Abstract The paper presents a formal hierarchical theory of carcinogenesis (the NOAH6 model) that interprets disease as a consequence of loss of multilayer regulation. The model is based on a fractal principle according to which the main regulatory system of the organism (R0–R5) contains within itself complete subsystems of identical structure, whereby the cellular level (R5 of the main system) is defined as a complete cellular regulatory subsystem (micro-NOAH6). Through a detailed analysis of the mechanism of action of Barbacid’s triple therapy (daraxonrasib, afatinib, SD36) in a mouse model of PDAC, it is shown that complete and durable tumor regression without the emergence of resistance is not a consequence of therapy strength, but of simultaneous hierarchical closure of multiple regulatory layers within that cellular subsystem. This leads to collapse of the pathological regulatory regime and re-locking of the archaic algorithm of survival and proliferation. The paper further resolves the mouse–human translational paradox by showing that in mice carcinogenesis arises as a bottom-up disturbance limited to the R5 layer with stable higher layers of the main system, whereas in humans carcinogenesis is often a top-down consequence of long-term destabilization of higher regulatory layers. Because of this, isolated closure of R5 in humans leads only to temporary remission and a structurally necessary relapse. The analysis shows that the hierarchical structure of the NOAH6 model is not only theoretically consistent, but also empirically validated, and introduces the criterion of regulatory completeness as a necessary condition for durable cancer remission.
Zakir Causevic (Mon,) studied this question.