Novel targeted drug therapies for the treatment of childhood acute leukemia

Expert Review of Hematology

Volumn 2, Issue 2, 2009, Pages 145-158

  Brown, Patrick ^a   Hunger, Steven P ^b   Smith, Franklin O ^c   Carroll, William L ^d   Reaman, Gregory H ^e,f  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF COLORADO   (United States)

^c UNIVERSITY OF CINCINNATI   (United States)

^d NEW YORK UNIVERSITY   (United States)

^e Childrens Oncology Group ^*

^f JOHNS HOPKINS UNIVERSITY   (United States)

Author keywords

Acute lymphoblastic leukemia; Acute myeloid leukemia; BCR ABL; Epigenetics; FLT3; Immunotherapy; MTOR; Notch; Proteasome; RAS

Indexed keywords

5 AZA 2' DEOXYCYTIDINE; AZACITIDINE; BCR ABL PROTEIN; BORTEZOMIB; CD33 ANTIGEN; DASATINIB; ENTINOSTAT; EPRATUZUMAB; FLT3 LIGAND; GAMMA SECRETASE INHIBITOR; GEMTUZUMAB OZOGAMICIN; HISTONE DEACETYLASE INHIBITOR; IMATINIB; LESTAURTINIB; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MK 0752; MONOCLONAL ANTIBODY; N2 [2 (3,5 DIFLUOROPHENYL) 2 HYDROXYACETYL] N1 (6,7 DIHYDRO 5 METHYL 6 OXO 5H DIBENZ[B,D]AZEPIN 7 YL)ALANINAMIDE; NOTCH RECEPTOR; PROTEASOME; PROTEASOME INHIBITOR; PROTEIN FARNESYLTRANSFERASE INHIBITOR; PROTEIN TYROSINE KINASE INHIBITOR; RAPAMYCIN; RAS PROTEIN; SEMAGACESTAT; TEMSIROLIMUS; TIPIFARNIB; UNCLASSIFIED DRUG; UNINDEXED DRUG; VORINOSTAT;

ACUTE GRANULOCYTIC LEUKEMIA; ACUTE LEUKEMIA; ACUTE LYMPHOBLASTIC LEUKEMIA; ACUTE LYMPHOCYTIC LEUKEMIA; ALANINE AMINOTRANSFERASE BLOOD LEVEL; AMINOTRANSFERASE BLOOD LEVEL; ANTINEOPLASTIC ACTIVITY; BONE MARROW SUPPRESSION; BURST FORMING UNIT E; CANCER COMBINATION CHEMOTHERAPY; CANCER IMMUNOTHERAPY; CHILD; CHILDHOOD LEUKEMIA; COLONY FORMING UNIT GM; DISEASE FREE SURVIVAL; DRUG CYTOTOXICITY; DRUG EFFICACY; DRUG SAFETY; EPIGENETICS; EVENT FREE SURVIVAL; FATIGUE; FOOD AND DRUG ADMINISTRATION; GASTROINTESTINAL SYMPTOM; GENE EXPRESSION; GENOMICS; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HIGH THROUGHPUT SCREENING; HUMAN; LEUKEMIA REMISSION; MOLECULAR THERAPY; MOLECULARLY TARGETED THERAPY; MONOTHERAPY; MULTIPLE CYCLE TREATMENT; NAUSEA; PATHOGENESIS; PHILADELPHIA 1 CHROMOSOME; PRIORITY JOURNAL; REVIEW; SEIZURE; SIDE EFFECT; VEIN OCCLUSION;

EID: 77953384502     PISSN: 17474086     EISSN: None     Source Type: Journal    
DOI: 10.1586/ehm.09.1     Document Type: Review

References (161)

