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Sophisticated animal models, like the mice genetically
engineered by Kwok-Kin Wong, MD, PhD, play numerous supporting roles in
translational research: revealing whether particular genetic
alterations are tumorigenic, informing the selection of patients
for targeted therapies already developed, and providing another
level of preclinical screening and validation, besides cell lines,
to hasten the development of new drugs for patients.
Increasingly, as clinicians inch closer to defining a patient's
cancer based on their genotype – or, at least, on their known
oncogene status – mouse models that recapitulate the genetic
complexity of human cancers are taking center stage in
translational research. "Figuring out which specific combination of
targeted therapies works best for which genotypes will become
crucial in personalized medicine," asserts Wong, whose research
focuses on lung cancer.
Yet the number of patients genetically qualified for such
combination studies is small and the process prohibitively
time-consuming and expensive, he explains. Complex animal models,
however, which carry several mutations that collectively lead to
cancer, offer an elegant and pragmatic platform in which to test
myriad targeted compounds simultaneously, says Wong, whose genetic
engineering technique can be readily adapted to create models of
any cancer type. "When we mix mutations in the mouse, we can study
in a meaningful manner how these impact or attenuate response to
different therapies." He and colleagues are now testing the
combination of a PI3K inhibitor and a MEK inhibitor in mice whose
lung tumors harbor K-ras mutations and concurrent loss of
a tumor suppressor, such as p53 or Lkb1.
"Our preclinical studies may determine whether a drug is likely
to be efficacious and therefore a good candidate for a clinical
trial," adds Wong. "That's the power of these genetically
engineered mouse models: helping us sort out which compounds we
should bring to patients."
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