Prioritizing therapeutic targets using patient-derived xenograft models

• Published in: Biochimica et biophysica acta Vol. 1855; no. 2; pp. 223 - 234
• Main Authors: Lodhia, K.A., Hadley, A.M., Haluska, P., Scott, C.L.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-04-2015
• Subjects: Animals; Disease Models, Animal; Drug Resistance, Neoplasm - genetics; Drug Resistance, Neoplasm - immunology; Genomics; Humans; Mice; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Patient-derived xenografts; Personalized medicine; Precision Medicine; Targeted therapy; Therapeutic targets; Xenograft Model Antitumor Assays; Patient-derived xenografts; Personalized medicine; Targeted therapy; WT; Genomics; Therapeutic targets
• ISSN: 0304-419X; 0006-3002; 1879-2561
• DOI: 10.1016/j.bbcan.2015.03.002

Effective systemic treatment of cancer relies on the delivery of agents with optimal therapeutic potential. The molecular age of medicine has provided genomic tools that can identify a large number of potential therapeutic targets in individual patients, heralding the promise of personalized treatment. However, determining which potential targets actually drive tumor growth and should be prioritized for therapy is challenging. Indeed, reliable molecular matches of target and therapeutic agent have been stringently validated in the clinic for only a small number of targets. Patient-derived xenografts (PDXs) are tumor models developed in immunocompromised mice using tumor procured directly from the patient. As patient surrogates, PDX models represent a powerful tool for addressing individualized therapy. Challenges include humanizing the immune system of PDX models and ensuring high quality molecular annotation, in order to maximize insights for the clinic. Importantly, PDX can be sampled repeatedly and in parallel, to reveal clonal evolution, which may predict mechanisms of drug resistance and inform therapeutic strategy design.
•Prioritizing potential therapeutic targets identified by genomics is challenging.•Well-annotated patient-derived xenografts (PDXs) can be powerful patient surrogates.•PDXs can be sampled serially and in parallel to reveal clonal evolution on treatment.•PDXs could predict likely mechanisms of drug resistance to inform therapeutic strategy.•Challenges include high quality annotation and humanizing the murine immune system.