Exploiting cellular pathways to develop new treatment strategies for AML

Cancer Treatment Reviews

Volumn 36, Issue 2, 2010, Pages 142-150

  Fathi, Amir T ^a   Grant, Steven ^b   Karp, Judith E ^a  

^a JOHNS HOPKINS UNIVERSITY   (United States)

^b VIRGINIA COMMONWEALTH UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Acute myeloid leukemia; Flavopiridol; FLT3; HDAC inhibitor; PARP; Targeted therapies

Indexed keywords

ANTHRACYCLINE; BELINOSTAT; CD135 ANTIGEN; CLOFARABINE; CYCLIN DEPENDENT KINASE; CYTARABINE; CYTOTOXIC AGENT; FLAVOPIRIDOL; HISTONE; HISTONE DEACETYLASE; HISTONE DEACETYLASE INHIBITOR; MIDOSTAURIN; MITOGEN ACTIVATED PROTEIN KINASE 1 INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE 2 INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; MITOXANTRONE; N (2 AMINOPHENYL) 4 [4 (3 PYRIDINYL) 2 PYRIMIDINYLAMINOMETHYL]BENZAMIDE; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE INHIBITOR; OLIGONUCLEOTIDE; PANOBINOSTAT; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PHOSPHOTRANSFERASE INHIBITOR; PROTEIN BCL 2; PROTEIN TYROSINE KINASE INHIBITOR; RAPAMYCIN; SNDX 273; SNDX 275; SORAFENIB; TOPOTECAN; UNCLASSIFIED DRUG; UNINDEXED DRUG; VORINOSTAT; ANTINEOPLASTIC AGENT;

ACETYLATION; ACUTE GRANULOCYTIC LEUKEMIA; APOPTOSIS; BLAST CELL; CANCER COMBINATION CHEMOTHERAPY; CANCER INHIBITION; CANCER RESEARCH; CELL PROLIFERATION; CLINICAL TRIAL; CONFORMATIONAL TRANSITION; CONTINUOUS INFUSION; DRUG DOSE ESCALATION; DRUG TARGETING; DRUG WITHDRAWAL; ENZYME INHIBITION; HIGH RISK PATIENT; HUMAN; LEUKEMOGENESIS; NUCLEOTIDE METABOLISM; REVIEW; TREATMENT OUTCOME; DRUG ANTAGONISM; DRUG EFFECT; PATHOLOGY; PRACTICE GUIDELINE; SIGNAL TRANSDUCTION;

ANTINEOPLASTIC AGENTS; APOPTOSIS; CYCLIN-DEPENDENT KINASES; HUMANS; LEUKEMIA, MYELOID, ACUTE; PRACTICE GUIDELINES AS TOPIC; SIGNAL TRANSDUCTION; TREATMENT OUTCOME;

EID: 77950620888     PISSN: 03057372     EISSN: 15321967     Source Type: Journal    
DOI: 10.1016/j.ctrv.2009.12.004     Document Type: Review

References (140)

