Bridging the Foundational Versus Actionable Cycle in Cancer: Hypoxia Domino Effect and Cancer Cell Microenvironment (CCME) “Drug” Delivery

Cancer therapy evolution has always been about combinations, Timing, and Sequencing. Identifying the optimum combination by clinical trials will take an indeterminate amount of time with the “web” of effective available therapy options today. Additionally, newer targets and effective drugs are added continually, making optimum evidence-based therapy challenging to catch up with. In such a situation, revisiting the foundational aspects of cancer therapy approaches to create actionable trial scaffolds for early and definitive conclusions about the optimum treatment would be appropriate. The trial foundational platform should also allow for the incorporation of effective treatments that will come up in the future. Four fundamental changes exist in cancer development and progression, namely vasculature-metabolic-immune-phenotypic cascades. Hypoxia is the maestro orchestrating interwoven changes through the master manipulator - HIF-1 α. Hypoxia in Cancer is like spider-weaving resistant webs with the potential to overcome every therapy intervention. This review conceptualizes bridging foundational and actionable approaches in cancer therapy to provide a scaffold for stepwise Combinations, Timing, and Sequencing (CTS) strategy with early resolutions in animal/clinical trials. Fundamentally, based on the golden principle of first opportunity, it is the best time to handle and reverse the cancer process’s ramifications. A shift in focus is proposed in the present article from the Tumor Microenvironment (TME) to the Cancer Cell Microenvironment (CCME).