Figure 5.

The use of GEM models. The use of GEM models for the development of SMO inhibitors followed a multi-step path that serves as a guideline for future drug development. Step I involves determining the level of inhibitor required to block the target in spontaneous tumours in vivo. This required the use of quantitative biomarkers as a read-out of pathway activity. Step II measures the consequences of target inhibition in terms of tumour growth. Step III assesses whether inhibition of tumour growth results in increased lifespan. Step IV represents follow-up studies to refine dosing regimens, identify drug-resistance mechanisms, explore potential co-treatments and investigate side effects.