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Ref Type Journal Article
PMID (24454684)
Authors Némati F, de Montrion C, Lang G, Kraus-Berthier L, Carita G, Sastre-Garau X, Berniard A, Vallerand D, Geneste O, de Plater L, Pierré A, Lockhart B, Desjardins L, Piperno-Neumann S, Depil S, Decaudin D
Title Targeting Bcl-2/Bcl-XL induces antitumor activity in uveal melanoma patient-derived xenografts.
Journal PloS one
Vol 9
Issue 1
Date 2014
URL
Abstract Text 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.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).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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
S44563 BCL-XL inhibitor 11 BCL2 inhibitor 17 S44563 binds to BCL-2 and BCL-XL and inhibits their interaction with BH3, which potentially results in increased tumor cell apoptosis and decreased tumor growth (PMID: 24454684).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown uveal melanoma not applicable Fotemustine + S44563 Preclinical - Pdx Actionable In a preclinical study, treatment with S44563 in combination with or after Fotemustine resulted in improved efficacy compared to either agent alone in patient-derived xenograft models of uveal melanoma (PMID: 24454684). 24454684