1. Pui CH, Relling MV, Downing JR. Acute lymphoblastic leukemia. N. Engl. J. Med. 350(15), 1535-1548 (2004).
2. Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N. Engl. J. Med. 354(2), 166-178 (2006).
3. Moricke A, Reiter A, Zimmermann M et al. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 111(9), 4477-4489 (2008).
4. Nguyen K, Devidas M, Cheng SC et al. Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children's Oncology Group study. Leukemia 22(12), 2142-2150 (2008).
5. Pui CH, Cheng C, Leung W et al. Extended follow-up of long-term survivors of childhood acute lymphoblastic leukemia. N. Engl. J. Med. 349(7), 640-649 (2003).
6. Mody R, Li S, Dover DC, Sallan S et al. Twenty-five-year follow-up among survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. Blood 111(12), 5515-5523 (2008).
7. Rubnitz JE. Childhood acute myeloid leukemia. Curr. Treat. Options Oncol. 9(1), 95-105 (2008).
8. Oliansky DM, Rizzo JD, Aplan PD et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myeloid leukemia in children: an evidence-based review. Biol. Blood Marrow Transplant. 13(1), 1-25 (2007).
9. Mulrooney DA, Dover DC, Li S et al. Twenty years of follow-up among survivors of childhood and young adult acute myeloid leukemia: a report from the Childhood Cancer Survivor Study. Cancer 112(9), 2071-2079 (2008).
10. Meshinchi S, Arceci RJ. Prognostic factors and risk-based therapy in pediatric acute myeloid leukemia. Oncologist 12(3), 341-355 (2007).
11. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 3(7), 730-737 (1997).
12. Michor F, Hughes TP, Iwasa Y et al. Dynamics of chronic myeloid leukaemia. Nature 435(7046), 1267-1270 (2005).
13. Graham SM, Jorgensen HG, Allan E et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 99(1), 319-325 (2002).
14. Grimwade D, Enver T. Acute promyelocytic leukemia: where does it stem from? Leukemia 18(3), 375-384 (2004).
15. le Viseur C, Hotfilder M, Bomken S et al. In childhood acute lymphoblastic leukemia, blasts at different stages of immunophenotypic maturation have stem cell properties. Cancer Cell 14(1), 47-58 (2008).
16. Cox CV, Evely RS, Oakhill A, Pamphilon DH, Goulden NJ, Blair A. Characterization of acute lymphoblastic leukemia progenitor cells. Blood 104(9), 2919-2925 (2004).
17. Castor A, Nilsson L, Astrand-Grundstrom I et al. Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia. Nat. Med. 11(6), 630-637 (2005).
18. Ross ME, Mahfouz R, Onciu M et al. Gene expression profiling of pediatric acute myelogenous leukemia. Blood 104(12), 3679-3687 (2004).
19. Ross ME, Zhou X, Song G et al. Classification of pediatric acute lymphoblastic leukemia by gene expression profiling. Blood 102(8), 2951-2959 (2003). (Pubitemid 37248870)
20. Yeoh EJ, Ross ME, Shurtleff SA et al. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell 1(2), 133-143 (2002).
21. Holleman A, den Boer ML, de Menezes RX et al. The expression of 70 apoptosis genes in relation to lineage, genetic subtype, cellular drug resistance, and outcome in childhood acute lymphoblastic leukemia. Blood 107(2), 769-776 (2006).
22. Cario G, Stanulla M, Fine BM et al. Distinct gene expression profiles determine molecular treatment response in childhood acute lymphoblastic leukemia. Blood 105(2), 821-826 (2005).
23. Bhojwani D, Kang H, Menezes RX et al. Gene expression signatures predictive of early response and outcome in high-risk childhood acute lymphoblastic leukemia: a Children's Oncology Group Study [corrected]. J. Clin. Oncol. 26(27), 4376-4384 (2008).
24. Mullighan CG, Goorha S, Radtke I et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 446(7137), 758-764 (2007).
25. Mullighan CG, Su X, Zhang J et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N. Engl. J. Med. 360(5), 470-480 (2009).
