Targeting Tumor Heterogeneity and Epithelial-Mesenchymal Plasticity (EMP) by Anti-Hallmark Combinations, Timing, and Sequencing (CTS) Strategy: Theoretical Basis, Hypothesis, and Proposed Protocol

It has been more than 25 years since the introduction of the Hallmarks of cancer by Hanahan D et al., in which they foresaw cancer research developing into a logical science based on its underlying principles. No doubt, since then, treatment approaches have evolved into personalized medicine, offering excellent benefits to a select patient population. However, three major underlying components of heterotypic interactions in cancer, i.e., the mutational evolution of cancer stem cells, epithelial-mesenchymal plasticity (EMP), and cancer remodeled extracellular matrix, remain vexing issues even today in patients who have failed therapy. Further, Epithelial-mesenchymal plasticity (EMP) is a set of to-and-fro transitions between mesenchymal & epithelial features, with interconnected signaling pathways across space and time, yielding hybrid phenotypes of evolutionary heterogeneity. The EMP, in turn, is embedded in the heterogeneous web of vascular, metabolic, mutational, and immune-suppressive reprogramming of the tumor microenvironment (TME) induced by the Hypoxia-ROS-HEF1α-TGFβ labyrinthine. Countering each hallmark of cancer requires a multiphase strategy with reprogramming/ reversion of transitional states. Incorporating epigenetic modifiers into the treatment protocol is the present frontier in oncology. Consequently, this review proposes a phased anti-hallmark-of-cancer protocol in a comprehensive Combination, Timing, and Sequencing (CTS) approach to improve outcomes while minimizing toxicities.