title: Targeting paediatric acute lymphoblastic leukaemia: novel therapies currently in development.
abstract: Modifications to the treatment of acute lymphoblastic leukaemia (ALL) in children have led to a dramatic increase in survival in the past 40 years. Despite this success, a significant subset of paediatric leukaemia patients either relapse or fail to ever achieve a complete remission. Additionally, some patients necessitate treatment with intensified chemotherapy regimens due to clinical or laboratory findings which identify them as high risk. These patients are unlikely to respond to further minor adjustments to the dosing or timing of administration of the same chemotherapy medications. Many novel targeted therapies for the treatment of childhood ALL provide potential mechanisms to further improve cure rates, and provide the possibility of minimizing toxicity to non-malignant cells, given their specificity to malignant cell phenotypes. This article explores many of the potential targeted therapies in varying stages of development, from those currently in clinical trials to those still being refined in the research laboratory.
authors.affiliation: Department of Paediatrics, Section of Haematology, Oncology, and Bone Marrow Transplantation, University of Colorado Denver School of Medicine, Aurora, CO, USA.
authors.forename: Alisa B
authors.initials: AB
authors.lastname: Lee-Sherick
authors.forename: Rachel M A
authors.initials: RM
authors.lastname: Linger
authors.forename: Lia
authors.initials: L
authors.lastname: Gore
authors.forename: Amy K
authors.initials: AK
authors.lastname: Keating
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Graham
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002648:Child; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D044127:Epigenesis, Genetic / Q000187:drug effects; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D010770:Phosphotransferases / Q000037:antagonists & inhibitors; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010770:Phosphotransferases
references.citation: Cell. 1995 Oct 20;83(2):289-99
references.pmid: 7585946
references.citation: Blood. 2009 Dec 24;114(27):5490-8
references.pmid: 19855078
references.citation: Mol Cancer Ther. 2009 Jul;8(7):1808-17
references.pmid: 19567821
references.citation: Klin Padiatr. 2006 Nov-Dec;218(6):327-33
references.pmid: 17080335
references.citation: Best Pract Res Clin Haematol. 2006;19(4):685-99
references.pmid: 16997177
references.citation: Cancer Res. 1998 Dec 1;58(23):5315-20
references.pmid: 9850056
references.citation: Leukemia. 2009 Jul;23(7):1342-3
references.pmid: 19322208
references.citation: Clin Cancer Res. 2005 Feb 15;11(4):1545-50
references.pmid: 15746059
references.citation: Blood. 2008 May 15;111(10):5093-100
references.pmid: 18349321
references.citation: J Exp Med. 1996 May 1;183(5):2283-91
references.pmid: 8642337
references.citation: Science. 2004 Oct 8;306(5694):269-71
references.pmid: 15472075
references.citation: Blood. 2007 Oct 1;110(7):2774-5
references.pmid: 17881645
references.citation: Blood. 2009 Dec 17;114(26):5271-8
references.pmid: 19843886
references.citation: Leuk Res. 2009 Feb;33(2):218-21
references.pmid: 18692895
references.citation: Oncogene. 2000 Dec 27;19(56):6680-6
references.pmid: 11426655
references.citation: Science. 1999 Jul 16;285(5426):418-22
references.pmid: 10411507
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18261-6
references.pmid: 17114293
references.citation: Adv Cancer Res. 2008;100:35-83
references.pmid: 18620092
references.citation: Pediatr Blood Cancer. 2008 Jun;50(6):1181-9
references.pmid: 18085673
references.citation: Blood. 2009 Sep 24;114(13):2678-87
references.pmid: 19643988
references.citation: Science. 2004 Jul 16;305(5682):399-401
references.pmid: 15256671
references.citation: Cell Death Differ. 2001 Oct;8(10):1014-21
references.pmid: 11598799
references.citation: Blood. 2008 Sep 1;112(5):2020-3
references.pmid: 18544682
references.citation: Blood. 2004 Jun 1;103(11):4268-75
references.pmid: 14976048
references.citation: Nat Med. 2009 Jan;15(1):50-8
references.pmid: 19098907
references.citation: Cancer Cell. 2009 Nov 6;16(5):401-12
references.pmid: 19878872
references.citation: Int J Biochem Cell Biol. 2007;39(7-8):1500-9
references.pmid: 17499001
references.citation: Haematologica. 2007 Aug;92(8):1043-50
references.pmid: 17640858
references.citation: Nature. 1998 Dec 10;396(6711):580-4
