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Advances in the preclinical testing of cancer therapeutic hypotheses

Nature Reviews Drug Discovery volume 10, pages 179–187 (2011)Cite this article

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Abstract

The genetic and epigenetic underpinnings of cancer are becoming increasingly clear owing to impressive and well-coordinated ventures occurring worldwide. As our understanding of the molecular alterations driving human cancer increases, there is an opportunity to direct the clinical application of cancer therapeutics with improved accuracy. The often empirical treatment of cancer — which was initially based on inhibiting DNA synthesis and cellular division — while having led to a number of remarkable successes, remains prone to a high rate of clinical failure that results partly from a lack of understanding of how best to implement drugs in the clinic. Consequently, it is vital that robust translational strategies be developed preclinically to both reduce failure rates in the clinic and shorten the time required to identify patient populations most likely to benefit from a given therapeutic. Here, we review both historical and current uses of preclinical model systems, being mindful that a combination of approaches will be needed to address all meritorious therapeutic hypotheses.

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Figure 1: The sensitivity of 602 cell lines to the kinase inhibitor TAE684 reveals a striking correlation with alterations in ALK.
Figure 2: The PI3K inhibitor BEZ235 regresses lung tumours bearing PI3K but not KRAS mutations.
Figure 3: Generation of chimeric mouse tumour models.

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Acknowledgements

We thank C. Emery and W. Hable for providing constructive feedback during the writing of this article.

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  1. Giordano Caponigro and William R. Sellers are at the Novartis Institutes For BioMedical Research, Oncology Research and Oncology Translational Medicine, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA,

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Correspondence to Giordano Caponigro.

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Giordano Caponigro and William R. Sellers are employees and shareholders of Novartis Pharmaceuticals.

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FURTHER INFORMATION

DTP Human Tumor Cell Line Screen

Glossary

Caretaker genes

The primary function of caretaker genes is to maintain the integrity of the genome. When mutated these genes are tumour suppressor genes, whereby their loss of function can indirectly promote tumorigenesis by increasing the rate of DNA mutation in cells. Examples of genes in this class include ATM, BRCA1/2, MLH and MSH2. P53 can act as both a caretaker and as a gatekeeper gene.

Cell Line Encyclopedia Project

A collaborative project between the Novartis Institutes for BioMedical Research and the Broad Institute in which ∼1,000 cancer cell lines are being characterized in terms of mRNA expression, copy-number alterations and point mutations. The project also includes large-scale compound sensitivity profiling.

Driver mutation

This is a genetic event in cancer that is statistically enriched across many representatives of a tumour type. It is different to a 'passenger' mutation, which may be acquired and propagated in much fewer tumours by a chance linkage with a driver mutation. Well-established druggable driver oncogenes include BCR–ABL, human epidermal growth factor receptor 2 (HER2; also known as ERBB2), KIT, platelet-derived growth factor receptor (PDGFR), EGFR and BRAF.

GI50

The drug concentration required to causes a 50% growth inhibitory effect.

NCI60

A collection of 57 cancer cell lines developed and used for high-throughput cytotoxicity assays. More than 50,000 compounds have been tested in this cell line set.

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Caponigro, G., Sellers, W. Advances in the preclinical testing of cancer therapeutic hypotheses. Nat Rev Drug Discov 10, 179–187 (2011). https://doi.org/10.1038/nrd3385

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