Treatmentoptionsthateffectivelycurepatientsdiagnosedwithacutemyeloidleukemia(AML)continueto representanareaofunmetneedinoncologyclinicalcare.WhileremissionratesinAMLpatientscanreach upwardsof80%underthecurrentfrontlinetherapyparadigm,nearlyallpatientsrelapsewithtreatment refractorydiseaselessthan5yearsafterdiagnosis.Relapsedrivenbytherapyresistantcellsthatpersistinthe bodyaftertreatment(definedasminimalresidualdisease)istheprincipalsourceoffatalityinAMLpatients. Therefore,understandinghowandwheretheseleukemiccellssurvivetreatmentinvivomayhelpadvancethe rationaldevelopmentofhighlysynergisticcombinationtherapiesforthetreatmentofAML.Usingafunctional genomicapproach(invivoRNAi)andanewmousemodelofAMLchemoresistance(ChemoR)generatedin ourlabs,wehaveidentifiedseveralputativemediatorsoftherapyresistance.Transcriptionalprofilingofthe ChemoRmodelallowedustogenerateachemoresistancegenesignaturethatweoverlappedwiththeresults oftheshRNAscreentoidentifyhigh-confidencegenesofinterest.Thetopgenesfromarankedlistofthemost highlyoverexpressedgenesinChemoRcellsandthetopdepletedgenesfromtheshRNAscreeninthecontext oftherapytreatmentwereselectedashighinteresthitsandsubsequentlytaggedforindividualfollow-up experiments.OneofthemosthighlyratedgenesonthatlistencodestheLiverKinaseB1(Lkb1)activator Strad?(STE20-relatedkinaseadaptoralpha),suggestingthatthisgenemayrepresentanuncharacterized therapeutictargetthatpromotesAMLresistance. ThegoalsofthisprojectaretoinvestigatewhatroleStrad?playsinhumanAMLchemoresistanceand todissecttheputativeresistancemechanismmediatedbythisgene. ToaddressthisquestionIproposeto: 1. AddresstheroleofSTRAD?inhumanAMLresponsetofrontlinechemotherapy. 2. CharacterizethebasicdrugresistancemechanismmediatedbyStrad?inAML. Byaddressingtheseaims,IcangaininsightintowhetherincreasedsignalingthroughSTRAD?representsa novelgeneticliabilityofAMLsinthecontextoffrontlinetherapythatcanbeexploitedtobettertreatthis disease.Workonthisprojectwillalsofostermydevelopmentasanindependentphysician-scientistbyplacing meattheinterfacebetweenclinicalandbasicscienceinvestigators.Sinceacriticalcomponentofthisworkis todeterminewhetherSTRAD?isbiologicallyrelevantinhumanAMLchemoresistance,Iwilllearnhowto translatebasicscienceobservationsgeneratedfromhypothesisdrivenexperimentsintopotentialtherapeutic strategiesthatcouldbeappliedclinicallytopotentiatetheeffectsoffrontlineagents.Ultimately,workingonthis projectwilltrainmeintheoverallapproachforaddressingkeytranslationalquestionsIwillfocusonlaterinmy career.

Public Health Relevance

Acutemyeloidleukemia(AML)isthemostcommonacuteleukemiainadultsandthemostdeadlyofallblood cancers,killingnearly80%ofpatientsdiagnosedwiththisdiseaseaftertheyrelapsewithprogressivelymore chemoresistantdisease.Usingafunctionalgenomicapproach(invivoRNAi)andanewmousemodelofAML chemoresistancegeneratedinourlabs,Ihaveidentifiedseveralputativemediatorsoftherapyresistancein vivo.Thisstudywillexaminetherolethatoneoftheseproteinsplaysinthechemotherapeuticresponseof humanAMLandthemechanism(s)bywhichitputativelypromotesresistance,inanefforttodetermine whethertargetingthisproteinoritsdownstreamsignalingcomponentssignificantlysensitizesAMLtofrontline therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31CA213902-03
Application #
10054170
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ogunbiyi, Peter
Project Start
2018-12-01
Project End
2021-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
3
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115