Towards evolutionary guided precision medicine of acute myeloid leukemia and Fanconi anemia associated bone marrow failure

Carcinogenesis and acquisition of multidrug resistance within established cancers are both multistep evolutionary processes in which stem cells play a role. This perspective will briefly review two corresponding theoretical constructs under development. Efficiency of carcinogenesis (EOC) considers multistep carcinogenesis and predicts the effect of differing dynamics on the efficiency of generating a transformed founder cell. EOC has been applied to evaluation of the role of genetic instability in carcinogenesis. Dynamic precision medicine (DPM) is a method for providing personalized treatment sequences for cancer while explicitly considering intracancer subclonal heterogeneity and evolutionary dynamics (growth and evolutionary rates). It adapts therapy frequently and proactively by anticipating the kinetics of multidrug resistance prior to its detection, and prioritizing its prevention. Simulations suggest potential to substantially increase survival and cure rates across a broad range of clinical presentations. Both of these problems implicate very small subclones within stem cell and/or differentiated compartments, and evolution may occur over months to years. We describe novel experimental technologies for quantifying longitudinal dynamics of very large numbers of cells for prolonged periods, allowing detection and tracking of rare events and their evolution over time. We further highlight two potential applications. In Fanconi anemia, optimal treatment sequences for minimizing bone marrow failure while not increasing the risk of leukemia may be designed using EOC and DPM and tested in laboratory models. In refractory acute myeloid leukemia, high throughput molecular characterization and drug sensitivity screening of subclones is showing clinical promise, and may be further optimized with DPM.