Abstract 2380: Head and neck patient derived xenografts acquire histopathological and growth rate changes over increasing passages
Authors: Pearson Alexander , Finkel Kelsey A. , Warner Kristy A. , Nor Felipe , Tice David A. , Martins Manoela D. , Jackson Trachette L. , Nor Jacques E. 
Published: July 2016

Abstract
The purpose of this work was to model the growth rate and histopathological features of patient derived xenograft (PDX) tumors across multiple in-vivo passages. PDX models are frequently deployed in translational cancer research, but the growth rate consistency over time is unclear. While growth rates are generally assumed to be stable, changes in PDX growth over time in the absence of treatment could significantly change the interpretation of translational studies. Here, we examined PDX tumors over time to determine if they have stable growth rates and histopathological features from initial implantation across multiple passages. We implanted and developed three distinct PDX models derived from primary human head and neck squamous cell carcinoma (HNSCC) and adenoid cystic carcinoma (ACC) through at least four passages. To compare growth rates over multiple mouse life spans, we developed a mathematical approach to merge growth data from different passages into a single measure of log relative tumor volume (log-RTV) normalized to study initiation size. We analyzed log-RTV over time with linear mixed effect models and found that tumor growth rate changed over time. In each of the three PDX models tested, the log-RTV was significantly better described by a positive quadratic function compared to a linear function (P &lt; 0.0001 in all three models). This finding implies that the growth rate is not stable over long periods of time, and changes across multiple xenograft passages. To further investigate the etiologies of these changes, two oral pathologists were blinded and analyzed PDX tissues for SCC and ACC models to determine if histopathological features changed over in-vivo passages. We found a significant correlation between passage number and HNSCC nuclear pleomorphism (p = 0.01), ACC histopathological pattern (p &lt; 0.0001), and other features indicative of higher tumor grade in both the squamous cell carcinoma and adenoid cystic models. Our log-RTV transformation of PDX data allows statistical analysis of tumor growth data over long periods of time, including over multiple xenograft passages. In conclusion, this new analysis method allows for the design of longer translational xenograft experiments that span across multiple in-vivo passages. Non-linear tumor growth in our regression models revealed the exponential growth rate of PDX models increased over time. The tumor growth rate changes corresponded with quantifiable histopathological features closely related to passage number in multiple types of head and neck cancer.
Citation Format: Alexander Pearson, Kelsey A. Finkel, Kristy A. Warner, Felipe Nor, David A. Tice, Manoela D. Martins, Trachette L. Jackson, Jacques E. Nor. Head and neck patient derived xenografts acquire histopathological and growth rate changes over increasing passages. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2380.