Fig. 2: Longitudinal modeling of synergy is complicated by uncertainties between phases where normalization, efficacy and resistance/relapse dominate.

Synergy can be underestimated because of the normalization as well as through the occurrence of therapy resistance or relapse after the end of the treatment (areas shown in pink). The borders between these three phases can differ between models due to differences in growth speed and the temporal-spatial occurrence of resistance as well as a function of the pharmacokinetic (PK) profiles of the combination of drugs in the tumor tissue. In each drug combination experiment, the phases can therefore have a different velocity and given the underlying uncertainties, we chose to determine synergies at each time point separately as shown by the numbers on the time axis. In some cases, the humane endpoint is reached for the control groups earlier than the treated mice, which makes it in some cases necessary to extrapolate the tumor volume (dotted box).