Modeling Differentiation Therapy for Cancer-Stem-Cell-Driven Tumors

J. FOTINÓS; L. BARBERIS; C.A. CONDAT

Conferencia; DSABNS; 2022

Many solid tumors have been found to be driven by chemo- and radiotherapy-resistantcancer stem cells (CSCs). A possible therapeutic avenue in these cases consists of usinga differentiating agent (DA) to force the differentiation of the CSCs and then applyingconventional therapeutic courses to eliminate the differentiated cancer cells (DCCs). Todescribe the effects of a DA that reprograms cancer stem cells into DCCs, we adapt a differential equation model developed to investigate tumorspheres, which are assumed to beformed by two jointly evolving cancer cell subpopulations, CSCs and DCCs. We analyzethe mathematical properties of the model, finding the equilibria and their stability. Wealso present numerical solutions and phase diagrams to describe the system evolution andthe therapy effects, characterizing the DA strength by a parameter adif . To obtain realistic predictions, we choose the other model parameters to be those determined previouslyfrom fits to various experimental datasets ([1, 2, 3]).In the case of a tumor that exhibits intraspecific competition and interspecific cooperation between the subpopulations ([1]), low adif values lead to their stable coexistence,with the final tumor size decreasing with adif , but there is a critical value above which theend state does not contain any stem cells. For growth on a hard substrate ([2]), the CSCscooperate, and the tumor grows without limits for small doses of the DA (low adif ). Themain effect of the therapy is to delay growth, but if exceeds a critical threshold, the tumorreaches a state formed solely by DCCs. We also studied the consequences of modifyingthe therapy starting time. In summary, our model shows how the effects of a differentiation therapy depend critically not only on the dosage and timing of the drug applicationbut also on the tumor nature and its environment.