MetabolicandGeneticHeterogeneityinCancer Targetingglucosemetabolismincancerisanattractivetherapeuticarea,buteffortstodevelopsuccessful glycolytic inhibitors have failed. A major barrier in the cancer metabolism field is a systems-level understanding of the differential regulation of glycolysis that results from metabolic rewiring. This limitationpromptedtheinvestigationtodeterminewhethermetaboliccontrolcanbeexploitedfortherapy. ThehypothesisoftheF99phaseisthatrationaltargetingofpivotalenzymesthatdifferentiallyregulate centralcarbonmetabolismincancercanresultinanti-tumorefficacyandcharacterizationofresistance mechanismstoglycolysisinhibitioncanadvancethedevelopmentofcombinationtherapy.Toaddress thishypothesis,Aim1characterizestheroleoftwoimportantenzymesincentralcarbonmetabolism,3- phosphoglyceratedehydrogenase(PHGDH)andglyceraldehyde-3-phosphatedehydrogenase(GAPDH) andhowtheseenzymescanbetargetedforcancertherapy.Sub-aim1.1usesCRISPR/Cas9mediated PHGDHknockout(KO)tovalidatetheselectivityandactivityoftwonovelallostericPHGDHinhibitors. Sub-aim1.2usesquantitativedeterminantsoftheWarburgEffect(WE)torevealGAPDHasarational therapeutictarget,andcomparativemetabolomicstonominateKAasapotentGAPDHinhibitorinhighly glycolyticcells,togetheruncoveringmetabolicpredictorsofdrugresponsetoGAPDHinhibition.These findingscontributetoashiftingparadigminthecurrentunderstandingofmetaboliccancertherapyand show the potential use of metabolic predictors, rather than genetic determinants, to predict response.
Aim 2 will seek to characterize the resistance mechanisms to GAPDH inhibition in order to develop combinationtherapyandbetterunderstandtherequirementsoftheWE.KA-sensitivecellswillbemade resistant and a lentiviral CRISPR/Cas9 sgRNA library loss-of-function screen will be employed to determine the metabolic enzymes driving resistance. The outcome will result in characterization of resistancedevelopmenttoglucosemetabolisminhibitionandthemechanismbywhichtheWEoccurs. Inaddition,sincetumorheterogeneitylargelycontributestolimitationsindrugtargeting,thereisanurgent need to better characterize the molecular determinants of microenvironment formation. The interplay amongenvironmentalfactors,genetics,andepigeneticshaverecentlybeenappreciated.Thehypothesis oftheK00phaseisthatadynamiccross-talkexistsbetweenoncogenicandepigeneticnetworksandis governedbytissueorigin.
Aim3 willexaminetheroleofoncogenicdriversandepigeneticregulatorsat different stages of cancer progression in different microenvironment settings to unravel the molecular componentscontributingtotumorheterogeneity.Theoutcomewillestablishabetterunderstandingof therelationshipbetweentumorheterogeneityandtherapeuticresponse.
Therewiringofmetabolicnetworksincancerishighlyintertwinedwithchangeswithinthegeneticand epigeneticlandscape,whichvariesamongdifferenttumorandtissuetypesandcanshapetherapeutic response. This project aims to elucidate the mechanisms by which metabolic alterations influence therapeuticresponseandresistance,andhowthecrosstalkamongmetabolic,genetic,andepigenetic factorscaninfluencethefateofcancerdevelopment.Theimplicationsofthesefindingsarecrucialfor advancement in precision medicine and for understanding the molecular mechanisms governing heterogeneityinthetumormicroenvironment.
| Reid, Michael A; Allen, Annamarie E; Liu, Shiyu et al. (2018) Serine synthesis through PHGDH coordinates nucleotide levels by maintaining central carbon metabolism. Nat Commun 9:5442 |
| Wang, Qian; Liberti, Maria V; Liu, Pei et al. (2017) Rational Design of Selective Allosteric Inhibitors of PHGDH and Serine Synthesis with Anti-tumor Activity. Cell Chem Biol 24:55-65 |
| Liberti, Maria V; Dai, Ziwei; Wardell, Suzanne E et al. (2017) A Predictive Model for Selective Targeting of the Warburg Effect through GAPDH Inhibition with a Natural Product. Cell Metab 26:648-659.e8 |
| Liberti, Maria V; Locasale, Jason W (2016) The Warburg Effect: How Does it Benefit Cancer Cells? Trends Biochem Sci 41:211-218 |
