High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response.

Nat Med 2015 Nov 19;21(11):1318-25. Epub 2015 Oct 19.

Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.

Profiling candidate therapeutics with limited cancer models during preclinical development hinders predictions of clinical efficacy and identifying factors that underlie heterogeneous patient responses for patient-selection strategies. We established ∼1,000 patient-derived tumor xenograft models (PDXs) with a diverse set of driver mutations. With these PDXs, we performed in vivo compound screens using a 1 × 1 × 1 experimental design (PDX clinical trial or PCT) to assess the population responses to 62 treatments across six indications. We demonstrate both the reproducibility and the clinical translatability of this approach by identifying associations between a genotype and drug response, and established mechanisms of resistance. In addition, our results suggest that PCTs may represent a more accurate approach than cell line models for assessing the clinical potential of some therapeutic modalities. We therefore propose that this experimental paradigm could potentially improve preclinical evaluation of treatment modalities and enhance our ability to predict clinical trial responses.

Download full-text PDF

Source
http://www.nature.com/articles/nm.3954
Publisher Site
http://dx.doi.org/10.1038/nm.3954DOI Listing
November 2015
150 Reads

Publication Analysis

Top Keywords

clinical trial
12
predict clinical
8
drug response
8
patient-derived tumor
8
clinical
6
driver mutations
4
mutations pdxs
4
pdxs performed
4
potential therapeutic
4
performed vivo
4
models assessing
4
experimental design
4
screens experimental
4
compound screens
4
vivo compound
4
assessing clinical
4
clinical potential
4
therapeutic modalities
4
∼1000 patient-derived
4
modalities propose
4

References

(Supplied by CrossRef)

J Arrowsmith et al.
Nat. Rev. Drug Discov. 2013

J Arrowsmith et al.
Nat. Rev. Drug Discov. 2011

JA DiMasi et al.
Clin. Pharmacol. Ther. 2013

SM Paul et al.
Nat. Rev. Drug Discov. 2010

JJ Tentler et al.
Nat. Rev. Clin. Oncol. 2012

D Siolas et al.
Cancer Res. 2013

E Rosfjord et al.
Biochem. Pharmacol. 2014

M Hidalgo et al.
Cancer Discov. 2014

A Bertotti et al.
Cancer Discov. 2011

G Migliardi et al.
Clin. Cancer Res. 2012

J Barretina et al.
Nature 2012

Similar Publications