TY - JOUR
T1 - Consecutive epigenetically-active agent combinations act in ID1-RUNX3-TET2 and HOXA pathways for Flt3ITD+ve AML
AU - Sayar, Hamid
AU - Liu, Yan
AU - Gao, Rui
AU - Zaid, Mohammad Abu
AU - Cripe, Larry D.
AU - Weisenbach, Jill
AU - Sargent, Katie J.
AU - Nassiri, Mehdi
AU - Li, Lang
AU - Konig, Heiko
AU - Suvannasankha, Attaya
AU - Pan, Feng
AU - Shanmugam, Rajasubramaniam
AU - Goswami, Chirayu
AU - Kapur, Reuben
AU - Xu, Mingjiang
AU - Scott Boswell, H.
N1 - Funding Information:
Hamid Sayar received research funding from Bayer/ Onyx. Other authors declare no conflict of interests.
Funding Information:
This work was supported in part by Department of Veterans Affairs Merit Review Award (HSB), the Wendy Will Case fund (HS), a research grant from Bayer/Onyx (HS), stipend in memory of Dr. Gary D. Tollefson (HSB), an Department of Defense Career Development Award CA120373 (YL) and a research grant from the Elsa Pardee Foundation (YL). We would like to thank Mrs. Marilyn
Publisher Copyright:
© Sayar et al.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - AML
KW - Bortezomib
KW - Epigenetics
KW - Sorafenib
KW - Vorinostat
UR - http://www.scopus.com/inward/record.url?scp=85040680186&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85040680186&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.23655
DO - 10.18632/oncotarget.23655
M3 - Article
AN - SCOPUS:85040680186
VL - 9
SP - 5703
EP - 5715
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 5
ER -