Targeting FLT3-ITD AML: The Synergistic Effect of GMI-1359 in Enhancing Chemotherapy Outcomes

The FLT3 gene mutation, specifically ITD, is a common cause of acute myeloid leukemia (AML) and a promising target for treatment. While FLT3 inhibitors like sorafenib have shown efficacy in reducing leukemia cells in the blood, they have limited effects on leukemic stem cells in the bone marrow. The bone marrow environment, rich in cytokines and adhesion molecules, such as CXCR4 and E-selectin, offers protection to AML cells from chemotherapy. Sorafenib treatment has been observed to increase CXCR4 levels in FLT3-mutated cells. Leukemia cells can also activate endothelial cells, leading to their adhesion and protection from chemotherapy.

A dual antagonist of CXCR4 and E-selectin, GMI-1359, was evaluated for its potential to target FLT3-ITD AML cells. The study found that CXCR4 expression was elevated in AML cell lines, especially under hypoxic conditions that mimic the bone marrow environment. FLT3-ITD cells expressed functional E-selectin ligands, with CD44 levels increasing under hypoxic conditions. GMI-1359 was found to significantly reduce leukemic cell adhesion to mesenchymal stem cells and endothelial cells, even in the presence of TNFa, which induces E-selectin expression.

In vivo studies in mice demonstrated that the combination of GMI-1359 and chemotherapy significantly improved survival rates compared to controls or chemotherapy alone. GMI-1359 alone did not show significant effects. The drug also appeared to disrupt the protective tumor microenvironment, mobilizing AML cells from the bone marrow niche.

Disclosures indicate that Zhang received research funding from Karyopharm, and both Fogler and Magnani have affiliations with GlycoMimetics, Inc., including employment, equity ownership, and board or advisory committee membership.