26. Den Boer ML, van Slegtenhorst M, De Menezes RX et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genomewide classification study. Lancet Oncol. 10(2), 125-134 (2009).
27. Yang JJ, Bhojwani D, Yang W et al. Genome-wide copy number profiling reveals molecular evolution from diagnosis to relapse in childhood acute lymphoblastic leukemia. Blood 112(10), 4178-4183 (2008).
28. Galm O, Herman JG, Baylin SB. The fundamental role of epigenetics in hematopoietic malignancies. Blood Rev. 20(1), 1-13 (2006).
29. Garzon R, Croce CM. MicroRNAs in normal and malignant hematopoiesis. Curr. Opin. Hematol. 15(4), 352-358 (2008).
30. Weinstein IB. Cancer. Addiction to oncogenes - the Achilles heal of cancer. Science 297(5578), 63-64 (2002).
31. Cheson BD, Leonard JP. Monoclonal antibody therapy for B-cell non-Hodgkin's lymphoma. N. Engl. J. Med. 359(6), 613-626 (2008).
32. Freeman SD, Kelm S, Barber EK, Crocker PR. Characterization of CD33 as a new member of the sialoadhesin family of cellular interaction molecules. Blood 85(8), 2005-2012 (1995).
33. Brashem-Stein C, Flowers DA, Smith FO, Staats SJ, Andrews RG, Bernstein ID. Ontogeny of hematopoietic stem cell development: reciprocal expression of CD33 and a novel molecule by maturing myeloid and erythroid progenitors. Blood 82(3), 792-799 (1993).
34. Sievers EL, Larson RA, Stadtmauer EA et al. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33- positive acute myeloid leukemia in first relapse. J. Clin. Oncol. 19(13), 3244-3254 (2001).
35. Larson RA, Sievers EL, Stadtmauer EA et al. Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33- positive acute myeloid leukemia in first recurrence. Cancer 104(7), 1442-1452 (2005).
36. Arceci RJ, Sande J, Lange B et al. Safety and efficacy of gemtuzumab ozogamicin in pediatric patients with advanced CD33+ acute myeloid leukemia. Blood 106(4), 1183-1188 (2005).
37. Zwaan CM, Reinhardt D, Corbacioglu S et al. Gemtuzumab ozogamicin: first clinical experiences in children with relapsed/refractory acute myeloid leukemia treated on compassionate-use basis. Blood 101(10), 3868-3871 (2003). (Pubitemid 36857859)
38. Aplenc R, Alonzo TA, Gerbing RB et al. Safety and efficacy of gemtuzumab ozogamicin in combination with chemotherapy for pediatric acute myeloid leukemia: a report from the Children's Oncology Group. J. Clin. Oncol. 26(14), 2390-3295 (2008).
39. Franklin J, Alonzo TA, Hurwitz CA et al. COG AAML03P1: efficacy and safety in a pilot study of intensive chemotherapy including gemtuzumab in children newly diagnosed with acute myeloid leukemia (AML). Blood 112(11), 136a (2008).
40. Linenberger ML, Hong T, Flowers D et al. Multidrug-resistance phenotype and clinical responses to gemtuzumab ozogamicin. Blood 98(4), 988-994 (2001).
41. Becton D, Dahl GV, Ravindranath Y et al. Randomized use of cyclosporin A (CsA) to modulate P-glycoprotein in children with AML in remission: Pediatric Oncology Group Study 9421. Blood 107(4), 1315-1324 (2006).
42. Hauswirth AW, Florian S, Printz D et al. Expression of the target receptor CD33 in CD34+/CD38-/CD123+ AML stem cells. Eur. J. Clin. Invest. 37(1), 73-82 (2007).
43. Florian S, Sonneck K, Hauswirth AW et al. Detection of molecular targets on the surface of CD34+/CD38- stem cells in various myeloid malignancies. Leuk. Lymphoma 47(2), 207-222 (2006).
44. Taussig DC, Pearce DJ, Simpson C et al. Hematopoietic stem cells express multiple myeloid markers: implications for the origin and targeted therapy of acute myeloid leukemia. Blood 106(13), 4086-4092 (2005).
45. Estey EH, Giles FJ, Beran M et al. Experience with gemtuzumab ozogamycin ("mylotarg") and all-trans retinoic acid in untreated acute promyelocytic leukemia. Blood 99(11), 4222-4224 (2002).
46. Lo-Coco F, Cimino G, Breccia M et al. Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood 104(7), 1995-1999 (2004).
47. Cesano A, Gayko U. CD22 as a target of passive immunotherapy. Semin. Oncol. 30(2), 253-257 (2003).
