The mighty mouse: genetically engineered mouse models in cancer drug development

Nature Reviews Drug Discovery | AOP, published online 18 August 2006; doi:10.1038/nrd2110REVIEWSXenograft modelXenograft mouse models of

cancer are created by

injecting homogeneous

human tumour cell lines into

immunodeficient (for

example, severe combined

immunodeficiency) mice.*Departments of Medicine

and Genetics, The Lineberger

Comprehensive Cancer

Center, The University of

North Carolina, Chapel Hill,

North Carolina

27599-7295, USA. Center for Applied Cancer

Science, Belfer Institute for

Innovative Cancer Science,

and Department of Medical

Oncology, Dana-Farber

Cancer Institute.Departments

of Medicine and Genetics,

Harvard Medical School,

Boston, Massachusetts

02115, USA.

e-mails: ron_depinho@dfci.

harvard.edu;

[e-mail]

doi:10.1038/nrd2110

Published online 18 August 2006Since Richard Nixon declared a war on cancer in 1971,

enormous resources more than US$200 billion by

one estimate1 have been invested in basic and clinical

research to eradicate malignant diseases. This represents a massive investment, but it is still dwarfed by the

economic costs of cancer over this period (estimated at

US$190 billion in the USA in 2004 alone2), and furthermore, the social and emotional impact on patients and

their families is huge. However, although the research

investments have translated into notable gains in the

long-term survival for all patients with cancer, most

patients with advanced malignancies still die within

five years of their diagnosis. This pace of progress has

led some to assert that the war on cancer has been lost,

and much ink has been devoted to the topic of why.

One claim has been that models for testing potential

anticancer therapeutics are imperfect; in particular, the

reliance on mouse models is blamed for notable failures

in translating basic science advances to clinically meaningful therapies. In this review, we address the significant

limitations, established uses and considerable promise of

murine models for cancer drug development.There is little debate about the importance of murine

models, which are the most experimentally tractable

mammalian systems, in advancing our basic understanding of cancer biology. The use of transgenic and

knockout technology has enabled several of the most

important basic scientific discoveries in cancer research

during the past two decades and will not be a focus of

this review. Moreover, it is generally acknowledged that

rodents are a vital and common fixture in pharmacokinetic, pharmacodynamic and toxicology studies of

novel therapeutic agents. However, reasonable scientists

involved in cancer drug discovery and development

disagree...