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Targeting FTO to treat acute myeloid leukemia

Award Number: R01CA243386
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Targeting FTO to treat acute myeloid leukemia - 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 Our unpublished data suggests that FTO may also play a role in the self-renewal of leukemia stem/initiating cells (LSCs/LICs).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).


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $542,055 )
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	001	5	4/16/2024	NON-COMPETING CONTINUATION	$28,529
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	5	11/13/2023	NON-COMPETING CONTINUATION	$513,526
														Subtotal = $542,055

Issue Date FY: 2023 ( Subtotal = $558,632 )
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	001	4	3/20/2023	NON-COMPETING CONTINUATION	$45,603
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	4	11/16/2022	NON-COMPETING CONTINUATION	$513,029
														Subtotal = $558,632

Issue Date FY: 2022 ( Subtotal = $558,898 )
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	001	3	5/13/2022	NON-COMPETING CONTINUATION	$45,625
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	3	11/24/2021	NON-COMPETING CONTINUATION	$513,273
														Subtotal = $558,898

Issue Date FY: 2021 ( Subtotal = $569,941 )
2021	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	001	2	1/21/2021	NON-COMPETING CONTINUATION	$28,497
2021	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	2	11/4/2020	NON-COMPETING CONTINUATION	$541,444
														Subtotal = $569,941

Issue Date FY: 2020 ( Subtotal = $569,670 )
2020	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	001	1	1/24/2020	NEW	$13,728
2020	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	1	11/19/2019	NEW	$555,942
														Subtotal = $569,670

Grand Total All Awards = $2,799,196

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Targeting FTO to treat acute myeloid leukemia

Award Number: R01CA243386

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/01/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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