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J Med Oncl Ther 2017 Volume 2 | Issue 3
International Conference on
Oncology and Cancer Therapeutics
October 30- November 01, 2017 | Chicago, USA
Targeting FOXM1 in cancer
Andrei L Gartel
UIC, 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 major
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
(NPM1mut) showed improved overall survival (OS) and
relapse-free survival (RFS). We proposed that mutated
NPM1 (NPM1mut) 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 result in its nuclear export which 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, PhD, 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