Co-occurrence ofFlt3ITDandTET2mutations provoke an animal model of AML by epigenetic repression of Wnt pathway antagonists, includingRUNX3,and by hyperexpression ofID1,encoding Wnt agonist. These affectHOXAover-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, includingFlt3ITD+ve,described with a signature of repressed tumor suppressor genes, involving Wnt antagonistRUNX3, occurring along withID1andHOXAover-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 linkingRUNX3/Wnt antagonist de-repression (80%) andID1downregulation (85%), to a response, also preceded by profoundHOXA9repression. Response occurred in context of concurrentTET2mutation/hypomorphy andFlt3ITD+vemutation (83% of complete responses). Addition of Bortezomib to the combination was vital to attainment of complete response inFlt3ITD+vecases exhibiting such Wnt pathway dysregulation.
Pharmacology, Toxicology and Pharmaceutical Science
1
9%
Agricultural and Biological Sciences
1
9%
Unknown
2
18%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 22 February 2018.
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