Targeting Bcl-2/Bcl-XL induces antitumor activity in uveal melanoma patient-derived xenografts.
OBJECTIVE
Uveal melanoma (UM) is associated with a high risk of metastases and lack of efficient therapies. Reduced capacity for apoptosis induction by chemotherapies is one obstacle to efficient treatments. Human UM is characterized by high expression of the anti-apoptotic protein Bcl-2. Consequently, regulators of apoptosis such as Bcl-2 family inhibitors may constitute an attractive approach to UM therapeutics. In this aim, we have investigated the efficacy of the Bcl-2/Bcl-XL inhibitor S44563 on 4 UM Patient-Derived Xenografts (PDXs) and derived-cell lines.


METHODS
Four well characterized UM PDXs were used for in vivo experiments. S44563 was administered alone or combined with fotemustine either concomitantly or after the alkylating agent. Bcl-2, Bcl-XL, and Mcl-1 expressions after S44563 administration were evaluated by immunohistochemistry (IHC).


RESULTS
S44563 administered alone by at 50 and 100 mg/kg i.p. induced a significant tumour growth inhibition in only one xenograft model with a clear dose effect. However, when S44563 was concomitantly administered with fotemustine, we observed a synergistic activity in 3 out of the 4 tested models. In addition, S44563 administered after fotemustine induced a tumour growth delay in 2 out of 3 tested xenografts. Finally, IHC analyses showed that Bcl-2, Bcl-XL, and Mcl-1 expression were not modified after S44563 administration.


CONCLUSIONS
The novel anti-apoptotic experimental compound S44563, despite a relative low efficacy when administered alone, increased the efficacy of fotemustine in either concomitant or sequential combinations or indeed subsequent to fotemustine. These data support further exploration of potential therapeutic effect of Bcl-2/Bcl-xl inhibition in human UM.
Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie, Paris, France.
Fariba
F
Némati
I.D.R.S., Institut de Recherches Servier, Croissy, France.
Catherine
C
de Montrion
Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie, Paris, France.
Guillaume
G
Lang
I.R.I.S., Institut de Recherches International Servier, Suresnes, France.
Laurence
L
Kraus-Berthier
Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie, Paris, France.
Guillaume
G
Carita
Department of Tumor Biology, Institut Curie, Paris, France.
Xavier
X
Sastre-Garau
Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie, Paris, France.
Aurélie
A
Berniard
Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie, Paris, France.
David
D
Vallerand
I.R.I.S., Institut de Recherches International Servier, Suresnes, France.
Olivier
O
Geneste
Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie, Paris, France.
Ludmilla
L
de Plater
I.D.R.S., Institut de Recherches Servier, Croissy, France.
Alain
A
Pierré
I.D.R.S., Institut de Recherches Servier, Croissy, France.
Brian
B
Lockhart
Department of Ophthalmological Oncology, Institut Curie, Paris, France.
Laurence
L
Desjardins
Department of Medical Oncology, Institut Curie, Paris, France.
Sophie
S
Piperno-Neumann
I.D.R.S., Institut de Recherches Servier, Croissy, France ; I.R.I.S., Institut de Recherches International Servier, Suresnes, France.
Stéphane
S
Depil
Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie, Paris, France ; Department of Medical Oncology, Institut Curie, Paris, France.
Didier
D
Decaudin
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005454:Fluorescence Polarization; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D007150:Immunohistochemistry; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D009607:Nitrosourea Compounds / Q000494:pharmacology / Q000627:therapeutic use; D009943:Organophosphorus Compounds / Q000494:pharmacology / Q000627:therapeutic use; D010455:Peptides / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D016019:Survival Analysis; D014604:Uveal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000098943:Uveal Melanoma
D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; D010455:Peptides; C000599183:S44563; D013449:Sulfonamides; D051020:bcl-X Protein; C054368:fotemustine