1. Lowenberg B., Downing J.R., Burnett A. Acute myeloid leukemia. N Engl J Med 1999, 341:1051-1062.
2. Karp J.E., Smith M.A. The molecular pathogenesis of treatment-induced (secondary) leukemias: foundations for treatment and prevention. Semin Oncol 1997, 24:103-113.
3. Bao T., Smith B.D., Karp J.E. New agents in the treatment of acute myeloid leukemia: a snapshot of signal transduction modulation. Clin Adv Hematol Oncol 2005, 3:287-296.
4. Klasa R.J., List A.F., Cheson B.D. Rational approaches to design of therapeutics targeting molecular markers. Hematol Am Soc Hematol Educ Program 2001, 443-462.
5. Sedlacek H.H. Mechanisms of action of flavopiridol. Crit Rev Oncol Hematol 2001, 38:139-170.
6. Chao S.H., Price D.H. Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo. J Biol Chem 2001, 276:31793-31799.
7. Karp J.E., Ross D.D., Yang W., et al. Timed sequential therapy of acute leukemia with flavopiridol: in vitro model for a phase I clinical trial. Clin Cancer Res 2003, 9:307-315.
8. Melillo G., Sausville E.A., Cloud K., Lahusen T., Varesio L., Senderowicz A.M. Flavopiridol, a protein kinase inhibitor, down-regulates hypoxic induction of vascular endothelial growth factor expression in human monocytes. Cancer Res 1999, 59:5433-5437.
9. Byrd J.C., Shinn C., Waselenko J.K., et al. Flavopiridol induces apoptosis in chronic lymphocytic leukemia cells via activation of caspase-3 without evidence of bcl-2 modulation or dependence on functional p53. Blood 1998, 92:3804-3816.
10. Decker R.H., Dai Y., Grant S. The cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in human leukemia cells (U937) through the mitochondrial rather than the receptor-mediated pathway. Cell Death Differ 2001, 8:715-724.
11. Bible K.C., Kaufmann S.H. Cytotoxic synergy between flavopiridol (NSC 649890, L86-8275) and various antineoplastic agents: the importance of sequence of administration. Cancer Res 1997, 57:3375-3380.
12. Karp J.E., Passaniti A., Gojo I., et al. Phase I and pharmacokinetic study of flavopiridol followed by 1-beta-D-arabinofuranosylcytosine and mitoxantrone in relapsed and refractory adult acute leukemias. Clin Cancer Res 2005, 11:8403-8412.
13. Karp J.E., Smith B.D., Levis M.J., et al. Sequential flavopiridol, cytosine arabinoside, and mitoxantrone: a phase II trial in adults with poor-risk acute myelogenous leukemia. Clin Cancer Res 2007, 13:4467-4473.
14. Karp JE, Blackford A, Smith BD, et al. Clinical activity of sequential flavopiridol, cytosine arabinoside, and mitoxantrone for adults with newly diagnosed, poor-risk acute myelogenous leukemia. Leuk Res 2009. doi:10.1016/jleukies.2009.11.007. doi:10.1016/jleukies.2009.11.007.
15. Blum W, Klisovic RB, Johnson A, et al. Final results of a dose escalation study of flavopiridol in acute leukemias using a novel treatment schedule. Blood, ASH Annual Meeting Abstracts 2007, part 1;110:Abstract 890.
16. Byrd J.C., Lin T.S., Dalton J.T., et al. Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Blood 2007, 109:399-404.
17. Resar L., Hillion J., Alino K., Rudek M., Karp J.E. Flavopiridol down-regulates genes involved in cell cycle regulation and tumor progression in adults with refractory or poor-risk acute leukemia. Blood 2008, 112:351.
18. Almenara J., Rosato R., Grant S. Synergistic induction of mitochondrial damage and apoptosis in human leukemia cells by flavopiridol and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). Leukemia 2002, 16:1331-1343.
19. Inoue S., Walewska R., Dyer M.J., Cohen G.M. Downregulation of Mcl-1 potentiates HDACi-mediated apoptosis in leukemic cells. Leukemia 2008, 22:819-825.
20. Rosato R.R., Almenara J.A., Yu C., Grant S. Evidence of a functional role for p21WAF1/CIP1 down-regulation in synergistic antileukemic interactions between the histone deacetylase inhibitor sodium butyrate and flavopiridol. Mol Pharmacol 2004, 65:571-581.
21. Gojo I., Zhang B., Fenton R.G. The cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in multiple myeloma cells through transcriptional repression and down-regulation of Mcl-1. Clin Cancer Res 2002, 8:3527-3538.
22. Ma Y., Cress W.D., Haura E.B. Flavopiridol-induced apoptosis is mediated through up-regulation of E2F1 and repression of Mcl-1. Mol Cancer Ther 2003, 2:73-81.
23. Nebbioso A., Clarke N., Voltz E., et al. Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nat Med 2005, 11:77-84.
