Methods of diagnosing and treating b cell acute lymphoblastic leukemia

Abstract

Methods for the diagnosis and treatment of B cell Acute Lymphoblastic Leukemia (B-ALL), based in part on the detection and/or inhibition of Focal Adhesion Kinase (FAK), e.g., phosphorylated FAK (pFAK).

What is claimed is: 
     
         1 . A method of treating a subject who has B cell Acute Lymphoblastic Leukemia (B-ALL), comprising
 (i) identifying a subject comprising leukemic cells having a mutation in IKZF1, wherein the mutation results in haploinsufficiency or expression of a dominant negative form of Ikaros and/or in hyperactivation of FAK activity; and   (ii) administering a therapeutically effective amount of an inhibitor of Focal Adhesion Kinase (FAK).   
     
     
         2 . The method of  claim 1 , wherein the inhibitor of FAK is Compound C4 (chloropyramine hydrochloride); FAK Inhibitor 14; Masitinib; PF 562271 (N-methyl-N-(3-(((2-((2-oxoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)methyl)pyridin-2-yl)methanesulfonamide); PF 431396 (N-Methyl-N-[2-[[[2-[(2,3-dihydro-2-oxo-1H-indol-5-yl)amino]-5-(trifluoromethyl)-4-pyrimidinyl]amino]methyl]phenyl]methanesulfonamide); PF 573228 (3,4-Dihydro-6-[[4-[[[3-(methylsulfonyl)phenyl]methyl]amino]-5-(trifluoromethyl)-2-pyrimidinyl]amino]-2(1H)-quinolinone); PF-00562271, the benzenesulfonate salt of PF-562271; VS-4718; VS-6063 (PF-04554878, defactinib); AG82; a 7H-pyrrolo[2,3-d]pyrimidine; GSK2256098; BI1853520; TAE-226; ME-TAE-226; NVP-TAE-226; FRNK; PND-1186; TAC-544; 1,2,4,5-Benzenetetraamine terrahydrochloride; or 2-[(5-chloro-2-[[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]ami-no]-4-pyridinyl)aminol-N-methoxybenzamide, or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The method of  claim 1 , wherein the inhibitor of FAK is an inhibitory nucleic acid selected from the group consisting of siRNA, shRNA, and antisense oligonucleotides; or a dominant negative FAK protein. 
     
     
         4 . The method of  claim 1 , wherein the inhibitor of FAK is administered in combination with an ABL1 kinase inhibitor or a JAK/STAT pathway inhibitor. 
     
     
         5 . The method of  claim 4 , wherein the ABL1 inhibitor is selected from the group consisting of dasatinib, imatinib, nilotinib, bosutinib, ponatinib, bafetinib, and 1,3,4 thiadiazole derivatives. 
     
     
         6 . The method of  claim 4 , wherein the JAK/STAT pathway inhibitor is selected from the group consisting of INCB018424 (Ruxolitinib); SAR302503 (TG101348); CEP-701 (Lestaurtinib); CYT387; SB1518 (pacritinib); LY2784544; XL019; AZD1480; BMS-911543; and NS-018. 
     
     
         7 . The method of  claim 1 , further comprising selecting the subject for treatment by a method comprising:
 obtaining a sample from the subject comprising B cells that are known or suspected to be leukemic;   performing an assay to determine a level of FAK activity in the sample;   comparing the level of FAK activity in the sample to a reference level of FAK activity; and   identifying a subject as having cells with a level of FAK activity that is above the reference level.   
     
     
         8 . The method of  claim 7 , wherein performing an assay to determine a level of FAK activity in the sample comprises determining a level of phosphorylated FAK in the subject. 
     
     
         9 . The method of  claim 1 , further comprising selecting the subject for treatment by a method comprising:
 obtaining a sample from the subject comprising B cells that are known or suspected to be leukemic;   performing an assay to detect the presence or absence of a mutation in IKZF1 in the cells; and   identifying a subject as having cells with a mutation in IKZF1.   
     
     
         10 . The method of  claim 1 , wherein the subject has been diagnosed with B-ALL. 
     
     
         11 . The method of  claim 1 , wherein the subject has not been diagnosed with B-ALL. 
     
     
         12 . The method of  claim 7 , wherein the sample comprises peripheral blood B cells or bone marrow B cells. 
     
     
         13 . The method of  claim 9 , wherein the sample comprises peripheral blood B cells or bone marrow B cells.