Targeting the Inhibitor of Apoptosis Proteins as a novel therapeutic strategy in medulloblastoma
Menée sur des lignées cellulaires de médulloblastome et à l'aide de xénogreffes, cette étude évalue l'activité d'un composé appelé LBW242, une petite molécule inhibant la famille des protéines inhibitrices de l'apoptose, en combinaison avec une chimiothérapie
Medulloblastoma is the most common malignant brain tumor of childhood. Novel therapeutic strategies are urgently needed to overcome cytotoxic resistance. We hypothesised that anti-apoptotic signals contribute to resistance and that treatment with pro-apoptotic agents could increase the efficacy of conventional therapies. A PCR array was used to assess the status of the apoptotic signalling pathway in medulloblastoma cells after treatment with cytotoxic chemotherapy. Treatment with cisplatin led to the upregulation of anti-apoptotic signals, including Inhibitor of Apoptosis Proteins (IAPs), in medulloblastoma cells. We subsequently investigated the synergistic effect of a small molecule IAP inhibitor, LBW242, in combination with cisplatin and / or radiotherapy in three human medulloblastoma cell lines and 5 short term primary patient medulloblastoma cultures. The addition of LBW242 to chemotherapy, resulted in significantly increased antitumor activity, with a similar effect observed in combination with radiotherapy. Measurement of caspase 8 and 9 activity indicated that the synergy resulted from induction of both the intrinsic and extrinsic apoptotic pathways. Apoptosis was confirmed by Annexin V staining and activation of caspases 3/7. Xenograft models were used to evaluate the mechanism of action and efficacy in vivo. The combination therapy significantly reduced the tumor burden in a medulloblastoma xenograft model and TUNEL analysis in a medulloblastoma orthograft confirmed in vivo induction of apoptosis. These findings support the strategy of targeting IAPs in combination with cytotoxic therapy as a novel treatment strategy for medulloblastoma patients.
http://mct.aacrjournals.org/content/early/2012/09/25/1535-7163.MCT-12-0352.abstract