The pharmacological audit trail (PhAT): Use of tumor models to address critical issues in the preclinical development of targeted anticancer drugs

Abstract

The Pharmacological Audit Trail (PhAT) is designed as a biomarker-driven roadmap to support discovery and development of anticancer drugs. The PhAT outlines key questions that deal with the use of biomarkers to (1) determine the right patient population, (2) describe the drug’s pharmacokinetics, (3) determine the drug’s pharmacodynamics, (4) predict tumor response at an intermediate time point, (5) assess tumor response at end of treatment, and (6) understand tumor resistance paradigms. Rigorous implementation of the PhAT ensures discovery and clinical development of high quality drug candidates and helps optimize clinical trials by guiding informed decisions by clinicians. While the later stages of the PhAT deal with the clinical validation of the therapeutic hypothesis, early preclinical experiments are essential to define a number of the PhAT parameters, including identification of biomarkers and early demonstration of efficacy and proof of mechanism. This review focuses on how various preclinical tumor models, which range from simple two-dimensional cell cultures to state-of-the-art patient-derived xenografts, can be best used to answer many of these questions preclinically.