48. Leung SO, Goldenberg DM, Dion AS et al. Construction and characterization of a humanized, internalizing, B-cell (CD22)- specific, leukemia/lymphoma antibody, LL2. Mol. Immunol. 32(17-18), 1413-1427 (1995).
49. Carnahan J, Wang P, Kendall R et al. Epratuzumab, a humanized monoclonal antibody targeting CD22: characterization of in vitro properties. Clin. Cancer Res. 9(10 Pt 2), 3982S-3890S (2003).
50. Leonard JP, Coleman M, Ketas JC et al. Phase I/II trial of epratuzumab (humanized anti-CD22 antibody) in indolent non-Hodgkin's lymphoma. J. Clin. Oncol. 21(16), 3051-3059 (2003).
51. Leonard JP, Coleman M, Ketas JC et al. Epratuzumab, a humanized anti-CD22 antibody, in aggressive non-Hodgkin's lymphoma: Phase I/II clinical trial results. Clin. Cancer Res. 10(16), 5327-5334 (2004).
52. Leonard JP, Coleman M, Ketas J et al. Combination antibody therapy with epratuzumab and rituximab in relapsed or refractory non-Hodgkin's lymphoma. J. Clin. Oncol. 23(22), 5044-5051 (2005).
53. Strauss SJ, Morschhauser F, Rech J et al. Multicenter Phase II trial of immunotherapy with the humanized anti-CD22 antibody, epratuzumab, in combination with rituximab, in refractory or recurrent non-Hodgkin's lymphoma. J. Clin. Oncol. 24(24), 3880-3886 (2006).
54. Micallef IN, Kahl BS, Maurer MJ et al. A pilot study of epratuzumab and rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated, diffuse large B-cell lymphoma. Cancer 107(12), 2826-2832 (2006).
55. Raetz EA, Cairo MS, Borowitz MJ et al. Chemoimmunotherapy reinduction with epratuzumab in children with acute lymphoblastic leukemia in marrow relapse: a Children's Oncology Group Pilot Study. J. Clin. Oncol. 26(22), 3756-3762 (2008).
56. Kreitman RJ, Squires DR, Stetler-Stevenson M et al. Phase I trial of recombinant immunotoxin RFB4(dsFv)- PE38 (BL22) in patients with B-cell malignancies. J. Clin. Oncol. 23(27), 6719-6729 (2005).
57. Kreitman RJ, Wilson WH, Bergeron K et al. Efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy-cell leukemia. N. Engl. J. Med. 345(4), 241-247 (2001).
58. Bang S, Nagata S, Onda M, Kreitman RJ, Pastan I. HA22 (R490A) is a recombinant immunotoxin with increased antitumor activity without an increase in animal toxicity. Clin. Cancer Res. 11(4), 1545-1550 (2005).
59. Onda M, Beers R, Xiang L, Nagata S, Wang QC, Pastan I. An immunotoxin with greatly reduced immunogenicity by identification and removal of B cell epitopes. Proc. Natl Acad. Sci. USA 105(32), 11311-11316 (2008).
60. Weldon JE, Xiang L, Chertov O et al. A protease-resistant immunotoxin against CD22 with greatly increased activity against CLL and diminished animal toxicity. Blood DOI: blood-2008-08- 173195v1 (2008) (Epub ahead of print).
61. Herrera L, Farah RA, Pellegrini VA et al. Immunotoxins against CD19 and CD22 are effective in killing precursor-B acute lymphoblastic leukemia cells in vitro. Leukemia 14(5), 853-858 (2000).
62. Herrera L, Yarbrough S, Ghetie V, Aquino DB, Vitetta ES. Treatment of SCID/ human B cell precursor ALL with anti-CD19 and anti-CD22 immunotoxins. Leukemia 17(2), 334-338 (2003).
63. Messmann RA, Vitetta ES, Headlee D et al. A Phase I study of combination therapy with immunotoxins IgG-HD37- deglycosylated ricin A chain (dgA) and IgG-RFB4-dgA (Combotox) in patients with refractory CD19(+), CD22(+) B cell lymphoma. Clin. Cancer Res. 6(4), 1302-1313 (2000).
64. Arico M, Valsecchi MG, Camitta B et al. Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia. N. Engl. J. Med. 342(14), 998-1006 (2000). (Pubitemid 30180646)
65. Druker BJ, Talpaz M, Resta DJ et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med. 344(14), 1031-1037 (2001).
66. Gorre ME, Sawyers CL. Molecular mechanisms of resistance to STI571 in chronic myeloid leukemia. Curr. Opin. Hematol. 9(4), 303-307 (2002).
