1. Identification of predictive factors of response to the BH3-mimetic molecule ABT-737: An ex vivo experiment in human serous ovarian carcinoma.
- Author
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Lheureux, Stéphanie, N'Diaye, Monique, Blanc‐Fournier, Cécile, Dugué, Audrey Emmanuelle, Clarisse, Bénédicte, Dutoit, Soizic, Giffard, Florence, Abeilard, Edwige, Briand, Mélanie, Labiche, Alexandre, Grellard, Jean‐Michel, Crouet, Hubert, Martin, Sandrine, Joly, Florence, and Poulain, Laurent
- Abstract
Ovarian cancers are addicted to Bcl-x
L and Mcl-1, antiapoptotic members of the Bcl-2 family. Bcl-xL can be inhibited by the BH3-mimetic ABT-737. In vitro, ABT-737 can induce apoptosis of cancer cells, and its activity is potentiated by Mcl-1 inactivation. Herein, we assessed the sensitivity of human ovarian tumor nodes to ABT-737 when combined with carboplatin, which can indirectly inhibit Mcl-1. Fresh samples from 25 patients with high-grade serous ovarian cancer (HGSOC) who were chemo-naïve and had undergone surgery were prospectively exposed ex vivo to ABT-737 ± carboplatin. The treatment effect was studied on sliced tumor nodes by assessment of cleaved-caspase 3 immunostaining. We also studied the association between baseline Bcl-2 family protein expression ( via immunohistochemistry) and the response of nodes to treatment. ABT-737 induced apoptosis as a single agent but its efficacy was not improved by the addition of carboplatin. Bim was frequently expressed (20/25) and its absence or low expression was associated with the absence of response to ABT-737, p value = 0.019 by Fisher's test and sensitivity = 93%, (95% confidence interval, 66-100). Moreover, we observed that in tumors in which Bim was expressed, a low expression of phospho-Erk1/2 or Mcl-1 improved the proportion of responses. This pilot study showed that ABT-737 has promise as monotherapy for HGSOC in a specific subgroup of tumors. Bim, Mcl-1, and phospho-Erk1/2 appeared to be relevant biomarkers that could be used for the selection of patients in the design of clinical trials using Navitoclax (an orally available compound related to ABT-737). [ABSTRACT FROM AUTHOR]- Published
- 2015
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