24. Ruefli A.A., Ausserlechner M.J., Bernhard D., et al. The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell-death pathway characterized by cleavage of Bid and production of reactive oxygen species. Proc Natl Acad Sci USA 2001, 98:10833-10838.
25. Rosato R.R., Almenara J.A., Grant S. The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1 1. Cancer Res 2003, 63:3637-3645.
26. Bali P., Pranpat M., Bradner J., et al. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J Biol Chem 2005, 280:26729-26734.
27. Chen C.S., Wang Y.C., Yang H.C., et al. Histone deacetylase inhibitors sensitize prostate cancer cells to agents that produce DNA double-strand breaks by targeting Ku70 acetylation. Cancer Res 2007, 67:5318-5327.
28. Zhao Y., Tan J., Zhuang L., Jiang X., Liu E.T., Yu Q. Inhibitors of histone deacetylases target the Rb-E2F1 pathway for apoptosis induction through activation of proapoptotic protein Bim. Proc Natl Acad Sci USA 2005, 102:16090-16095.
29. Qiu L., Burgess A., Fairlie D.P., Leonard H., Parsons P.G., Gabrielli B.G. Histone deacetylase inhibitors trigger a G2 checkpoint in normal cells that is defective in tumor cells. Mol Biol Cell 2000, 11:2069-2083.
30. Reed-Inderbitzin E., Moreno-Miralles I., Vanden-Eynden S.K., et al. RUNX1 associates with histone deacetylases and SUV39H1 to repress transcription. Oncogene 2006, 25:5777-5786.
31. Garcia-Manero G., Yang H., Bueso-Ramos C., et al. Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood 2008, 111:1060-1066.
32. Garcia-Manero G., Assouline S., Cortes J., et al. Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia. Blood 2008, 112:981-989.
33. Bali P., George P., Cohen P., et al. Superior activity of the combination of histone deacetylase inhibitor LAQ824 and the FLT-3 kinase inhibitor PKC412 against human acute myelogenous leukemia cells with mutant FLT-3. Clin Cancer Res 2004, 10:4991-4997.
34. Yu C., Rahmani M., Conrad D., Subler M., Dent P., Grant S. The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571. Blood 2003, 102:3765-3774.
35. Dai Y., Chen S., Kramer L.B., Funk V.L., Dent P., Grant S. Interactions between bortezomib and romidepsin and belinostat in chronic lymphocytic leukemia cells. Clin Cancer Res 2008, 14:549-558.
36. Catley L., Weisberg E., Kiziltepe T., et al. Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood 2006, 108:3441-3449.
37. Badros A., Burger A.M., Philip S., et al. Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma. Clin Cancer Res 2009, 15:5250-5257.
38. Cortes J., Thomas D., Koller C., et al. Phase I study of bortezomib in refractory or relapsed acute leukemias. Clin Cancer Res 2004, 10:3371-3376.
39. Marchion D.C., Bicaku E., Daud A.I., Richon V., Sullivan D.M., Munster P.N. Sequence-specific potentiation of topoisomerase II inhibitors by the histone deacetylase inhibitor suberoylanilide hydroxamic acid. J Cell Biochem 2004, 92:223-237.
40. Shiozawa K., Nakanishi T., Tan M., et al. Preclinical studies of vorinostat (suberoylanilide hydroxamic acid) combined with cytosine arabinoside and etoposide for treatment of acute leukemias. Clin Cancer Res 2009, 15:1698-1707.
41. Cameron E.E., Bachman K.E., Myohanen S., Herman J.G., Baylin S.B. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet 1999, 21:103-107.
42. Gore S.D., Baylin S., Sugar E., et al. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res 2006, 66:6361-6369.
43. Garcia-Manero G., Kantarjian H.M., Sanchez-Gonzalez B., et al. Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia. Blood 2006, 108:3271-3279.
44. Levis M., Small D. FLT3: ITDoes matter in leukemia. Leukemia 2003, 17:1738-1752.
45. Frohling S., Schlenk R.F., Breitruck J., et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 2002, 100:4372-4380.
46. Kottaridis P.D., Gale R.E., Frew M.E., et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 2001, 98:1752-1759.
47. Schnittger S., Schoch C., Dugas M., et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood 2002, 100:59-66.
48. Smith B.D., 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 2004, 103:3669-3676.
49. Stone R.M., DeAngelo D.J., Klimek V., et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood 2005, 105:54-60.
50. Levis M., Smith B.D., 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. Blood 2005, 106:121a.
51. Fathi A.T., Levis M. Lestaurtinib: a multi-targeted FLT3 inhibitor. Expert Rev Hematol 2008, 2:17-26.
