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Principal Investigator: Theodore Paul Braun
Organization: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2024
Award: $488,445
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT
Kinase inhibitor therapy has made a minimal impact on the clinical treatment of patients with Acute Myeloid
Leukemia (AML). We have shown that inhibition of the epigenetic regulator lysine-specific demethylase 1 (LSD1)
augments the efficacy of kinase inhibition in AML, including drugs targeting FLT3, cKIT and JAK2. This occurs
via the repression of the MYC super enhancer (MYC-SE), leading to a loss of MYC gene expression and
consequently decreased expression of a pro-proliferative gene expression program. However, we lack a
complete mechanistic understating of how kinase plus LSD1 inhibition produces this effect, or whether the drug
combination has important effects that are independent from the MYC-SE. Our long-term objective is to establish
the efficacy of kinase plus LSD1 inhibition in AML, translating this concept into new effective treatment for
patients with AML. The overall objective of this proposal is to: 1) define the mechanistic basis for drug responses
to FLT3 plus LSD1 inhibition in FLT3-mutant AML and 2) evaluate the potential of dual MEK and LSD1 inhibition
in NRAS-mutant AML. Our central hypothesis is that the suppression of MYC-target genes is an essential
mechanism of kinase plus LSD1 inhibition-mediated cell death. In Aim 1, we will investigate three possible
mechanisms for FLT3 plus LSD1 inhibition-induced suppression of MYC target genes: 1) Via inactivation of the
MYC-SE leading to decreased MYC gene expression resulting in a loss of MYC-target gene expression, 2) Via
inhibition of LSD1-dependent activation of MYC-target genes and 3) through inhibition of signaling pathways
down-stream of activated FLT3, resulting in a loss of MYC binding to the promoters of target genes. We will also
perform correlative studies investigating these mechanisms in AML patients enrolled in the FRIDA trial, receiving
FLT3 plus LSD1-inhbitor therapy. In Aim 2, we will evaluate the efficacy and mechanism of action of MEK plus
LSD1 inhibitor therapy in NRAS-mutant AML, using an integrated evaluation of chromatin and signaling pathway
dynamics. We will also employ multiple mouse models of NRAS-mutant AML including a patient-derived
xenograft model. At the completion of these studies, our expected outcomes are to 1) have identified how FLT3
plus LSD1 inhibition drives cell death in FLT3-mutant AML and 2) establish the preclinical efficacy of dual MEK
plus LSD1 inhibition in NRAS-mutant AML. These studies will provide key pre-clinical rationale for expanding
the indications for kinase plus LSD1 inhibitor to a larger proportion of patients with AML.
Terms: <AML - Acute Myeloid Leukemia><AOF2><Acute Myeloblastic Leukemia><Acute Myelocytic Leukemia><Acute Myelogenous Leukemia><Automobile Driving><Avian Myelocytomatosis Viral Oncogene Homolog><Basal Transcription Factor><Basal transcription factor genes><Binding><CD114><CD114 Antigen><CSF3R><CSF3R gene><Cell Communication and Signaling><Cell Cycle><Cell Death><Cell Division Cycle><Cell Line><Cell Signaling><CellLine><Characteristics><Chromatin><Clinical><Clinical Treatment><Clinical Trials><Colony Stimulating Factor 3 Receptor><Complex><Correlative Study><Data><Development><Disease><Disorder><Drug Combinations><Drug Synergism><Drug Targeting><Drugs><Enhancers><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Evaluation><FLK2><FLT3><FLT3 gene><FLT3 inhibitor><FMS-like tyrosine kinase 3><Fms-Related Tyrosine Kinase 3><G-CSF Receptors><GCSF Receptor><GCSFR><Gene Expression><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Alteration><Genetic Change><Genetic defect><Granulocyte Colony-Stimulating Factor Receptors><Intracellular Communication and Signaling><Investigation><JAK-2><JAK2><JAK2 gene><JAK2 protein><Janus kinase 2><KDM1A><KDM1A gene><Kinases><LSD1><Link><Lysine-Specific Demethylase 1><Lysine-Specific Demethylase 1A><MEKs><MGF protein><MGSNF protein><MYC Family Protein><MYC Protein><MYC gene><Malignant Cell><Mediating><Medication><Minority><Molecular><Molecular Interaction><Mutation><Oncogenic><Outcome><PDX model><PTK Inhibitors><Patient derived xenograft><Patients><Pharmaceutical Preparations><Phase 1b Trial><Phase Ib Trial><Phosphotransferase Gene><Phosphotransferases><Play><Protein Tyrosine Kinase Inhibitors><Refractory><Regulation><Relapse><Repression><Resistance><Role><STAT5><STAT5A><STAT5A gene><STAT5a Transcription Factor><STK-1 kinase><STK1><Sampling><Signal Pathway><Signal Transducer and Activator of Transcription 5A><Signal Transduction><Signal Transduction Systems><Signaling><Stat5 protein><Stat5a protein><Stat5alpha protein><Stem Cell Tyrosine Kinase 1><Strains Cell Lines><TK Inhibitors><Testing><Therapeutic><Transcription Factor Proto-Oncogene><Transcription factor genes><Translating><Transphosphorylases><Tyrosine Kinase Inhibitor><Tyrosine-Protein Kinase JAK2><Work><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><antileukemic activity><biological signal transduction><cancer cell><clinical translation><clinically translatable><cultured cell line><determine efficacy><developmental><driving><drug/agent><effective therapy><effective treatment><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><epigenetic profiling><epigenetically><evaluate efficacy><examine efficacy><expression subtypes><fetal liver kinase-2><fetal liver kinase-3><genome mutation><improved><inhibitor><inhibitor drug><inhibitor therapeutic><inhibitor therapy><kinase inhibitor><mammary gland factor><mammary gland-specific nuclear factor><member><molecular sub-types><molecular subsets><molecular subtypes><mouse model><murine model><mutant><myc Oncogenes><necrocytosis><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><participant enrollment><patient derived xenograft model><patient enrollment><pre-clinical><pre-clinical efficacy><preclinical><preclinical efficacy><programs><promoter><promotor><resistant><response><response to therapy><response to treatment><signal tranducer and activator of transcription 5><social role><synergism><therapeutic response><therapy response><transcription factor><treatment response><treatment responsiveness><trial regimen><trial treatment>