Figure 3

Parallel approach to clinic setting. (a) Our fitness-based staging method leverages the concept that mice health status varies despite carrying the same tumor burden. Mice which are healthier, will be able to tolerate additional drug doses during our preclinical testing phase, and by staging their fitness level, we are able to identify and deliver more drug doses to these mice to evaluate the true drug efficacy, instead of a short drug treatment due to their reduced laboratory lifespan. This method enabled us to circumvent a laboratory problem employing such preclinical models of aggressive tumors, with very short laboratory life span, hence a narrow drug delivery time window. Aggressive brain tumors have rapid clinical progression in patients. Some patients become sick more quickly while others remain in overall good health over the treatment course (for illustration purpose only, ratio of healthier versus sicker patients varies in different settings). Patients in good overall health status will be fit to receive further cycles of therapy. In contrast, sicker patients will not be able to tolerate further therapy. (b) Multiplier effect of our fitness-based approach necessitated only 4 PDOX mice in the treatment group (example shown here for Batch B experiment), yielding a net 16 mice-cycles of drug treatment. This lessened animal numbers for drug testing, hence reducing the cost of preclinical studies. Further, our approach enabled healthier mice to receive a higher cumulative drug dose over a longer time period, to evaluate the in-vivo drug efficacy against the tumor. A statistically significant improvement in progression-free and overall survival was achieved using small animal cohorts, and this effect was replicated (Batch A and Batch B).