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Review

Patient-derived xenograft models for oncology drug discovery

Gang Li
Ignyta Inc., San Diego, CA 92121, USA.
Correspondence to: Dr. Gang Li, Ignyta Inc., 11111 Flintkote Avenue, San Diego, CA 92121, USA. E-mail: garyli1210@yahoo.com

ABSTRACT

The success of targeted therapies for cancer patients rests on three major components: the right target(s), the right drug and drug
combination, and the right patient population. Although much progress has been made in understanding the mechanism of disease
and in refi ning pharmaceutical properties of therapeutic agents, the attrition rates between target discovery and drug marketing
approval have been high, especially in oncology. One of the main reasons underlying this undesirable statistics is believed to be the
lack of predictive power of the model systems used in the preclinical setting. Several strategies have been employed with the aim
of improving the predictive value of the preclinical studies, such as incorporating genomic profi ling and molecular segmentation
into model selection, and enhancing the development and application of patient-derived xenograft models even during early stage
of drug discovery. This brief review will summarize some of the recent concept and practice in incorporating patient-derived
models into all stages of drug discovery process, from target to clinical development.

Key words: Animal models, drug discovery, oncology, patient-derived xenograft, translational research

Introduction research and drug development. Finally, there is a need
for bi-directional fl ow of information between preclinical
The past decades have witnessed an explosive growth and clinical investigators, and for increased collaboration
of scientifi c understanding of human diseases especially between industry, academia and regulatory agencies to
those of highly unmet medical needs. In the fi eld of ensure optimal alignment of interests and resources. This
oncology, the signifi cant progress in basic research short review will only focus on patient-derived models as
coupled with technology advancement in drug discovery a promising approach for improving the successful rate
has resulted in a signifi cant number of breakthrough
therapies with improved effi cacy and manageable of oncology programs.
toxicity. However, the overall track record of oncology Patient-derived Xenograft Models for Target
drug research and development remains one of the Identifi cation and Validation
worst in all therapeutic areas, with high attrition rate
and prohibitive cost. [1,2] Recent survey indicated that in In the past 4 decades, signifi cant progress has been
oncology drug development, close to 95% of drugs tested made in the understanding of cancer biology and
in Phase I trials failed to reach marketing authorization emergency of new classes of targeted therapies that have
stage. Signifi cant efforts have been invested in signifi cantly changed the landscape of cancer treatment
[3]
scrutinizing every aspect of the drug discovery and and management. The key to these successes has been
development process and looking for ways to improve the identifi cation and validation of cancer targets that
the success rate and effi ciency. Among all, three distinguish cancer cells and tissues from normal ones,
pivotal areas have received much attention. First, it is as elegantly summarized in the landmark articles by
commonly accepted that more refi ned, clinically relevant Hanahan and Weinberg. [4,5] Although a dauntingly
preclinical models are critical for accurately predicting complex disease, cancer can be viewed as evolved
patient response in clinical trials. Second, as we have around a number of rational commonalities, or hallmarks,
fully embraced the concept and practice of personalized necessary for tumor initiation, progression, metastasis,
medicine and targeted therapy, tumor profi ling and evasion of immune surveillance and resistance to
patient segmentation based on predictive biomarkers therapeutic intervention. These processes involve not
need to be an integral part of preclinical and clinical only genetic and epigenetic changes in the cancer cells
themselves, but also recruitment and alterations in the
Access this article online tumor-associated stroma and micro-environmental factors.
Quick Response Code: Therefore, it is conceivable that therapeutic approaches
Website: involving targeting multiple hallmark functions will
www.jcmtjournal.com
continue to be the cornerstone for targeted cancer therapy
and management. [6]
DOI:
10.4103/2394-4722.152769 Cancer target identifi cation traditionally involves the search
for differential expression and function between cancer

8 Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 1 ¦ April 15, 2015 ¦