Abstract 3830: Plucked anagen scalp hair: A reproducible surrogate tissue to monitor drug induced transcriptional changes and provide pharmacodynamic biomarker and target engagement information from cancer patients

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 13_Supplement; p. 3830
• Main Authors: Reed, Benjamin J., Mefo, Timothy, Harrison, Elliott, Haggart, Ross, Grimes, Emma, Murdoch, Alan, Miele, Gino
• Format: Journal Article
• Language: English
• Published: 01.07.2017
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-3830

Abstract Monitoring target engagement is crucial to inform on early drug development decisions, and development of a peripheral tissue-based gene expression signature indicative of pathway inhibition could facilitate the continued clinical development of compounds. Plucked anagen scalp hair is an ideal source of epithelial tissue to monitor drug induced transcriptional changes. High vascularisation of the hair follicle, frequent epithelial origin of tumors, ease of sampling and high degree of congruence of expression in hair of pathways dysregulated in cancers, make the cellular bulb of plucked human scalp hair an excellent surrogate tissue for the non-invasive monitoring of pharmacodynamic (PD) and mechanism of action (MOA) effects in clinical trials. Using our ex vivo plucked hair culture platform, hair bulbs from several healthy donors were exposed to BEZ235, a dual pan-class PI3K and mTOR inhibitor at different concentrations and durations. Total RNA was isolated from the cellular bulb of individual anagen hair post-culture and used for microarray analysis to assess global transcriptional alterations and develop a gene expression signature indicative of BEZ235 exposure. The results of the ex vivo plucked assessment generated a dose dependent appreciable and biologically relevant transcriptional signature following exposure to BEZ235. Transcriptional readouts from patients also revealed strong correlations (0.97-0.99) in the genes expressed in anagen scalp hair between donors and across samples taken from the same donor. In addition, global gene expression data indicated that assessing three plucked scalp hairs or less at each collection point was sufficient to detect significant differential expression (p<0.05 & 1.5 fold change) underpinning the low variance in the majority of target genes in plucked hair as a biomarker platform. Gene signatures for compounds targeting the PI3K/mTOR pathway that were established using the ex vivo plucked scalp hair platform were used to support clinical trials and scalp hair taken from patients receiving treatment showed an excellent post-exposure target signature modulation. In summary, our results substantiate that plucked anagen scalp hair is an ideal non-invasive surrogate tissue to obtain drug-induced pharmacodynamic biomarker and target engagement information from oncology patients. Citation Format: Benjamin J. Reed, Timothy Mefo, Elliott Harrison, Ross Haggart, Emma Grimes, Alan Murdoch, Gino Miele. Plucked anagen scalp hair: A reproducible surrogate tissue to monitor drug induced transcriptional changes and provide pharmacodynamic biomarker and target engagement information from cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3830. doi:10.1158/1538-7445.AM2017-3830