Abstract 3242: Xenograft dose-response from intra-mouse dose escalation
Authors: Chen Andrew , Zopf Christopher J. , Wu Jing-Tao , Shyu Wen Chyi , Chakravarty Arijit 
Published: August 2015

Introduction

Xenograft response has been shown to hold predictive value for the clinical efficacy of a drug, but growth sensitivity to a drug candidate can vary widely between xenografts models. As the ability to test pre-clinically for broad biological activity across many xenografts models is often resource-limited, in this work we develop a mathematical approach based on evolutionary dynamics to derive dose-response information from a single xenograft tumor.

Methods

We propose to estimate a dose-response curve of xenograft growth inhibition by treating a single tumor with a series of different dose strengths. Exponential tumor growth rate (GR) may be quickly estimated to determine the inhibition effect of a particular exposure during week-long intervals of constant dose strength. We next considered the possibility of a dose strength ordering effect on tumor growth due to cellular heterogeneity in GR and drug sensitivity within a tumor. To determine to what extent dose history could influence the observed growth inhibition, we developed an evolutionary model of tumor growth for a heterogeneous population of cancer cells with joint-distributed clonal GR and drug sensitivities, and simulated tumor response to treatment for distributions having variable degrees of correlation. Finally, we tested the ability to estimate dose-response curves from single tumors in vivo compared to the typical method of assessing drug effect based on multiple dose-groups.

Results

For the three possible orders of dosing three different treatment strengths, we found that the simulated study design with escalating dose intervals lead to the least error compared to assessing each dose in a separate tumor. Additionally, the discrepancy between the growth inhibition effects of different dose orders peaks when the correlation between GR and drug sensitivity decreases to negative. We then show that this study design allows efficient, accurate estimation of the range of dose-responses in a broad set of simulated tumor types (e.g., fast-growing and sensitive, or slow-growing and insensitive). An in vivo dose-response study validates the estimation of dose-response curves from a single xenograft by comparing favorably with the single dose per mouse method.

Conclusions

The mathematical approach described here allows efficient estimation of a dose-response curve for a xenograft model using a single tumor. By reducing the resources required to determine the response of a single model, a molecule's anticancer effect can be tested against a larger sample of tumor types pre-clinically. A more accurate picture of a drug candidate's broad biological activity will allow for greater confidence in translational projections of clinical efficacy.

Citation Format: Andrew Chen, Christopher J. Zopf, Jing-Tao Wu, Wen Chyi Shyu, Arijit Chakravarty. Xenograft dose-response from intra-mouse dose escalation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3242. doi:10.1158/1538-7445.AM2015-3242