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3682 A Novel Isoflavone, ME-344, Targets the Cytoskeleton in Acute Myeloid Leukemia

Molecular Pharmacology and Drug Resistance in Myeloid Diseases
Program: Oral and Poster Abstracts
Session: 604. Molecular Pharmacology and Drug Resistance in Myeloid Diseases: Poster III
Monday, December 7, 2015, 6:00 PM-8:00 PM
Hall A, Level 2 (Orange County Convention Center)

Danny V Jeyaraju1*, Rose Hurren1*, Xiaoming Wang1*, Neil MacLean1*, Marcela Gronda1*, Craig T Jordan, PhD2, Mark D. Minden, MD, PhD3, Guri Giaever4* and Aaron D. Schimmer, MD, PhD5

1Princess Margaret Cancer Centre, Toronto, ON, Canada
2Division of Hematology, University of Colorado School of Medicine, Aurora, CO
3Princess Margaret Cancer Centre, University Health Network, Leukemia Program, Division of Medical Oncology and Hematology, Toronto, ON, Canada
42. Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada
5Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

The isoflavone ME-344 is a potent anti-cancer agent with preclinical efficacy in solid tumors in vitro and in vivo. In a recently completed phase I clinical trial in patients with refractory solid tumors, ME-344 was well tolerated and clinical responses in refractory patients were observed. ME-344 has been shown to reduce mitochondrial ATP generation in a tumor selective manner, though other potential activities have not been fully defined. In addition, the preclinical efficacy of ME-344 in leukemia has not been established. Therefore, we investigated the anti-leukemic properties and the mechanism of action of ME-344.

We treated a panel of 7 leukemia cell lines with increasing concentrations of ME-344, and measured cell growth and viability. ME-344 was cytotoxic to the 7 leukemia cell lines with an IC50 in the range of 70-260 nM. In addition, ME-344 induced preferential death in primary AML patient samples over normal hematopoietic cells. In an OCI-AML2 xenograft model, ME-344 reduced tumor growth by up to 95% of control without evidence of toxicity.

Mechanistically, as reported in studies in solid tumors, ME-344 increased mitochondrial ROS generation in leukemic cells. However, antioxidant treatment did not rescue cell death, suggesting that ME-344 has additional targets beyond the mitochondria. To identify additional targets of ME-344, we conducted haplo-insufficiency profiling in S.cerevisiae to identify genes whose heterozygous deletion confers increased sensitivity to ME-344. The top hits from the screen were genes involved in cytoskeletal organization. Therefore, we tested the effects of ME-344 on actin and tubulin polymerization in cell free assays. While ME-344 did not inhibit actin polymerization, it inhibited tubulin polymerization by interacting near the colchicine-binding site and at a site distinct from vinca alkaloids. Furthermore, cells resistant to tubulin inhibitors due to tubulin point mutations were also resistant to ME-344. Finally, we showed that ME-344 synergizes with vinblastine in leukemia cells. Thus, our study demonstrates that ME-344 displays preclinical efficacy in leukemia through a mechanism at least partly related to targeting tubulin polymerization.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH