Abstract 3350: Plucked hair as a biomarker platform for monitoring transcriptional consequences of clinical exposure to antagonism of the HDM2/P53 interaction in tumors.

Abstract

Abstract The ability to assess and monitor target engagement is crucial for informing early drug development decisions. High vascularisation of the hair follicle, frequent epithelial origin of tumors, and high degree of congruence of expression in hair of pathways dysregulated in cancers, makes the cellular bulb on plucked human scalp hair an excellent surrogate tissue for non-invasive monitoring of PD effects in clinical trials. Disruption of the p53-HDM2 interaction with small molecules has demonstrated single agent anti-tumor activity in preclinical models and represents an attractive treatment strategy in oncology. Development of a peripheral tissue based gene expression signature of inhibition of the p53-HDM2 interaction could facilitate the early development of these compounds. To develop a peripheral PD biomarker of antagonism of this interaction, we used two selective p53-HDM2 antagonists, Nutlin-3 and Sanofi's SAR405838 and applied our plucked hair biomarker platform to develop a gene expression signature indicative of compound exposure. SAR405838 displays potent activity in vitro and in vivo against p53 WT cell lines / xenograft models, but not in the p53 mutant context. Three hairs from each of four healthy donors were exposed to either SAR405838 or Nutlin-3 over a range of compound concentrations for 6hr or 24hr in our proprietary ex vivo cultures. We extracted RNA from the cellular bulb of individual hairs and assessed the transcriptome by microarray analysis. Biological enrichment analysis of genes differentially expressed revealed strong correlation to activated P53 signaling pathways. Further analysis revealed a core set of congruent genes as candidate PD biomarkers of p53-HDM2 antagonism, one of which was MIC-1, a secreted plasma protein that demonstrates a strong PK/PD relationship in patients treated with p53-MDM2 antagonists in Phase 1 trials. In ex vivo plucked hair, we have demonstrated biologically relevant differential expression of a panel of transcriptional markers exhibiting common response to Nutlin-3 and SAR405838. These reflect compound mechanism of action, and can provide further evidence of target engagement in addition to plasma MIC-1 levels. While the temporal and kinetic relationship between gene expression changes, toxicity, and clinical efficacy remains to be determined, the genes identified in this study may be used to provide further MOA information in clinical settings to monitor PD responses in plucked scalp hair obtained from patients exposed to SAR405838. Citation Format: Gino Miele, Elliot Harrison, Tim Mefo, Jo Read, Lydia Meyer Turkson, Alan Murdoch, Michael Teufel, Laurent Debussche, Donald Bergstrom, James Watters. Plucked hair as a biomarker platform for monitoring transcriptional consequences of clinical exposure to antagonism of the HDM2/P53 interaction in tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3350. doi:10.1158/1538-7445.AM2013-3350