Abstract C2: Selection for combinational studies through biomarker stratification in colorectal patient-derived explant models.

Abstract

Abstract Patient-derived explant models (PTX) show a higher genetic and pathological heterogeneity than cell line derived xenograft models, and may have greater clinical relevance in cancer drug development and personalised oncology treatments than cell line derived xenograft models. Therefore PTX models can potentially be used to provide additional confidence in patient stratification hypotheses for novel therapies or combination approaches. To examine comparative pharmacological responses in PTX models, the monotherapy activity of the MEK inhibitor selumetinib was determined in colorectal cancer PTX models that were stratified according to a MEK pathway “functional activation” mRNA signature, originally derived using a broad human tumor cell line panel (1). Tumor passage, immunohistochemical and genetic markers of target pathway activity were also assessed to collectively select 6 models of high interest for examining response to treatment. In addition, to monotherapy treatment, 3 models were also used to examine the combination of selumetinib with the mTORC1/2 kinase inhibitor AZD8055. The results suggest that the MEK pathway mRNA signature is applicable in colorectal PTX models and enables selumetinib responsive versus non-responsive models to be identified. Combination therapy of selumetinib and AZD8055 has also shown additional therapeutic benefit, similar to that observed in selected cell line derived xenografts. These data illustrate that use of PTX panels can be applied to substantiate in-vitro derived biomarker-led hypotheses for a given therapeutic approach. In addition, biomarker stratification has focused experimental design to test novel:novel combinations and may enable stratification for prospective patient subsets. Collectively this approach to disease modelling could significantly reduce wide screening in vivo studies and steer more refined clinically relevant hypotheses, whilst allowing for a reduction in animal usage. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C2.