references.pmid: 9859993
references.citation: Cancer Immunol Immunother. 2006 May;55(5):503-14
references.pmid: 16032400
references.citation: Leuk Res. 1992 Jun-Jul;16(6-7):597-605
references.pmid: 1635378
references.citation: Nature. 1987 Feb 12-18;325(6105):631-5
references.pmid: 3543692
references.citation: Adv Exp Med Biol. 1999;457:325-33
references.pmid: 10500808
references.citation: Clin Cancer Res. 2008 Mar 15;14(6):1639-48
references.pmid: 18347165
references.citation: Nat Med. 2010 Feb;16(2):205-13
references.pmid: 20072130
references.citation: Leukemia. 2000 Mar;14(3):399-402
references.pmid: 10720133
references.citation: Nat Med. 2005 Jan;11(1):71-6
references.pmid: 15619634
references.citation: Blood. 2005 Jan 15;105(2):812-20
references.pmid: 15374878
references.citation: Biochem Biophys Res Commun. 1995 Oct 4;215(1):292-301
references.pmid: 7575604
references.citation: Br J Cancer. 2005 Apr 25;92(8):1430-41
references.pmid: 15846298
references.citation: Cancer Chemother Pharmacol. 2006 Jul;58(1):13-23
references.pmid: 16292537
references.citation: Clin Cancer Res. 2007 Mar 15;13(6):1789-93
references.pmid: 17363534
references.citation: Blood. 2010 Feb 18;115(7):1425-32
references.pmid: 20007803
references.citation: Clin Cancer Res. 2003 Oct 1;9(12):4483-93
references.pmid: 14555522
references.citation: J Cell Biol. 2006 Jun 19;173(6):833-7
references.pmid: 16769825
references.citation: Leukemia. 2004 Mar;18(3):521-9
references.pmid: 14712291
references.citation: Cell. 1991 Aug 23;66(4):649-61
references.pmid: 1831692
references.citation: J Clin Invest. 1999 Jul;104(2):155-62
references.pmid: 10411544
references.citation: Blood. 2002 Jun 1;99(11):3885-91
references.pmid: 12010785
references.citation: J Clin Oncol. 2009 Nov 10;27(32):5459-68
references.pmid: 19826124
references.citation: Pediatr Res. 2005 Mar;57(3):430-7
references.pmid: 15659698
references.citation: Biochemistry. 2001 Jan 30;40(4):1117-23
references.pmid: 11170436
references.citation: Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15113-8
references.pmid: 14657335
references.citation: Leuk Lymphoma. 2007 Jul;48(7):1269-82
references.pmid: 17613754
references.citation: J Biol Chem. 1999 Jun 25;274(26):18141-4
references.pmid: 10373409
references.citation: Pediatr Blood Cancer. 2010 Feb;54(2):307-10
references.pmid: 19856388
references.citation: Clin Exp Immunol. 1992 Dec;90(3):368-75
references.pmid: 1281055
references.citation: Blood. 1996 Apr 1;87(7):2870-7
references.pmid: 8639906
references.citation: Leukemia. 2010 Feb;24(2):355-70
references.pmid: 20016527
references.citation: Clin Cancer Res. 2006 May 1;12(9):2662-9
references.pmid: 16675557
references.citation: Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7638-43
references.pmid: 12794186
references.citation: J Clin Oncol. 1994 May;12(5):909-15
references.pmid: 8164041
references.citation: Cell. 2000 Oct 13;103(2):253-62
references.pmid: 11057898
references.citation: Nat Genet. 2009 Nov;41(11):1243-6
references.pmid: 19838194
references.citation: Pediatr Blood Cancer. 2008 Jul;51(1):34-41
references.pmid: 18260120
references.citation: Invest New Drugs. 2007 Feb;25(1):31-40
references.pmid: 16865529
references.citation: Leukemia. 2007 Nov;21(11):2240-5
references.pmid: 17657218
references.citation: Leukemia. 2004 Apr;18(4):676-84
references.pmid: 14961035
references.citation: Blood. 2000 Jul 15;96(2):676-84
references.pmid: 10887134
references.citation: Blood. 2007 Jul 15;110(2):678-85
references.pmid: 17395781
references.citation: Nat Med. 2007 Jan;13(1):70-7
references.pmid: 17173050
references.citation: J Clin Oncol. 2005 Nov 1;23(31):7942-50
references.pmid: 16258094
references.citation: Cancer Chemother Pharmacol. 2005 Aug;56(2):126-37
references.pmid: 15841378
references.citation: Leukemia. 1998 Sep;12(9):1344-8
references.pmid: 9737681
references.citation: Immunity. 1999 May;10(5):547-58
references.pmid: 10367900
references.citation: Blood. 2005 Nov 15;106(10):3532-7
references.pmid: 16051737
references.citation: Blood. 2005 Jul 1;106(1):376-83
references.pmid: 15755898
references.citation: J Biol Chem. 1990 Sep 5;265(25):14701-4
references.pmid: 2203759
references.citation: Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):680-5
references.pmid: 9892693
references.citation: Oncologist. 2008 Nov;13(11):1181-92
references.pmid: 18987046
references.citation: Science. 1987 Jan 2;235(4784):85-8
