PROJECT SUMMARY (ABSTRACT):
Title: Targeting FTO to treat acute myeloid leukemia
Background: Acute myeloid leukemia (AML) is a major form of leukemia with unfavorable prognosis. With
currently available therapies, over 70% of patients with AML cannot survival over five years. Thus, it is urgent to
develop more effective novel therapeutics. N6-methyladenosine (m6A) modification is the most abundant internal
modification in eukaryotic messenger RNAs, and can be removed by m6A demethylases such as FTO. Recently,
we reported that, as an m6A demethylase, FTO plays a critical oncogenic role in AML pathogenesis and drug
response (Li Z., et al. Cancer Cell. 2017). Moreover, we showed that by suppression of the FTO/m6A signaling,
R-2-hydroxyglutarate (R-2HG) displays intrinsic and broad anti-leukemia effects (Su et al. Cell. 2018). Our
unpublished data suggests that FTO may also play a role in the self-renewal of leukemia stem/initiating cells
(LSCs/LICs). Thus, our results have shown the functional importance of FTO in AML pathogenesis and drug
response, and highlight the therapeutic potential of targeting FTO and the associated RNA epitranscriptome to
treat FTO-high AMLs, which account for >60% of total AML cases and are often associated with unfavorable
prognosis. More recently, we have identified a highly effective/selective small-molecule FTO inhibitor, namely
CS-1, which shows the highest anti-leukemia efficacy amongst a panel of 213 FTO inhibitor hits, with IC50 values
around 100 nM in suppression of viability of human AML cells (primary AML cells and cell line cells). Moreover,
we have also demonstrated that this compound binds directly to FTO protein and substantially prolongs survival
of AML mice in vivo. In addition, we also showed that this FTO inhibitor can substantially sensitize FTO-high
AML cells to other therapeutic agents.
Objective/Hypothesis: Pharmacological inhibition of FTO with selective small molecule inhibitors alone or
in combination with other anti-leukemia therapeutics is an effective novel treatment approach in AML.
Specific Aims: (1) To optimize CS-1 and develop clinically applicable effective and selective FTO inhibitors;
(2) To develop effective FTO inhibitor-based therapeutic strategies to treat unfavorable-risk FTO-high AMLs; and
(3) To decipher the cellular and molecular mechanisms underlying the anti-AML efficacy of the FTO inhibitor(s).
Study Design: 1) We will develop more effective CS-1 analogs, and then assess and compare their FTO-
inhibition efficacy, selectivity, drug-like properties and therapeutic efficacy, and conduct PK/PD/toxicity studies
for the top 2 compounds (Aim 1). 2) We will further use murine AML and patient-derived xeno-transplantation
(PDX) AML models to assess the therapeutic efficacy of our top FTO inhibitor(s), alone or in combination with
other therapeutic agents, in treating unfavorable-risk FTO-high AMLs (Aim 2). 3) We will assess the effect of
genetic depletion or pharmaceutical inhibition of FTO on LSC/LIC self-renewal, and also decipher the molecular
mechanism by which FTO inhibition or FTO depletion displays potent anti-leukemia effects (Aim 3).