TY - JOUR
KW - Antineoplastic Agents
KW - Data Interpretation, Statistical
KW - Drug Discovery
KW - Drug Evaluation, Preclinical
KW - Humans
KW - Molecular Targeted Therapy
KW - Neoplasms
KW - Reproducibility of Results
KW - Research Design
KW - Signal-To-Noise Ratio
AU - William G. Kaelin
AB - An alarming number of papers from laboratories nominating new cancer drug targets contain findings that cannot be reproduced by others or are simply not robust enough to justify drug discovery efforts. This problem probably has many causes, including an underappreciation of the danger of being misled by off-target effects when using pharmacological or genetic perturbants in complex biological assays. This danger is particularly acute when, as is often the case in cancer pharmacology, the biological phenotype being measured is a 'down' readout (such as decreased proliferation, decreased viability or decreased tumour growth) that could simply reflect a nonspecific loss of cellular fitness. These problems are compounded by multiple hypothesis testing, such as when candidate targets emerge from high-throughput screens that interrogate multiple targets in parallel, and by a publication and promotion system that preferentially rewards positive findings. In this Perspective, I outline some of the common pitfalls in preclinical cancer target identification and some potential approaches to mitigate them.
BT - Nature Reviews. Cancer
DA - 2017-07
DO - 10.1038/nrc.2017.32
IS - 7
LA - eng
N2 - An alarming number of papers from laboratories nominating new cancer drug targets contain findings that cannot be reproduced by others or are simply not robust enough to justify drug discovery efforts. This problem probably has many causes, including an underappreciation of the danger of being misled by off-target effects when using pharmacological or genetic perturbants in complex biological assays. This danger is particularly acute when, as is often the case in cancer pharmacology, the biological phenotype being measured is a 'down' readout (such as decreased proliferation, decreased viability or decreased tumour growth) that could simply reflect a nonspecific loss of cellular fitness. These problems are compounded by multiple hypothesis testing, such as when candidate targets emerge from high-throughput screens that interrogate multiple targets in parallel, and by a publication and promotion system that preferentially rewards positive findings. In this Perspective, I outline some of the common pitfalls in preclinical cancer target identification and some potential approaches to mitigate them.
PY - 2017
SP - 425
EP - 440
T2 - Nature Reviews. Cancer
TI - Common pitfalls in preclinical cancer target validation
VL - 17
SN - 1474-1768
ER -