Consecutive epigenetically-active agent combinations act in ID1-RUNX3-TET2 and HOXA pathways for Flt3ITD+ve AML.

Co-occurrence of and mutations provoke an animal model of AML by epigenetic repression of Wnt pathway antagonists, including and by hyperexpression of encoding Wnt agonist. These affect over-expression and treatment resistance. A comparable epigenetic phenotype was identified among adult AML patients needing novel intervention. We chose combinations of targeted agents acting on distinct effectors, at the levels of both signal transduction and chromatin remodeling, in relapsed/refractory AML's, including described with a signature of repressed tumor suppressor genes, involving Wnt antagonist , occurring along with and over-expressions. We tracked patient response to combination of Flt3/Raf inhibitor, Sorafenib, and Vorinostat, pan-histone deacetylase inhibitor, without or with added Bortezomib, in consecutive phase I trials. A striking association of rapid objective remissions (near-complete, complete responses) was noted to accompany induced early pharmacodynamic changes within patient blasts in situ, involving these effectors, significantly linking /Wnt antagonist de-repression (80%) and downregulation (85%), to a response, also preceded by profound repression. Response occurred in context of concurrent mutation/hypomorphy and mutation (83% of complete responses). Addition of Bortezomib to the combination was vital to attainment of complete response in cases exhibiting such Wnt pathway dysregulation.