67. Druker BJ, Sawyers CL, Kantarjian H et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N. Engl. J. Med. 344(14), 1038-1042 (2001).
68. Ottmann OG, Druker BJ, Sawyers CL et al. A Phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 100(6), 1965-1971 (2002).
69. Thomas DA, Faderl S, Cortes J et al. Treatment of Philadelphia chromosomepositive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood 103(12), 4396-4407 (2004).
70. Lee KH, Lee JH, Choi SJ et al. Clinical effect of imatinib added to intensive combination chemotherapy for newly diagnosed Philadelphia chromosomepositive acute lymphoblastic leukemia. Leukemia 19(9), 1509-1516 (2005).
71. Schultz KR, Bowman WP, Aledo A et al. Improved early event free survival with imatinib in Philadelphia chromosomepositive acute lymphoblastic leukemia: a Children's Oncology Group study. J. Clin. Oncol. (2009) (In Press).
72. Lee S, Kim YJ, Min CK et al. The effect of first-line imatinib interim therapy on the outcome of allogeneic stem cell transplantation in adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 105(9), 3449-3457 (2005).
73. Hu Y, Liu Y, Pelletier S, Buchdunger E et al. Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Nat. Genet. 36(5), 453-461 (2004).
74. O'Hare T, Walters DK, Stoffregen EP et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res. 65(11), 4500-4505 (2005).
75. Carter TA, Wodicka LM, Shah NP et al. Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proc. Natl Acad. Sci. USA 102(31), 11011-11016 (2005).
76. Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305(5682), 399-401 (2004).
77. Talpaz M, Shah NP, Kantarjian H et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N. Engl. J. Med. 354(24), 2531-2541 (2006). (Pubitemid 43882349)
78. Brown P, Small D. FLT3 inhibitors: a paradigm for the development of targeted therapeutics for paediatric cancer. Eur. J. Cancer 40(5), 707-721 (2004).
79. Levis M, Small D. FLT3 tyrosine kinase inhibitors. Int. J. Hematol. 82(2), 100-107 (2005).
80. Carow CE, Levenstein M, Kaufmann SH et al. Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. Blood 87(3), 1089-1096 (1996).
81. Kiyoi H, Towatari M, Yokota S et al. Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product. Leukemia 12(9), 1333-1337 (1998).
82. Meshinchi S, Woods WG, Stirewalt DL et al. Prevalence and prognostic significance of Flt3 internal tandem duplication in pediatric acute myeloid leukemia. Blood 97(1), 89-94 (2001).
83. Yamamoto Y, Kiyoi H, Nakano Y et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 97(8), 2434-2439 (2001).
84. Iwai T, Yokota S, Nakao M et al. Internal tandem duplication of the FLT3 gene and clinical evaluation in childhood acute myeloid leukemia. The Children's Cancer and Leukemia Study Group, Japan. Leukemia 13(1), 38-43 (1999).
85. Kondo M, Horibe K, Takahashi Y et al. Prognostic value of internal tandem duplication of the FLT3 gene in childhood acute myelogenous leukemia. Med. Pediatr. Oncol. 33(6), 525-529 (1999).
86. Meshinchi S, Alonzo TA, Stirewalt DL et al. Clinical implications of FLT3 mutations in pediatric AML. Blood 108(12), 3654-3661 (2006).
87. Thiede C, Steudel C, Mohr B et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 99(12), 4326-4335 (2002).
88. Whitman SP, Archer KJ, Feng L et al. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Res. 61(19), 7233-7239 (2001).
89. Levis M, Allebach J, Tse KF et al. A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Blood 99(11), 3885-3891 (2002).
90. Brown P, Meshinchi S, Levis M et al. Pediatric AML primary samples with FLT3/ITD mutations are preferentially killed by FLT3 inhibition. Blood 104(6), 1841-1849 (2004).
91. Smith BD, Levis M, Beran M et al. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood 103(10), 3669-3676 (2004).
