Abstract 2197: Surface marker and gene expression profiling of tumors from PDX models of small cell lung cancer with varying sensitivity to growth inhibition by the p70S6K/AKT1/3 inhibitor M2698
Authors: Hahn Friedrich , Porter Warren , Snowden Eileen , Ferguson Mitchell , Tong Frances , Dillmore William S. , Clark Anderson , Zhang Hong , Blaesius Rainer 
Published: August 2018

Small Cell Lung Cancer (SCLC) is characterized by rapid tumor growth and currently, there are few therapeutic options. As part of the development of M2698, a potent, selective inhibitor of p70S6K and AKT 1/3, the compound was tested in a preclinical screen of 45 patient derived xenograft (PDX) models of SCLC. In this screen, two mice were implanted subcutaneously with tumors for each model; one mouse was treated with vehicle while the other was treated with M2698 25 mg/kg QD po and tumors were measured 2x/week until the tumor in the vehicle-treated mouse reached ~1200 mm3. Tumor control (tumor stasis or regression) was seen in 12 (27%) of the models. From these data, a subset of models that were the most and the least sensitive to M2698 (n=7) were selected for implantation into a new set of mice. Tumors were profiled once they reached ~800 mm3 for tumor cell surface markers potentially correlating with sensitivity to M2698 seen in the previous study.

PDX model systems are capable of recapitulating the intra-tumor heterogeneity (ITH) observed in the original patient tumor. The relationship between ITH and drug response/acquired drug resistance has been clearly demonstrated. Thus, a more detailed examination of this complexity in PDX tissue enables one to elucidate the underlying mechanisms in a reproducible, biologically relevant system.

We have previously shown that cell surface marker profiles of PDX derived tumor tissue demonstrate high intra-model reproducibility whereas each model has a unique profile. In addition, some markers have a distinct heterogeneity. Gene expression profiling of tumor cell subpopulations identified by some of these specific markers suggest different biological roles for these subpopulations with relevance to their drug responses.

Here we show surface marker and gene expression profiles of multiple PDX models for SCLC. We have evaluated 50+ markers commonly used to identify tumor initiating cells (e.g. CD44, CD90, CD133, CD166, CD184), EMT or aggressiveness (e.g. CD166, EphB2, CD324, CD325) or drug targets (e.g. CD184, EGFR, Her2) to establish extensive marker profiles.

Our data reveal that surface marker profiles in SCLC PDX models are consistent among tumors from mice bearing the same model, show major differences from other PDX (e.g. breast) cancer types and heterogeneity exists for several markers of interest. By correlating gene expression and surface marker profiles in the current preclinical study, we aim to illuminate the interactions of major cell subpopulations within SCLC PDX tumor tissue and also investigate potential markers of sensitivity to growth inhibition by treatment with M2698. Overall, our workflow of deep phenotyping may provide tools for sample characterization, quality control and possibly study of cellular response to varying selective pressures such as drug challenges.

Citation Format: Friedrich Hahn, Warren Porter, Eileen Snowden, Mitchell Ferguson, Frances Tong, William S. Dillmore, Anderson Clark, Hong Zhang, Rainer Blaesius. Surface marker and gene expression profiling of tumors from PDX models of small cell lung cancer with varying sensitivity to growth inhibition by the p70S6K/AKT1/3 inhibitor M2698 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2197.