Abstract
Co-occurrence of
Flt3ITD
and
TET2
mutations provoke an animal model of AML by epigenetic repression of Wnt pathway antagonists, including
RUNX3,
and by hyperexpression of
ID1,
encoding Wnt agonist. These affect
HOXA
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
Flt3ITD+ve,
described with a signature of repressed tumor suppressor genes, involving Wnt antagonist
RUNX3
, occurring along with
ID1
and
HOXA
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
RUNX3
/Wnt antagonist de-repression (80%) and
ID1
downregulation (85%), to a response, also preceded by profound
HOXA9
repression. Response occurred in context of concurrent
TET2
mutation/hypomorphy and
Flt3ITD+ve
mutation (83% of complete responses). Addition of Bortezomib to the combination was vital to attainment of complete response in
Flt3ITD+ve
cases exhibiting such Wnt pathway dysregulation.