92. Knapper S, Burnett AK, Littlewood T et al. A Phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy. Blood 108(10), 3262-3270 (2004).
93. Levis M, Smith BD, Beran M et al. A randomized, open-label study of lestaurtinib (CEP-701), an oral FLT3 inhibitor, administered in sequence with chemotherapy in patients with relapsed AML harboring FLT3 activating mutations: clinical response correlates with successful FLT3 inhibition. ASH Annual Meeting Abstracts 106(11), 403 (2005).
94. Levis M, Pham R, Smith BD, Small D. In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects. Blood 104(4), 1145-1150 (2004).
95. Brown P, Levis M, McIntyre E, Griesemer M, Small D. Combinations of the FLT3 inhibitor CEP-701 and chemotherapy synergistically kill infant and childhood MLL-rearranged ALL cells in a sequencedependent manner. Leukemia 20(8), 1368-1376 (2006).
96. Kottaridis PD, Gale RE, Langabeer SE, Frew ME, Bowen DT, Linch DC. Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors. Blood 100(7), 2393-2398 (2002).
97. Levis M, Murphy KM, Pham R et al. Internal tandem duplications of the FLT3 gene are present in leukemia stem cells. Blood 106(2), 673-680 (2005).
98. Pollard JA, Alonzo TA, Gerbing RB et al. FLT3 internal tandem duplication in CD34+/CD33- precursors predicts poor outcome in acute myeloid leukemia. Blood 108(8), 2764-2769 (2006).
99. Armstrong SA, Staunton JE, Silverman LB et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat. Genet. 30(1), 41-47 (2002).
100. Armstrong SA, Mabon ME, Silverman LB et al. FLT3 mutations in childhood acute lymphoblastic leukemia. Blood 103(9), 3544-3546 (2004).
101. Zheng R, Levis M, Piloto O et al. FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells. Blood 103(1), 267-274 (2004).
102. Brown P, Levis M, Shurtleff S, Campana D, Downing J, Small D. FLT3 inhibition selectively kills childhood acute lymphoblastic leukemia cells with high levels of FLT3 expression. Blood 105(2), 812-820 (2005).
103. Armstrong SA, Kung AL, Mabon ME et al. Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification. Cancer Cell 3(2), 173-183 (2003).
104. Stam RW, den Boer ML, Schneider P et al. Targeting FLT3 in primary MLL-generearranged infant acute lymphoblastic leukemia. Blood 106(7), 2484-2490 (2005).
105. Taketani T, Taki T, Sugita K et al. FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy. Blood 103(3), 1085-1088 (2004).
106. Pyatt DW, Stillman WS, Yang Y, Gross S, Zheng JH, Irons RD. An essential role for NF-κB in human CD34+ bone marrow cell survival. Blood 93(10), 3302-3308 (1999).
107. Guzman ML, Neering SJ, Upchurch D et al. Nuclear factor-κB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood 98(8), 2301-2307 (2001).
108. Guzman ML, Swiderski CF, Howard DS et al. Preferential induction of apoptosis for primary human leukemic stem cells. Proc. Natl. Acad. Sci. USA 10, 99(25), 16220-16225 (2002).
109. Cortes J, Thomas D, Koller C et al. Phase I study of bortezomib in refractory or relapsed acute leukemias. Clin. Cancer Res. 10(10), 3371-3376 (2004).
110. Orlowski RZ, Voorhees PM, Garcia RA et al. Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Blood 105(8), 3058-3065 (2004).
111. Horton TM, Pati D, Plon SE et al. A Phase 1 study of the proteasome inhibitor bortezomib in pediatric patients with refractory leukemia: a Children's Oncology Group study. Clin. Cancer Res. 13(5), 1516-1522 (2007).
112. Houghton PJ, Morton CL, Kolb EA et al. Initial testing (stage 1) of the proteasome inhibitor bortezomib by the pediatric preclinical testing program. Pediatr. Blood Cancer 50(1), 37-45 (2008).
113. Horton TM, Gannavarapu A, Blaney SM, D'Argenio DZ, Plon SE, Berg SL. Bortezomib interactions with chemotherapy agents in acute leukemia in vitro. Cancer Chemother. Pharmacol. 58(1), 13-23 (2006).
