Introduction: Inhibitors of apoptosis proteins (IAPs) are key negative regulators of programmed cell death. Their frequent deregulation in most cancer types contributes to tumor cell survival and resistance to cancer therapy, making IAPs attractive therapeutic targets. Debio 1143 (formerly named AT-406), a new potent orally-available monovalent SMAC mimetic, targets multiple IAP members and is currently in clinical trials for cancer treatment. In this study, pharmaco-imaging was used to evaluate the effects of Debio 1143 on tumor cell death and metabolism in the triple negative breast cancer (TNBC) cell line MDA-MB-231.
Material and Methods: The effects of Debio 1143 on caspase-3 activation (FACS), apoptosis-induced membrane changes (FACS and radioactive detection of Annexin V binding), and cell proliferation (MTS assay) were evaluated in MDA-MB-231 cells. In vivo pharmaco-imaging experiments were performed in CB17 SCID mice bearing subcutaneous MDA-MB-231 TNBC tumors. 99mTc-Annexin V SPECT/CT (Single Photon Emission Computed Tomography/Computed Tomography) imaging was performed 6 hours and 24 hours after a single treatment with vehicle, Debio 1143 (100 mg/kg per os) or paclitaxel (7.5 mg/kg intravenously), and was completed by gamma counting of organs. Tumor metabolism was evaluated by 18F-FDG (fluorodeoxyglucose) PET/CT (Positron Emission Tomography) while animals received repeated administrations of vehicle, Debio 1143 (100 mg/kg per os) or paclitaxel (7.5 mg/kg intravenously).
Results: In MDA-MB-231 cells, Debio 1143 as a single agent was highly effective in inducing apoptosis. This was reflected by a dose-dependent activation of caspase-3, an increase of Annexin V cell binding, and a cytotoxic activity with a mean IC50 of 224 nM. In MDA-MB-231 tumor-bearing mice, Debio 1143 showed an effect on 99mTc-Annexin V tumor binding with an increased tumor SPECT signal and gamma counting results 6 hours after oral administration, while paclitaxel maximum effects were detected at 24 hours post-treatment. During repeated administration, oral Debio 1143 inhibited tumor growth, which was associated with a decreased tumor 18F-FDG uptake when measured during treatment (after 1 and 2 weeks of treatment). The effects on tumor growth and 18F-FDG uptake were still present 1 week after the end of the treatment period.
Conclusion: This pharmaco-imaging study of the effects of Debio 1143 in TNBC showed that Debio 1143 induced apoptosis both in vitro and in vivo. Moreover, 18F-FDG PET imaging made it possible to observe the effect of Debio 1143, suggesting that this imaging technique may be useful in a clinical setting. To conclude, this study supports the use of Debio 1143 in the treatment of TNBC - a still unmet medical need.
Citation Format: Alexandra Oudot, Olivier Raguin, Lucile Bauché, Francis Bichat, Anne Vaslin, Hélène Maby-El Hajjami, Claudio Zanna, Grégoire Vuagniaux, Pierre Fumoleau, François Brunotte, Bertrand Collin. Pharmaco imaging study of the effects of Debio 1143, a new orally available IAP inhibitor, in a triple negative breast cancer model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2757. doi:10.1158/1538-7445.AM2014-2757