references.pmid: 3541203
references.citation: Bioconjug Chem. 2009 Aug 19;20(8):1587-94
references.pmid: 19572629
references.citation: Pediatr Blood Cancer. 2009 Sep;53(3):505-8
references.pmid: 19418547
references.citation: Blood. 2005 Aug 15;106(4):1400-6
references.pmid: 15878982
references.citation: Leuk Res. 2005 Sep;29(9):1049-58
references.pmid: 16038731
references.citation: Toxicol Sci. 2004 Nov;82(1):341-58
references.pmid: 15319485
references.citation: Leukemia. 2006 Aug;20(8):1368-76
references.pmid: 16761017
references.citation: N Engl J Med. 2003 Mar 13;348(11):994-1004
references.pmid: 12637609
references.citation: Oncogene. 2006 Oct 5;25(45):6092-100
references.pmid: 16652142
references.citation: Blood. 2003 Jul 1;102(1):269-75
references.pmid: 12623837
references.citation: J Biol Chem. 2008 Jun 27;283(26):18292-302
references.pmid: 18434310
references.citation: Blood. 2006 Apr 1;107(7):2643-52
references.pmid: 16352804
references.citation: Blood. 1993 Feb 15;81(4):1025-31
references.pmid: 8427984
references.citation: Cancer. 2008 Sep 1;113(5):985-94
references.pmid: 18615627
references.citation: Nat Med. 1996 May;2(5):561-6
references.pmid: 8616716
references.citation: Cancer Res. 2007 Oct 1;67(19):9490-500
references.pmid: 17909059
references.citation: Biochem Biophys Res Commun. 1991 Feb 28;175(1):134-42
references.pmid: 1998499
references.citation: Curr Pharm Des. 2002;8(25):2255-7
references.pmid: 12369853
references.citation: Pediatr Blood Cancer. 2009 Dec;53(6):978-83
references.pmid: 19637330
references.citation: Oncogene. 2002 Nov 21;21(53):8173-7
references.pmid: 12444553
references.citation: Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9414-8
references.pmid: 19470474
references.citation: Nature. 1984 Aug 16-22;310(5978):583-6
references.pmid: 6087162
references.citation: Pediatr Blood Cancer. 2008 Jan;50(1):37-45
references.pmid: 17420992
references.citation: Mol Cancer Ther. 2008 May;7(5):1101-9
references.pmid: 18483299
references.citation: Oncogene. 1996 Dec 19;13(12):2589-94
references.pmid: 9000132
references.citation: Blood. 2010 Jul 1;115(26):5312-21
references.pmid: 20139093
references.citation: J Pediatr Hematol Oncol. 2009 Dec;31(12):936-41
references.pmid: 19875969
references.citation: Nat Genet. 1998 Oct;20(2):189-93
references.pmid: 9771714
references.citation: Pathol Oncol Res. 2008 Sep;14(3):275-9
references.pmid: 18575824
references.citation: Genes Cells. 2002 Nov;7(11):1173-82
references.pmid: 12390251
references.citation: J Biol Chem. 2001 Dec 7;276(49):46639-46
references.pmid: 11583996
references.citation: Int J Cancer. 1999 Mar 1;80(5):715-22
references.pmid: 10048973
references.citation: Br J Cancer. 2000 Sep;83(6):817-25
references.pmid: 10952788
references.citation: J Clin Oncol. 2008 Aug 1;26(22):3756-62
references.pmid: 18669463
references.citation: Blood. 2003 Feb 15;101(4):1637-44
references.pmid: 12393484
references.citation: J Biol Chem. 1998 Oct 16;273(42):27084-90
references.pmid: 9765224
references.citation: Nature. 1996 Feb 15;379(6566):645-8
references.pmid: 8628398
references.citation: Science. 1998 Sep 11;281(5383):1680-3
references.pmid: 9733516
references.citation: J Biol Chem. 2002 Jul 5;277(27):24057-66
references.pmid: 11929866
references.citation: Semin Immunol. 1998 Aug;10(4):287-97
references.pmid: 9695185
references.citation: Ann Intern Med. 2003 May 20;138(10):819-30
references.pmid: 12755554
references.citation: Am J Pathol. 1998 Jan;152(1):43-9
references.pmid: 9422522
references.citation: Blood. 2003 Sep 1;102(5):1824-32
references.pmid: 12738674
references.citation: Clin Cancer Res. 2007 Mar 15;13(6):1783-8
references.pmid: 17363533
references.citation: Blood. 1992 Dec 1;80(11):2826-34
references.pmid: 1280479
references.citation: Semin Oncol. 2008 Oct;35(5):484-93
references.pmid: 18929147
references.citation: Blood. 2002 Sep 15;100(6):1965-71
references.pmid: 12200353
references.citation: Blood. 2004 May 1;103(9):3544-6
references.pmid: 14670924
references.citation: Blood. 2006 Jul 15;108(2):711-7
references.pmid: 16822902
references.citation: J Clin Oncol. 2009 Nov 1;27(31):5175-81
references.pmid: 19805687
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):252-7
references.pmid: 20018760
references.citation: Nat Rev Cancer. 2004 May;4(5):349-60
references.pmid: 15122206
references.citation: Leuk Lymphoma. 2009 Jun;50(6):886-91
references.pmid: 19455460