz A, Badran B, Larsimont D, Awada A, Ghanem G. Tyrosinase-related protein 1 mRNA expression in lymph node metastases predicts overall survival in high-risk melanoma patients. Br J Cancer 2013;108:1641-7
» PubMed
2012 / 10.1111/j.1755-148X.2012.01018.x
Anghel SI, Correa-Rocha R, Budinska E, Boligan KF, Abraham S, Colombetti S, Fontao L, Mariotti A, Rimoldi D, Ghanem GE, Fisher DE, Lévy F, Delorenzi M, Piguet V. Breast cancer suppressor candidate-1 (BCSC-1) is a melanoma tumor suppressor that down regulates MITF. Pigment Cell Melanoma Res. 2012 Jul;25(4):482-7
» PubMed
2012 / 10.1038/nm.2863
Gembarska A, Luciani F, Fedele C, Russell EA, Dewaele M, Villar S, Zwolinska A, Haupt S, de Lange J, Yip D, Goydos J, Haigh JJ, Haupt Y, Larue L, Jochemsen A, Shi H, Moriceau G, Lo RS, Ghanem G, Shackleton M, Bernal F, Marine JC. MDM4 is a key therapeutic target in cutaneous melanoma. Nat Med. 2012 Jul 22
» PubMed
2011 / 10.1016/j.ejca.2010.10.005
Bouwhuis MG, Suciu S, Kruit W, Salès F, Stoitchkov K, Patel P, Cocquyt V, Thomas J, Liénard D, Eggermont AM, Ghanem G; European Organisation for Research and Treatment of Cancer Melanoma Group. Prognostic value of serial blood S100B determinations in stage IIB-III melanoma patients: a corollary study to EORTC trial 18952. Eur J Cancer. 2011 Feb;47(3):361-8
» PubMed
2011 / 10.1210/me.2010-0217
Herraiz C, Journé F, Abdel-Malek Z, Ghanem G, Jiménez-Cervantes C, García-Borrón JC. Signaling from the human melanocortin 1 receptor to ERK1 and ERK2 mitogen-activated protein kinases involves transactivation of cKIT. Mol Endocrinol. 2011 Jan;25(1):138-56
» PubMed
2011 / 10.1016/j.bone.2011.08.013
Id Boufker H, Lagneaux L, Fayyad-Kazan H, Badran B, Najar M, Wiedig M, Ghanem G, Laurent G, Body JJ, Journé F. Role of farnesoid X receptor (FXR) in the process of differentiation of bone marrow stromal cells into osteoblasts. Bone. 2011 Dec;49(6):1219-31
» PubMed
2011 / 10.1038/bjc.2011.451
Journe F, Id Boufker H, Van Kempen L, Galibert MD, Wiedig M, Salès F, Theunis A, Nonclercq D, Frau A, Laurent G, Awada A, Ghanem G. TYRP1 mRNA expression in melanoma metastases correlates with clinical outcome. Br J Cancer. 2011 Nov 22;105(11):1726-32
» PubMed
2010 / 10.1186/1471-2407-10-298
Id Boufker H, Lagneaux L, Najar M, Piccart M, Ghanem G, Body JJ, Journé F. The Src inhibitor dasatinib accelerates the differentiation of human bone marrow-derived mesenchymal stromal cells into osteoblasts. BMC Cancer. 2010 Jun 17;10:298
» PubMed