%0 Journal Article %A Jill A. Gallaher %A Pedro M. Enriquez-Navas %A Kimberly A. Luddy %A Robert A. Gatenby %A Alexander R. A. Anderson %T Adaptive vs continuous cancer therapy: Exploiting space and trade-offs in drug scheduling %D 2017 %R 10.1101/128959 %J bioRxiv %P 128959 %X The treatment of advanced cancers has greatly benefited from the introduction of new agents, such as targeted therapy and checkpoint inhibitors, to supplement or bypass conventional therapies. However, even the most effective therapy usually fails over time as cancer cells are able to deploy a wide range of molecular and micro environmental resistance strategies. Here we propose that, while molecular dynamics largely govern response and resistance to therapy, evolutionary dynamics determine survival and proliferation of treatment-resistant cells. We hypothesize that understanding these evolutionary interactions may identify strategies to delay or prevent proliferation of the resistant population using conventional therapies thus prolonging time to recurrence.Here we use an off-lattice, agent-based framework to model competition among sensitive and resistant populations during therapy in a spatially competitive resource-limited tumor micro environment. Our model applies a classic evolutionary trade-off between fecundity (cellular proliferation) and survivorship (drug sensitivity). We simulate the application of an anti-proliferative drug on varying ratios of mixed sensitive and resistant cells using two general treatment strategies: a continuous schedule of maximum tolerated dose or an evolution-informed schedule that incorporates dose modulation and treatment vacations to sustain control of the tumor through competition between sensitive and resistant cell populations. We find tumors consisting only of sensitive cells can be cured with continuous treatment, but the presence of any significant population of resistant cells will lead to eventual recurrence. We identify two treatment strategies that control heterogeneous tumors: one emphasizes continuous dose modulation, and the other relies on treatment vacations. Both strategies control tumors over a wide range of resistant/sensitive population ratios but the average dose given is significantly lower with dose modulation while a more vacation-oriented schedule can control more aggressive tumors. %U https://www.biorxiv.org/content/biorxiv/early/2017/05/30/128959.full.pdf