114. Messinger YH, Gaynon PS, Raetz EA et al. Remarkable activity of bortezomib combined with chemotherapy in a Phase I study of relapsed childhood acute lymphoblastic leukemia. Blood 112(11), 1919a (2008).
115. Hudes G, Carducci M, Tomczak P et al. Temsirolimus, interferon α or both for advanced renal-cell carcinoma. N. Engl. J. Med. 356(22), 2271-2281 (2007). (Pubitemid 46849157)
116. Xu Q, Simpson SE, Scialla TJ, Bagg A, Carroll M. Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood 102(3), 972-980 (2003).
117. Min YH, Eom JI, Cheong JW et al. Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukemia: its significance as a prognostic variable. Leukemia 17(5), 995-997 (2003).
118. Recher C, Beyne-Rauzy O, Demur C et al. Antileukemic activity of rapamycin in acute myeloid leukemia. Blood 105(6), 2527-2534 (2005). (Pubitemid 40387055)
119. Yee KW, Zeng Z, Konopleva M et al. Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin. Cancer Res. 12(17), 5165-5173 (2006).
120. Brown VI, Fang J, Alcorn K et al. Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling. Proc. Natl Acad. Sci. USA 100(25), 15113-15118 (2003).
121. Teachey DT, Sheen C, Hall J et al. mTOR inhibitors are synergistic with methotrexate: an effective combination to treat acute lymphoblastic leukemia. Blood 112(5), 2020-2023 (2008).
122. Wei G, Twomey D, Lamb J et al. Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance. Cancer Cell 10(4), 331-342 (2006).
123. Herman JG, Civin CI, Issa JP, Collector MI, Sharkis SJ, Baylin SB. Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies. Cancer Res. 57(5), 837-841 (1997).
124. Seedhouse CH, Das-Gupta EP, Russell NH. Methylation of the hMLH1 promoter and its association with microsatellite instability in acute myeloid leukemia. Leukemia 17(1), 83-88 (2003).
125. Esteller M. Epigenetics in cancer. N. Engl. J. Med. 358(11), 1148-1159 (2008).
126. Jones PA, Baylin SB. The epigenomics of cancer. Cell 128(4), 683-692 (2007).
127. Gore SD. Combination therapy with DNA methyltransferase inhibitors in hematologic malignancies. Nat. Clin. Pract. Oncol. 2(Suppl. 1), S30-S35 (2005).
128. Friedman AD. Leukemogenesis by CBF oncoproteins. Leukemia 13(12), 1932-1942 (1999).
129. Tenen DG, Hromas R, Licht JD, Zhang DE. Transcription factors, normal myeloid development, and leukemia. Blood 90(2), 489-519 (1997).
130. Liu S, Shen T, Huynh L et al. Interplay of RUNX1/MTG8 and DNA methyltransferase 1 in acute myeloid leukemia. Cancer Res. 65(4), 1277-1284 (2005).
131. Liu S, Klisovic RB, Vukosavljevic T et al. Targeting AML1/ETO-histone deacetylase repressor complex: a novel mechanism for valproic acid-mediated gene expression and cellular differentiation in AML1/ETOpositive acute myeloid leukemia cells. J. Pharmacol. Exp. Ther. 321(3), 953-960 (2007).
132. Klisovic MI, Maghraby EA, Parthun MR et al. Depsipeptide (FR 901228) promotes histone acetylation, gene transcription, apoptosis and its activity is enhanced by DNA methyltransferase inhibitors in AML1/ETO-positive leukemic cells. Leukemia 17(2), 350-358 (2003).
133. Grignani F, De Matteis S, Nervi C et al. Fusion proteins of the retinoic acid receptor-a recruit histone deacetylase in promyelocytic leukaemia. Nature 391(6669), 815-818 (1998).
134. Lin RJ, Nagy L, Inoue S, Shao W, Miller WH Jr, Evans RM. Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature 19, 391(6669), 811-814 (1998).
135. Di Croce L, Raker VA, Corsaro M et al. Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 295(5557), 1079-1082 (2002).
136. Heibert SW, Lutterbach B, Durst K et al. Mechanisms of transcriptional repression by the t(8;21)-, t(12;21)-, and inv(16)-encoded fusion proteins. Cancer Chemother. Pharmacol. 48(Suppl. 1), S31-S34 (2001). (Pubitemid 33738369)
137. Whitman SP, Liu S, Vukosavljevic T et al. The MLL partial tandem duplication: evidence for recessive gain-of-function in acute myeloid leukemia identifies a novel patient subgroup for molecular-targeted therapy. Blood 106(1), 345-352 (2005).
