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

Hamid Sayar1, Yan Liu2, Rui Gao2

  • 1Indiana University Melvin and Bren Simon Cancer Center, Department of Medicine, Hematology/Oncology Division, Indiana University School of Medicine, Indianapolis, IN, USA.

Oncotarget
|February 22, 2018
PubMed

Insights

The combination of targeted agents, including Sorafenib and Vorinostat, shows promise in treating relapsed/refractory acute myeloid leukemia (AML) by reversing epigenetic changes. Bortezomib addition improved complete response rates in specific AML subtypes.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Acute myeloid leukemia (AML) with FLT3-ITD and TET2 mutations exhibits a distinct epigenetic phenotype.
  • This phenotype involves Wnt pathway dysregulation, including repression of antagonists like RUNX3 and hyperexpression of agonists like ID1.
  • This epigenetic signature is also observed in adult AML patients, indicating a need for novel therapeutic strategies.

Purpose of the Study:

  • To investigate the efficacy of targeted agent combinations in relapsed/refractory AML with a specific epigenetic profile.
  • To evaluate the impact of Sorafenib (FLT3/Raf inhibitor) and Vorinostat (pan-histone deacetylase inhibitor), with or without Bortezomib, on patient response.
  • To correlate early pharmacodynamic changes with clinical outcomes in AML patients.

Main Methods:

  • Phase I clinical trials were conducted on relapsed/refractory AML patients, including those with FLT3-ITD mutations.
  • Patients received a combination of Sorafenib and Vorinostat, with some also receiving Bortezomib.
  • Pharmacodynamic analyses were performed on patient blasts to assess changes in key genes (RUNX3, ID1, HOXA9) and Wnt pathway activity.

Main Results:

  • Rapid objective remissions were observed, strongly associated with early pharmacodynamic changes.
  • De-repression of RUNX3 (80%) and downregulation of ID1 (85%) were significantly linked to treatment response.
  • Profound HOXA9 repression preceded objective responses, particularly in patients with concurrent TET2 and FLT3-ITD mutations.
  • Addition of Bortezomib was crucial for achieving complete responses in FLT3-ITD positive AML with Wnt pathway dysregulation.

Conclusions:

  • Combination therapy with Sorafenib and Vorinostat can reverse the aberrant epigenetic phenotype in AML.
  • Targeting both signal transduction and chromatin remodeling pathways offers a promising strategy for relapsed/refractory AML.
  • Bortezomib plays a vital role in achieving complete remission in specific FLT3-ITD positive AML cases.
Keywords:
AMLbortezomibepigeneticssorafenibvorinostat

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