Functionalist Oncology to Model the Contextuality of Dynamics and Treatment in Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML) is a disease with a high degree of intra- and interpatient heterogeneity. Current treatments almost uniformly employ the standardized 7+3 regimen, which is based on cytarabine combined with an anthracycline, with long-term survival rates below 30%. Our work specifically focuses on the cytarabine component of this regimen. Functionalist oncology utilizes edge-weighted digraphs as a representational tool to model the mathematical functional interdependencies of disease factors. This methodology enables a conceptual and mechanistic analysis of key factors influencing therapeutic success, providing a framework that can be parameterized to explore patient-specific treatment responses when suitable data are available. It incorporates the oligoclonal nature of AML to perform, in principle, comprehensive cost-benefit analyses regarding the addition of individual drugs to existing treatment regimens and the number and type of chemotherapy courses to be given. Extrapolating from experimental data, we investigate the therapeutic potential and risks of SAMHD1 inhibitors in AML treatment as a proof-of-concept. We also provide a web-based interactive application to visualize hypothetical AML treatment scenarios, which can be combined with ex vivo single-cell phenotypic (gene expression), genotypic (somatic mutations), and functional (drug responses) analyses. Functionalist oncology can thus be used to generate testable hypotheses that might contribute to improving oncological decision-making, e.g., by identifying the optimal number, nature and sequence of chemotherapy blocks, including both existing AML-directed blocks and additional drugs, such as SAMHD1 inhibitors.