52. Smith B.D., 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 2004, 103:3669-3676.
53. Levis M., Smith B.D., 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. Blood 2005, 106:121a.
54. Knapper S., Burnett A.K., 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 2006, 108:3262-3270.
55. Stone R.M., DeAngelo D.J., Klimek V., et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood 2005, 105:54-60.
56. Stone R.M., Fischer T., Paquette R., et al. Phase IB study of PKC412, an oral FLT3 kinase inhibitor, in sequential and simultaneous combinations with daunorubicin and cytarabine (DA) induction and high-dose cytarabine consolidation in newly diagnosed patients with AML. Blood 2005, 106:121a.
57. Deangelo D.J., Stone R.M., Heaney M.L., et al. Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics. Blood 2006, 108:3674-3681.
58. Clark J.W., Eder J.P., Ryan D., Lathia C., Lenz H.J. Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors. Clin Cancer Res 2005, 11:5472-5480.
59. Ng R., Chen E.X. Sorafenib (BAY 43-9006): review of clinical development. Curr Clin Pharmacol 2006, 1:223-228.
60. Escudier B., Eisen T., Stadler W.M., et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007, 356:125-134.
61. Llovet J.M., Ricci S., Mazzaferro V., et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008, 359:378-390.
62. Christiansen D.H., Andersen M.K., Desta F., Pedersen-Bjergaard J. Mutations of genes in the receptor tyrosine kinase (RTK)/RAS-BRAF signal transduction pathway in therapy-related myelodysplasia and acute myeloid leukemia. Leukemia 2005, 19:2232-2240.
63. Auclair D., Miller D., Yatsula V., et al. Antitumor activity of sorafenib in FLT3-driven leukemic cells. Leukemia 2007, 21:439-445.
64. Zhang W., Konopleva M., Ruvolo V.R., et al. Sorafenib induces apoptosis of AML cells via Bim-mediated activation of the intrinsic apoptotic pathway. Leukemia 2008, 22:808-818.
65. Delmonte J, Kantarjian HM, Andreef M, et al. Update of a phase I atudy of sorafenib in patients with refractory/relapsed acute myeloid leukemia or high-risk myelodysplastic syndrome. Blood (ASH Annual Meeting Abstracts 2007); 110: Abstract 893.
66. Pratz KW, Cho E, Karp J, et al. Phase I dose escalation trial of sorafenib as a single agent for adults with relapsed and refractory acute leukemias. J Clin Oncol 2009;27((suppl; abstr 7065)):15s.
67. Metzelder S., Wang Y., Wollmer E., et al. Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation. Blood 2009, 113:6567-6571.
68. Ravandi F, Cortes J, Faderl SH, et al. Combination of sorafenib, idarubicin, and cytarabine has a high response rate in patients with newly diagnosed acute myeloid leukemia (AML) younger than 65 years. Blood (ASH Annual Meeting Abstracts 2008);112(Abstract):768.
69. Cortes J, Roboz GJ, Kantarjian H, et al. A phase I dose escalation study of KW-2449, an oral multi-kinase inhibitor against FLT3, Abl, FGFR1 and Aurora in patients with relapsed/refractory AML, ALL and MDS or resistant/intolerant CML. Blood 2008;112 (Abstract 2967).
70. Pratz K.W., Cortes J., Roboz G.J., et al. A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response. Blood 2009, 113:3938-3946.
71. Shiotsu Y., Kiyoi H., Ishikawa Y., et al. KW-2449, a novel multi-kinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation. Blood 2009, 114:1607-1617.
72. Cortes J, Ghirdaladze D, Foran JM, et al. Phase 1 AML study of AC220, a potent and selective second generation FLT3 receptor tyrosine kinase inhibitor. Blood (ASH Annual Meeting Abstracts 2008);112:(Abstract 767).
73. Zarrinkar P.P., Gunawardane R.N., Cramer M.D., et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood 2009, 114:2984-2992.
74. James J, Pratz KW, Stine A, et al. Clinical pharmacokinetics and FLT3 phosphorylation of AC220, a highly potent and selective inhibitor of FLT3. Blood (ASH Annual Meeting Abstracts 2008);112:(Abstract 2637).
75. Kim K.T., Baird K., Ahn J.Y., et al. Pim-1 is up-regulated by constitutively activated FLT3 and plays a role in FLT3-mediated cell survival. Blood 2005, 105:1759-1767.
76. Kim K.T., Levis M., Small D. Constitutively activated FLT3 phosphorylates BAD partially through pim-1. Br J Haematol 2006, 134:500-509.
77. Fathi AT, Swinnen I, Rajkhowa T, et al. PIM: an integral component of FLT3 signaling and a potential therapeutic target in acute myeloid leukemia. (ASH Annual Meeting Abstracts 2009);(Abstract no.1735).
