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  • Translational Research

    Mouse Models Play Pivotal Role in Testing Combination Therapies

    pasi-janne-and-kwok-kin-wong.jpgPasi Jänne, MD, PhD and Kwok-Kin Wong, MD, PhD 

    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.

    mice-and-tumor.jpgA mouse expressing the PI3K P110α activating mutation H1047R was serially imaged using 18FDG PET-CT. Before treatment (left image), a lung tumor was visualized; the tumor dramatically reduced in size after four days of treatment with the PI3K inhibitor NVP-BEZ 235 (right image). 

    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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