Translating Guidelines and Clinical Trial Data to and ... - Amazon S3

Targeted Therapy• Every agent has molecular targets– MTX and DHFR• Targeted therapy requires a patient population for whom themolecular target is critical– ATRA → acute promyelocytic leukemia– TKIs → chronic myelogenous leukemia– Abnormal gene product (BCR-ABL; RARα)– Over-expression?expression?• Target should clonal—not sub-clonal• “Early” vs “late” disease– Chronic myelogenous leukemia vs Ph+ ALLDHFR = dihydrofolate reductase; ATRA = all-trans-retinoic acid; TKIs = tyrosine-kinase inhibitors;RARα = retinoic acid receptor-alpha.CRLF2 and JAK2 in B-Cell Progenitor ALL:A Novel Association in OncogenesisRuxolitinib?Overexpression of CRLF2PotentialtherapeuticinterventionAnti-CRLF2antibodyapproachesJAK2-WTCRLF2overexpression(5%-15% B-ALL,60% DS-ALL)Normal CRLF2function(part of TSLPreceptor with IL7Rα)MonomerHomodimerHeterodimer(with unknownpartner)MutanthomodimerMutantheterodimer(with unknownpartner)JAK2mutation(30%-70%)JAK2-WTCRLF2mutation(10%-20%)Mutation ofother kinases?(10%-60%)UnknownKinasesJAK2-MTorUnknownKinasesJAK2-WTorUnknownKinasesJAK2-MTJAK2-WTJAK2-WTKinase-MTKinaseinhibitorsAberrant growthcontrol signalingin B-ALLAberrant signaling contributingto B-ALL developmentCRLF2Unknown= CRLF2 = F232C = IL7Rα = HeterodimericMutantReceptorWT = wild-type; MT = mutated; TSLP = thymic stromal lymphopoietin; IL7Rα = interleukin 7 receptoralpha.Roll JD, et al. Cancer Res. 2010;70(19):7347-7352.