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Principal Investigator: Jianjun Chen
Organization: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
Fiscal Year: 2024
Award: $542,055
Funding agency: National Cancer Institute
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unpublished data suggests that FTO may also play a role in the self-renewal of leukemia stem/initiating cells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).
Terms: <11q23><AML - Acute Myeloid Leukemia><Acute Myeloblastic Leukemia><Acute Myelocytic Leukemia><Acute Myelogenous Leukemia><B23><Basic Research><Basic Science><Binding><Biology><Blast Cell><Brain Cancer><Breast Cancer><CD34><CD34 gene><CLIP-Seq><Cancer Treatment><Cancers><Cell Body><Cell Communication and Signaling><Cell Line><Cell Signaling><CellLine><Cells><Chromosome 11q23><Cyclic GMP><Cytogenetics><Data><Development><Disease Progression><Drugs><Enzyme Inhibition><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology Research><Exhibits><FLK2><FLT3><FLT3 gene><FMS-like tyrosine kinase 3><Fms-Related Tyrosine Kinase 3><Genetic><Goals><Guanosine Cyclic Monophosphate><HITS-CLIP><HPCA1><Hematopoietic Cell Tumor><Hematopoietic Malignancies><Hematopoietic Neoplasms><Hematopoietic Neoplasms including Lymphomas><Hematopoietic Tumor><Hematopoietic and Lymphoid Cell Neoplasm><Hematopoietic and Lymphoid Neoplasms><Heterograft><Heterologous Transplantation><High-throughput sequencing of CLIP cDNA library><Human><In Vitro><Intracellular Communication and Signaling><Investigators><Kidney Cancer><Kidney Carcinoma><MLL rearranged><MLL rearrangement><MLL-rearranged leukemia><Malignant Breast Neoplasm><Malignant Cell><Malignant Hematopoietic Neoplasm><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Brain><Malignant neoplasm of brain><Medical><Medication><Medicine><Messenger RNA><Mice><Mice Mammals><Modeling><Modern Man><Modification><Molecular><Molecular Interaction><Murine><Mus><Mutate><Myelogenous><Myeloid><NPM><NPM1><NPM1 gene><Non-Polyadenylated RNA><Obesity><Oncogenic><Over weight><Overweight><PK/PD><Pathogenesis><Pathway interactions><Patients><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Play><Prognosis><Property><Protein Inhibition><Protein Overexpression><Proteins><Proteomics><RNA><RNA Gene Products><RNA Seq><RNA methylation><RNA sequencing><RNAseq><Refractory><Relapse><Renal Cancer><Renal Carcinoma><Reporting><Research Design><Research Personnel><Researchers><Ribonucleic Acid><Risk><Role><STK-1 kinase><STK1><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Single Base Polymorphism><Single Nucleotide Polymorphism><Specificity><Stem Cell Tyrosine Kinase 1><Strains Cell Lines><Structure><Study Type><Talents><Testing><Therapeutic><Therapeutic Agents><Toxic effect><Toxicities><Transcript><Translational Research><Translational Science><Treatment Efficacy><Treatment Failure><Validation><Variant><Variation><Xenograft><Xenograft procedure><Xenotransplantation><acute granulocytic leukemia><acute granulocytic leukemia cell><acute myeloblastic leukemia cell><acute myelocytic leukemia cell><acute myelogenous leukemia cell><acute myeloid leukemia><acute myeloid leukemia cell><acute nonlymphocytic leukemia cell><adiposity><analog><anti-cancer><anti-cancer therapy><anti-tumor effect><antitumor effect><biological signal transduction><blood cancer><cGMP><cancer cell><cancer of blood><cancer of the blood><cancer therapy><cancer type><cancer-directed therapy><clinical applicability><clinical application><combinatorial><corpulence><crosslinking and immunoprecipitation sequencing><cultured cell line><design><designing><developmental><drug/agent><druggable target><epidemiologic investigation><epidemiology study><epitranscriptome><experience><fat and obesity-associated protein><fat mass and obesity-associated><fat mass and obesity-associated protein><fetal liver kinase-2><fetal liver kinase-3><high risk><in vivo><inhibit protein><inhibit proteins><inhibitor><innovate><innovation><innovative><intervention efficacy><leukemia><mRNA><malignancy><malignant breast tumor><manufacture><mutant><neoplasm/cancer><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapeutics><new therapy><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapeutics><novel therapy><novel therapy approach><novel therapy target><pathway><pharmaceutical><pharmacokinetics and pharmacodynamics><pharmacologic><protein inhibitions><relapse patients><response><self-renew><self-renewal><side effect><single nucleotide variant><small molecular inhibitor><small molecule><small molecule inhibitor><social role><stem><study design><success><therapeutic efficacy><therapeutically effective><therapy efficacy><therapy failure><transcriptome sequencing><transcriptomic sequencing><translation research><translational investigation><validations><xeno-transplant><xeno-transplantation>