Optimizing Adaptive Therapy Based on the Reachability to Tumor Resistant Subpopulation

SIMPLE SUMMARY: The intra-competition among tumor subpopulations is a promising target to modify and control the outgrowth of the resistant subpopulation. Adaptive therapy lives up to this principle well, but the gain of tumors with an aggressive resistant subpopulation is not superior to maximum tolerated dose therapy (MTD). How to integrate these two therapies to maximize the outcome? According to the model and system reachability, the ‘restore index’ is proposed to evaluate the timing of the transition from the treatment cycle of adaptive therapy to high-frequency administration, and to juggle the benefits of intra-competition and killing of the sensitive subpopulation. Based on the simulation and animal experiment, the effectiveness of this method in treating tumors with an aggressive resistant subpopulation has been confirmed. ABSTRACT: Adaptive therapy exploits the self-organization of tumor cells to delay the outgrowth of resistant subpopulations successfully. When the tumor has aggressive resistant subpopulations, the outcome of adaptive therapy was not superior to maximum tolerated dose therapy (MTD). To explore methods to improve the adaptive therapy’s performance of this case, the tumor system was constructed by osimertinib-sensitive and resistant cell lines and illustrated by the Lotka-Volterra model in this study. Restore index proposed to assess the system reachability can predict the duration of each treatment cycle. Then the threshold of the restore index was estimated to evaluate the timing of interrupting the treatment cycle and switching to high-frequency administration. The introduced reachability-based adaptive therapy and classic adaptive therapy were compared through simulation and animal experiments. The results suggested that reachability-based adaptive therapy showed advantages when the tumor has an aggressive resistant subpopulation. This study provides a feasible method for evaluating whether to continue the adaptive therapy treatment cycle or switch to high-frequency administration. This method improves the gain of adaptive therapy by taking into account the benefits of tumor intra-competition and the tumor control of killing sensitive subpopulation.