PDX/PDO models for Precision Cancer Medicine Beyond Mutations

Novel annotated Patient-Derived tumor Xenografts (PDX) propagated in immunodeficient mice and Organoids (PDO) in Matrigel have become essential models to study inter- and intra-tumor heterogeneity, drug sensitivity and mechanisms of drug resistance. The establishment and utility of these models are shown from work with researchers at the Princess Margaret Cancer Centre (PM) and the PM living biobank, Toronto, Canada. Collectively, we have established over 1000 PDX models and 200 PDO models derived from tumors including lung, mesothelium, pancreas, bile duct, duodenum, esophagus, colon, breast, ovarian, and head and neck. Non-small cell lung cancer (NSCLC) is our largest clinically annotated and proteogenomics profiled set, which includes adenocarcinomas characterized by drug targetable alterations EGFR, ALK and KRAS. These models were derived from patient tumors with varying successes dependent on tumor cellularity of different tumor sources including fluids, biopsies and resections, as well as tumor stage and treatment exposure. These PDX models with activating mutations mirror patient tumors in targeted therapy responses including initial sensitivity, followed by an intermediate drug tolerant persister cell phase, and eventually developing resistance. Preliminary organoid drug sensitivity results show reliability of targeted drug effects on models with activating mutations. We continue to use PDX/PDO systems in parallel to evaluate their utility in recapitulating their parent tumor genotype and phenotype relationships. These models have allowed us to track drug action during treatment phases which are otherwise clinically challenging to monitor. 

Learning Objectives:

1. Apply current practices for PDX/PDO studies.

2. Describe experimental design and utility of PDX/PDO to study drug sensitivity and resistance mechanisms.

3. Identify resources to access models and support for PDX/PDO methodology.