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academies
Cell Science, Stem Cell Research &
Pharmacological Regenerative Medicine
November 29-30, 2017 | Atlanta, USA
Annual Congress on
Adv cel sci tissue cul 2017 | Volume 1 Issue 2
Targeting FOXM1 in cancer
Andrei L Gartel
University of Illinois at Chicago, USA
T
he outcomes for acute myeloid leukemia (AML) have
remained abysmally poor for the past 30 years. 20-
40% of patients fail to achieve remission with induction
chemotherapy and 50 -70% of patients who achieve a
complete remission relapse within 3 years. A breakthrough in
dissecting out prognostic subgroups came with the discovery
of the nucleophosmin (NPM1) mutation in 40%-60% of CN-
AML cases. In subsequent analyses it has been shown that
AML patients with wild-type FMS-like receptor tyrosine
kinase (FLT3), bearing mutated NPM1 (
NPM1
mut
) showed
improved overall survival (OS) and relapse-free survival
(RFS). We proposed that mutated NPM1 (
NPM1
mut
) confers
this advantage in CN-AML via sequestration of FOXM1 in the
cytoplasm where FOXM1 is inactive. We have demonstrated
that FOXM1, an oncogenic transcription factor, co-localizes
with NPM in AML cells. Mutations in NPM1 resulting in its
nuclear export will drive FOXM1 to the cytoplasm where
it is inactive as a transcription factor. We have shown a
correlation between the expression of nuclear FOXM1 and
the outcome for AML patients using primary AML samples.
Stable knockdown of FOXM1 in AML KG-1 cell line resulted
in increased sensitivity to this chemotherapeutic agent This
data suggests that targeting FOXM1 in AML could increase
sensitivity to standard chemotherapy. Knockdown of NPM1
in cancer cells led to significant down-regulation of FOXM1
suggesting that NPM/FOXM1 interaction is required for
FOXM1 expression. in preliminary experiments we identified
two compounds that inhibit NPM/FOXM1 interaction
and suppress FOXM1 expression in AML cell lines. These
compounds preclude binding of NPM and FOXM1 and
modulate the suppression of FOXM1. We found that these
compounds suppress FOXM1 in a variety of human cancer
cell lines of different origin. Overall, our data validate FOXM1
as important target in human cancer and novel NPM/FOXM1
inhibitors that could be developed for cancer patients.
Speaker Biography
Andrei L Gartel is an Associate Professor in the Department of Medicine at the
University of Illinois at Chicago and is the Academic Editor of PLOS ONE. He is the
author of 89 peer-reviewed publications that include more than 20 reviews. He has
more than 10000 citations and his h-index is 39. His scientific interests include: cancer,
cell cycle, protein-protein interactions, regulation of CDK inhibitor p21 and regulation
of oncogenic transcription factors FOXM1 and c-Myc. Specifically, his lab is interested
in identification of new FOXM1 inhibitors. He received his funding from NIH, DOD and
private companies/foundations.
e:
agartel@uic.edu