Antitumor activity of targeted and cytotoxic agents in murine subcutaneous tumor models correlates with clinical response.

Abstract

PURPOSE:

Immunodeficient mice transplanted with subcutaneous tumors (xenograft or allograft) are widely used as a model of preclinical activity for the discovery and development of anticancer drug candidates. Despite their widespread use, there is a widely held view that these models provide minimal predictive value for discerning clinically active versus inactive agents. To improve the predictive nature of these models, we have carried out a retrospective population pharmacokinetic-pharmacodynamic (PK-PD) analysis of relevant xenograft/allograft efficacy data for eight agents (molecularly targeted and cytotoxic) with known clinical outcome.

EXPERIMENTAL DESIGN:

PK-PD modeling was carried out to first characterize the relationship between drug concentration and antitumor activity for each agent in dose-ranging xenograft or allograft experiments. Next, simulations of tumor growth inhibition (TGI) in xenografts/allografts at clinically relevant doses and schedules were carried out by replacing the murine pharmacokinetics, which were used to build the PK-PD model with human pharmacokinetics obtained from literature to account for species differences in pharmacokinetics.

RESULTS:

A significant correlation (r = 0.91, P = 0.0008) was observed between simulated xenograft/allograft TGI driven by human pharmacokinetics and clinical response but not when TGI observed at maximum tolerated doses in mice was correlated with clinical response (r = 0.36, P = 0.34).

CONCLUSIONS:

On the basis of these analyses, agents that led to greater than 60% TGI in preclinical models, at clinically relevant exposures, are more likely to lead to responses in the clinic. A proposed strategy for the use of murine subcutaneous models for compound selection in anticancer drug discovery is discussed.

• Authors: Harvey Wong, Edna F Choo, Bruno Alicke, Xiao Ding, Hank La, Erin McNamara, Frank-Peter Theil, Jay Tibbitts, Lori S Friedman, Cornelis E C A Hop, Stephen E Gould
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 14 Pg. 3846-55 (Jul 15 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22648270 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics)
• Cell Line, Tumor
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Humans
• Mice
• Mice, Nude
• Neoplasms, Experimental (drug therapy)
• Predictive Value of Tests
• Retrospective Studies
• Xenograft Model Antitumor Assays