title: Identification of predictive factors of response to the BH3-mimetic molecule ABT-737: an ex vivo experiment in human serous ovarian carcinoma.
abstract: Ovarian cancers are addicted to Bcl-xL 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).
authors: Normandy University, Caen, France; UNICAEN, Unité "Biologie et Thérapies Innovantes des Cancers Localement Agressifs" (EA 4656), Centre de Lutte Contre le Cancer François Baclesse, 14076 Caen Cedex 05, France; Centre de Lutte Contre le Cancer François Baclesse, 3 Avenue du Général Harris, BP5026, 14076 Caen Cedex 05, France; Service de recherche clinique, Centre de Lutte Contre le Cancer François Baclesse, 14076 Caen Cedex 05, France; Comité d'Uro-gynécolgie Oncologique, Centre de Lutte Contre le Cancer François Baclesse, 14076 Caen Cedex 05, France.
authors: Stéphanie
authors: S
authors: Lheureux
authors: Monique
authors: M
authors: N'Diaye
authors: Cécile
authors: C
authors: Blanc-Fournier
authors: Audrey Emmanuelle
authors: AE
authors: Dugué
authors: Bénédicte
authors: B
authors: Clarisse
authors: Soizic
authors: S
authors: Dutoit
authors: Florence
authors: F
authors: Giffard
authors: Edwige
authors: E
authors: Abeilard
authors: Mélanie
authors: M
authors: Briand
authors: Alexandre
authors: A
authors: Labiche
authors: Jean-Michel
authors: JM
authors: Grellard
authors: Hubert
authors: H
authors: Crouet
authors: Sandrine
authors: S
authors: Martin
authors: Florence
authors: F
authors: Joly
authors: Laurent
authors: L
authors: Poulain
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D014408:Biomarkers, Tumor / Q000378:metabolism; D001713:Biphenyl Compounds / Q000378:metabolism*; D016190:Carboplatin / Q000494:pharmacology; D003131:Combined Modality Therapy; D018284:Cystadenocarcinoma, Serous / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009596:Nitrophenols / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D010879:Piperazines / Q000378:metabolism; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013449:Sulfonamides / Q000378:metabolism*
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D014408:Biomarkers, Tumor; D001713:Biphenyl Compounds; C579095:MCL1 protein, human; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D016190:Carboplatin; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: ABT-737; Bim; Mcl-1; P-Erk; apoptosis; ovarian carcinoma