Abstract 4731: Cytotoxic versus cytostatic effects in tumor models by spiro-oxindole-based modulators of the MDM2-p53 interaction

Abstract

Abstract Two spiro-oxindole-based modulators -compounds A and B - of the MDM2-p53 protein-protein interaction display suitable pharmacological properties and are currently under advanced preclinical development (1). In vitro, these compounds induce massive cell death in a subset of relevant tumor models such as MDM2-amplified SJSA-1, while they can significantly block cell proliferation without detectable cytotoxic effect in other human cell lines (e.g. HCT116). To better characterize in vivo the different tumor cell sensitivity of these novel MDM2 antagonists, quantitative and longitudinal pharmacodynamic effects have been determined in several preclinical settings: i) anti-tumor efficacy, ii) activation of p53-dependent molecular biomarkers such as p53 itself, p21, MDM2, PUMA, Noxa, Bax and MIC-1 and iii) downstream biological effects monitored by immuno-assays as well as by in vivo fluorescence tomography and PET imaging. The results obtained from these studies have revealed striking differences in the biological read-outs associated with the observed cytotoxic versus cytostatic effects and provide guidance for the use of certain biomarkers in the clinical development of this new generation of anti-cancer agents. 1. Wang S. et al., AACR, Orlando FL, 2011, Abstract LB-204 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4731. doi:1538-7445.AM2012-4731