The APL paradigm and the "co-clinical trial" project

Abstract

Tremendous advances in technologies have allowed the attainment of powerful insights into the molecular and genetic determinants that drive human cancers. However, this acquired knowledge has been translated into effective therapeutics very slowly, in part due to difficulty in predicting which drug or drug combination is likely to be effective in the complex mutational background of human cancers. To address this difficulty we have proposed and initiated the "co-clinical trial" project, in which we exploit mouse models that faithfully replicate the variety of mutational events observed in human cancers, to conduct preclinical trials that parallel ongoing human phase I/II clinical trials. Here, we focus on concepts relevant to the application of this novel paradigm and the essential components required for its implementation to ultimately achieve the rational and rapid development of new therapeutic treatments.

Figure 1. Modeling APL in the mouse

Transgenic mice, in which the human PML-RARα fusion gene is under the control of the regulatory elements of the myeloid/promyelocytic specific cathepsin-G gene, develop leukemias with classic APL features.

Figure 2. Preclinical trials in mouse models of APL

A, mouse models of APL respond differentially to As₂O₃. PLZF-RARα leukemia proved resistant to therapy as it was resistant to RA as single agent. By contrast, PML-RARα leukemia proved exquisitely sensitive to As₂O₃, which triggers the degradation of the fusion protein, suggesting that this drug could be used successfully in large-scale clinical trials. B, treatment of PML-RARα mice with RA and As₂O₃ in combination leads to a longer lasting remission compared to the treatment with RA alone.

Figure 3. The co-clinical trial project

Synchronizing preclinical with clinical trials to be run in parallel in human patients and mouse models, either GEM models (1) or human xenograft models (2), will allow real-time integration of information.

Figure 4. Co-clinical trials in patients and in mouse models of human cancer

The same drug and exactly the same protocol will be utilized in mouse models and human patients. Data will be accrued and analyzed in parallel toward disease stratification in primary tumors as well as in acquired treatment resistance.

Figure 5. Critical components of a co-clinical center

Fundamental components of the co-clinical effort (in red) and their relationship with the infrastructures and pharmaceutical companies.