Mouse models for pre-clinical drug testing in leukemia

ABSTRACT

Introduction: The development of novel drugs which specifically target leukemic cells, with the overall aim to increase complete remission and to reduce toxicity and morbidity, is the most important prerequisite for modern leukemia treatment. In this regard, the current transition rate of potential novel drugs from bench to bedside is remarkably low. Although many novel drugs show promising data in vitro and in vivo, testing of these medications in clinical phase I trials is often sobering with intolerable toxic side effects leading to failure in FDA approval.

Areas covered: In this review, the authors discuss the development of murine model generation in the context of targeted therapy development for the treatment of childhood leukemia, aiming to decrease the attrition rate of progressively complex targeted therapies ranging from small molecules to cell therapy. As more complex therapeutic approaches develop, more complex murine models are needed, to recapitulate closely the human phenotype.

Expert opinion: Combining xenograft models for efficacy testing and GEMMs for toxicity testing will be a global approach for pre-clinical testing of complex therapeutics and will contribute to the clinical approval of novel compounds. Finally, this approach is likely to increase clinical approval of novel compounds.

KEYWORDS:

• Leukemia
• GEMMs
• gene therapy
• HDACi
• humanized mouse models
• targeted therapy

Article highlights

• The transition rate of potentially novel drugs from bench to bedside is remarkably low.

• An increased rate of FDA approval after phase I clinical trials is desired.

• Pre-clinical testing of drug efficacy and potential off-target activity need to be strictly evaluated before proceeding to clinical trials.

• Numerous murine models – xenograft and GEM models - have been generated to investigate novel treatment options for leukemia.

• Complex murine models, which recapitulate closely the human phenotype, are required to develop effective and safe future therapeutics.

• Combining xenograft models for efficacy and GEMMs for toxicity testing will be a global approach for pre-clinical testing of complex therapeutics.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

The authors are funded by Deutsche Krebshilfe [110997] and the Forschungskommission of the Medical faculty of Heinrich-Heine University.