138. Dorrance AM, Liu S, Yuan W et al. Mll partial tandem duplication induces aberrant Hox expression in vivo via specific epigenetic alterations. J. Clin. Invest. 116(10), 2707-2716 (2006).
139. So CW, Lin M, Ayton PM, Chen EH, Cleary ML. Dimerization contributes to oncogenic activation of MLL chimeras in acute leukemias. Cancer Cell 4(2), 99-110 (2003).
140. Gore SD, Baylin S, Sugar E et al. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res. 66(12), 6361-6369 (2006).
141. Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B et al. Phase 1/2 study of the combination of 5-aza-2́-deoxycytidine with valproic acid in patients with leukemia. Blood 108(10), 3271-3279 (2006).
142. Case M, Matheson E, Minto L et al. Mutation of genes affecting the RAS pathway is common in childhood acute lymphoblastic leukemia. Cancer Res. 68(16), 6803-6809 (2008).
143. Meshinchi S, Stirewalt DL, Alonzo TA et al. Activating mutations of RTK/ras signal transduction pathway in pediatric acute myeloid leukemia. Blood 102(4), 1474-1479 (2003).
144. MacKenzie KL, Dolnikov A, Millington M, Shounan Y, Symonds G. Mutant N-ras induces myeloproliferative disorders and apoptosis in bone marrow repopulated mice. Blood 93(6), 2043-2056 (1999).
145. Loh ML, Vattikuti S, Schubbert S et al. Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. Blood 103(6), 2325-2331 (2004).
146. Emanuel PD, Snyder RC, Wiley T, Gopurala B, Castleberry RP. Inhibition of juvenile myelomonocytic leukemia cell growth in vitro by farnesyltransferase inhibitors. Blood 95(2), 639-645 (2000).
147. Emanuel PD. Juvenile myelomonocytic leukemia. Curr. Hematol. Rep. 3(3), 203-209 (2004).
148. Khosravi-Far R, Cox AD, Kato K, Der CJ. Protein prenylation: key to ras function and cancer intervention? Cell Growth Differ. 3(7), 461-469 (1992).
149. Harousseau JL, Lancet JE, Reiffers J et al. A Phase 2 study of the oral farnesyltransferase inhibitor tipifarnib in patients with refractory or relapsed acute myeloid leukemia. Blood 109(12), 5151-5156 (2007).
150. Lancet JE, Gojo I, Gotlib J et al. A Phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia. Blood 109(4), 1387-1394 (2007).
151. Zimmerman TM, Harlin H, Odenike OM et al. Dose-ranging pharmacodynamic study of tipifarnib (R115777) in patients with relapsed and refractory hematologic malignancies. J. Clin. Oncol. 22(23), 4816-4822 (2004).
152. Cortes J, Albitar M, Thomas D et al. Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies. Blood 101(5), 1692-1697 (2003).
153. Karp JE, Lancet JE, Kaufmann SH et al. Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a Phase 1 clinical-laboratory correlative trial. Blood 97(11), 3361-3369 (2001).
154. Radtke F, Wilson A, MacDonald HR. Notch signaling in T- and B-cell development. Curr. Opin. Immunol. 16(2), 174-179 (2004).
155. Ellisen LW, Bird J, West DC et al. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66(4), 649-661 (1991).
156. Weng AP, Ferrando AA, Lee W et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306(5694), 269-271 (2004).
157. O'Neil J, Grim J, Strack P et al. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to γ-secretase inhibitors. J. Exp. Med. 204(8), 1813-1824 (2007).
158. Pear WS, Aster JC, Scott ML et al. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J. Exp. Med. 183(5), 2283-2291 (1996).
159. Real PJ, Tosello V, Palomero T et al. γ-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat. Med. 15(1), 50-58 (2009).
160. Vilimas T, Mascarenhas J, Palomero T et al. Targeting the NF-κB signaling pathway in Notch1-induced T-cell leukemia. Nat. Med. 13(1), 70-77 (2007).
161. Palomero T, Lim WK, Odom DT et al. NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc. Natl Acad. Sci. USA 103(48), 18261-18266 (2006).