Akeyhallmarkofhumancanceriscancer-specificmetabolicrewiring.Notably,thisareaofresearchhasgained renewedattentioninthelastdecadeafterseveralstudiesdemonstratedthatkeyoncogenesinhumancancer, such as AKT, KRas, MYC or NOTCH1, have differential and specific effects on primary cellular metabolism, leadingtothehypothesisthatselectivetargetingofthoseroutesmightbeanattractivetherapeuticapproach.In thiscontext,IrecentlyidentifiedglutaminolysisasacriticalpathwayinNOTCH1-drivenT-lineageacute lymphoblasticleukemia(T-ALL),ahematologicalmalignancywhererelapsesoccurinupto20%ofpediatric and50%ofadultpatients,whoultimatelysuccumbtorefractorydisease.Importantly,inhibitionofglutaminolysis genetically,viadeletionofglutaminase(Gls),orpharmacologically,usingGlsinhibitors,resultsinanti-leukemic effectsandishighlysynergisticwithanti-NOTCH1therapies.Notably,Glsselectiveinhibitorsarecurrentlybeing explored in clinical trials for hematological malignancies, and glutaminolysis has also been proposed as a therapeutictargetinavarietyofsolidtumors.However,theroleofglutamineinvivoisstillnotwellunderstood and Gls-deficient T-ALLs eventually progress, underscoring the need to understand the mechanisms of relapse. My preliminary data suggests that glutamine-derived carbon might feed into the TCA cycle and Gls- deficient T-ALLs might still use glutamine even in the absence of glutaminase. Moreover, my preliminary data points to a role of glutaminase in stemness. Therefore, this research proposal seeks to: 1) dissect the role of glutaminase in T-ALL in vivo and unravel the mechanisms of escape to Gls loss;? 2) address the role of glutaminolysis in stemness;? and 3) identify synthetic lethal pathways/genes with pharmacological inhibition of glutaminase or with genetic loss of glutaminase using CRIPSR/Cas9 screens in vitro and experimental therapeutic experiments in vivo. These studies will reveal as yet undiscovered fundamental mechanisms implicatedinthemetabolicandepigeneticrewiringofT-ALL,willadvanceourunderstandingoftheroleofGls andglutaminolysisincancer,andwillhelpusrationallydesigncombinationsofmetabolicorepigenetictargeted therapiesthatwillresultinstrongertherapeuticeffectswithdecreasedchancesofrelapse.
Glutaminolysis is an attractive novel target currently being investigated in clinical trials for the treatment of hematological malignancies and solid tumors but cancer cells can become resistant to inhibition/loss of glutaminase. Our unique genetic and technical tools will allow us to dissect the mechanisms of escape from glutaminase loss, to address its effects on cancer cell stemness as well as to discover synthetic lethal pathways with inhibition of glutaminolysis. Thus, our results will help us identify novel combination therapies that might deliver stronger antileukemic effects in patients and might have a broader impact for multiple other cancer types that are also sensitive to glutaminase inhibition.