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Principal Investigator: Kayvan R Keshari
Organization: SLOAN-KETTERING INST CAN RESEARCH
Fiscal Year: 2024
Award: $35,552
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT (unchanged from initial application)
Acute myeloid leukemia (AML) is a genetically complex and heterogeneous set of diseases characterized by a
diverse set of mutations. Although many patients initially respond to treatment, many end up relapsing. Over the
last decade, an appreciation of the genetic diversity and clonal hierarchy in AML has opened the door to novel
therapeutic targets and therapeutic approaches to specific AML subtypes. Moreover, AML has been found to
bear unique metabolic features with therapeutic implications. Most importantly, mutations in the enzymes
isocitrate dehydrogenase (IDH1/2) have led to clinically approved drugs. However, many patients become
resistant to this therapy as well, further underscoring the need for new strategies to target dysregulated
metabolism in leukemia. Through the development of novel microcoil platforms to explore leukemia metabolism
with HP MR (Jeong et al. Science Advances 2017) we have identified a new metabolic vulnerability in the
glycolytic metabolism of leukemia (Jeong et al. Cell Metabolism 2021). This reliance on glycolytic metabolism
alters not only glucose flux to lactate, but also one-carbon flux through the serine pathway, which facilitates the
metabolism of glutamine. Moreover, we found that genetically targeting or pharmacologically inhibiting the
enzyme that mediates flux through this pathway (PHGDH) capitalizes on a new vulnerability in these cells.
Importantly, this targeting does not affect normal hematopoietic cell growth. Thus, building upon extensive
collaboration between our labs and ample preliminary data, we aim to employ innovative approaches to study
metabolism (Keshari Lab), including by developing non-invasive probes to measure changes in glycolysis and
oxidative stress with hyperpolarized magnetic resonance imaging. This metabolism will be characterized in well-
defined models of AML (Kharas Lab), with both genetic and pharmacological modulation, in order to develop a
strategy to assess leukemia-stem-cell-driven AML metabolism and the inhibition of serine metabolism.
Altogether, these studies will result in new mechanistic insights and novel cancer therapies.
Terms: <3-phosphoglycerate dehydrogenase><3-phosphoglycerate-NAD+ 2-oxidoreductase><AML - Acute Myeloid Leukemia><Abnormal Assessment of Metabolism><Acute Myeloblastic Leukemia><Acute Myelocytic Leukemia><Acute Myelogenous Leukemia><Address><Anabolism><Automobile Driving><Biological Markers><Cancer Treatment><Cancers><Carbohydrates><Carbon><Cell Body><Cell Compartmentation><Cell Compartmentations><Cell Line><CellLine><Cells><Cellular Expansion><Cellular Growth><Cellular Metabolic Process><Clinical><Collaborations><Companions><Complex><D-3-phosphoglycerate dehydrogenase><D-Glucose><Data><Dependence><Development><Dextrose><Diet><Disease><Disorder><Drugs><Environment><Enzyme Gene><Enzyme Inhibition><Enzymes><FLK2><FLT3><FLT3 gene><FMS-like tyrosine kinase 3><Fms-Related Tyrosine Kinase 3><Future><Genetic><Genetic Alteration><Genetic Change><Genetic Diversity><Genetic Variation><Genetic defect><Gln><Glucose><Glutamine><Glycolysis><Goals><Granulocytic Leukemia><Hematopoietic><Heterogeneity><Human><Image><Intermediary Metabolism><Isocitrate Dehydrogenase><Isotopes><Knowledge><L-Glutamine><L-Serine><Leukemic progenitor and stem cell><Link><Lipids><MALD-MS><MALDI><MALDI-MS><MLL-AF9><MLL/AF9 AML><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance><Magnetic Resonance Imaging><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Measures><Mediating><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medication><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolic Studies><Metabolism><Metabolism Studies><Mice><Mice Mammals><Modeling><Modern Man><Motivation><Murine><Mus><Mutation><Myelocytic Leukemia><Myelogenous Leukemia><Myeloid Leukemia><NMR Imaging><NMR Tomography><Non-Lymphoblastic Leukemia><Non-Lymphocytic Leukemia><Nonlymphoblastic Leukemia><Nonlymphocytic Leukemia><Nuclear Magnetic Resonance Imaging><Nutrient><Organism><Oxidation-Reduction><Oxidative Stress><Oxidative Stress Induction><Pathogenesis><Pathway interactions><Patients><Pharmaceutical Preparations><Phosphoglycerate dehydrogenase><Phosphoglycerate oxidoreductase><Progenitor Cells><Publishing><Pyruvate><Q Levoglutamide><Q. Levoglutamide><Redox><Relapse><Research><Resistance><Role><STK-1 kinase><STK1><Sampling><Science><Serine><Sorting><Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization><Spectroscopy, Mass, Matrix-Assisted Laser Desorption-Ionization><Stem Cell Tyrosine Kinase 1><Stem Cell like><Strains Cell Lines><Therapeutic><Translating><Visualization><Work><Zeugmatography><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><anti-cancer therapy><bio-markers><biologic marker><biomarker><biosynthesis><cancer cell metabolism><cancer metabolism><cancer therapy><cancer-directed therapy><cell growth><cell metabolism><cellular metabaolism><chemotherapy><cultured cell line><customized therapy><customized treatment><dehydroascorbate><design><designing><developmental><diets><driving><drug/agent><fetal liver kinase-2><fetal liver kinase-3><genome mutation><hemopoietic><human cord blood CD34+ cell><imaging><imaging approach><imaging based approach><imaging biomarker><imaging marker><imaging mass spectrometry><imaging-based biological marker><imaging-based biomarker><imaging-based marker><in vivo><individualized medicine><individualized patient treatment><individualized therapeutic strategy><individualized therapy><individualized treatment><innovate><innovation><innovative><insight><leukemia><leukemic progenitor><leukemic stem cell><living system><malignancy><mass spectrometric imaging><matrix assisted laser desorption ionization><metabolic abnormality assessment><metabolic imaging><myeloid granulocytic leukemia><myelosis><neoplasm/cancer><new approaches><new drug target><new drug treatments><new druggable target><new drugs><new marker><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 approaches><novel biomarker><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel marker><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapeutics><novel therapy><novel therapy approach><novel therapy target><overexpress><overexpression><oxidation reduction reaction><pathway><patient specific therapies><patient specific treatment><pharmacologic><progenitor biology><progenitor cell biology><programs><resistance to therapy><resistant><resistant to therapy><response><response to therapy><response to treatment><social role><stem and progenitor biology><stem cell biology><stem cell characteristics><stem cells><stemness><stress state><tailored medical treatment><tailored therapy><tailored treatment><therapeutic agent development><therapeutic development><therapeutic resistance><therapeutic response><therapy resistant><therapy response><tool><treatment planning><treatment resistance><treatment response><treatment responsiveness><tumor cell metabolism><tumor metabolism><unique treatment>