78. Chen L.S., Redkar S., Bearss D., Wierda W.G., Gandhi V. Pim kinase inhibitor, SGI-1776, induces apoptosis in chronic lymphocytic leukemia cells. Blood 2009, 114:4150-4157.
79. Witzig T.E., Kaufmann S.H. Inhibition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in hematologic malignancies. Curr Treat Options Oncol 2006, 7:285-294.
80. Tokunaga C., Yoshino K., Yonezawa K. MTOR integrates amino acid- and energy-sensing pathways. Biochem Biophys Res Commun 2004, 313:443-446.
81. Cappellini A., Tabellini G., Zweyer M., et al. The phosphoinositide 3-kinase/Akt pathway regulates cell cycle progression of HL60 human leukemia cells through cytoplasmic relocalization of the cyclin-dependent kinase inhibitor p27(Kip1) and control of cyclin D1 expression. Leukemia 2003, 17:2157-2167.
82. Martelli A.M., Nyakern M., Tabellini G., et al. Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia. Leukemia 2006, 20:911-928.
83. Sandsmark D.K., Zhang H., Hegedus B., Pelletier C.L., Weber J.D., Gutmann D.H. Nucleophosmin mediates mammalian target of rapamycin-dependent actin cytoskeleton dynamics and proliferation in neurofibromin-deficient astrocytes. Cancer Res 2007, 67:4790-4799.
84. Hennessy B.T., Smith D.L., Ram P.T., Lu Y., Mills G.B. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 2005, 4:988-1004.
85. Xu Q., Simpson S.E., Scialla T.J., Bagg A., Carroll M. Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood 2003, 102:972-980.
86. Zhao S., Konopleva M., Cabreira-Hansen M., et al. Inhibition of phosphatidylinositol 3-kinase dephosphorylates BAD and promotes apoptosis in myeloid leukemias. Leukemia 2004, 18:267-275.
87. Bertrand F.E., Spengemen J.D., Shelton J.G., McCubrey J.A. Inhibition of PI3K, mTOR and MEK signaling pathways promotes rapid apoptosis in B-lineage ALL in the presence of stromal cell support. Leukemia 2005, 19:98-102.
88. Grandage V.L., Gale R.E., Linch D.C., Khwaja A. PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-kappaB, Mapkinase and p53 pathways. Leukemia 2005, 19:586-594.
89. Brandts C.H., Sargin B., Rode M., et al. Constitutive activation of Akt by Flt3 internal tandem duplications is necessary for increased survival, proliferation, and myeloid transformation. Cancer Res 2005, 65:9643-9650.
90. Recher C., Beyne-Rauzy O., Demur C., et al. Antileukemic activity of rapamycin in acute myeloid leukemia. Blood 2005, 105:2527-2534.
91. Xu Z., Wang M., Wang L., et al. Aberrant expression of TSC2 gene in the newly diagnosed acute leukemia. Leuk Res 2009, 33:891-897.
92. Sehgal S.N. Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem 1998, 31:335-340.
93. Vignot S., Faivre S., Aguirre D., Raymond E. MTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol 2005, 16:525-537.
94. Zeng Z., Sarbassov dos D., Samudio I.J., et al. Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 2007, 109:3509-3512.
95. Sarbassov D.D., Guertin D.A., Ali S.M., Sabatini D.M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005, 307:1098-1101.
96. Callera F., Lopes C.O., Rosa E.S., Mulin C.C. Lack of antileukemic activity of rapamycin in elderly patients with acute myeloid leukemia evolving from a myelodysplastic syndrome. Leuk Res 2008, 32:1633-1634.
97. Yee K.W., 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 2006, 12:5165-5173.
98. Xu Q., Thompson J.E., Carroll M. MTOR regulates cell survival after etoposide treatment in primary AML cells. Blood 2005, 106:4261-4268.
99. Campos L., Rouault J.P., Sabido O., et al. High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood 1993, 81:3091-3096.
100. Karakas T., Miething C.C., Maurer U., et al. The coexpression of the apoptosis-related genes bcl-2 and wt1 in predicting survival in adult acute myeloid leukemia. Leukemia 2002, 16:846-854.
101. Klasa R.J., Gillum A.M., Klem R.E., Frankel S.R. Oblimersen Bcl-2 antisense: facilitating apoptosis in anticancer treatment. Antisense Nucleic Acid Drug Dev 2002, 12:193-213.
102. Marcucci G., Byrd J.C., Dai G., et al. Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia. Blood 2003, 101:425-432.
103. Marcucci G., Stock W., Dai G., et al. Phase I study of oblimersen sodium, an antisense to Bcl-2, in untreated older patients with acute myeloid leukemia: pharmacokinetics, pharmacodynamics, and clinical activity. J Clin Oncol 2005, 23:3404-3411.
104. Marcucci G, Moser B, Blum W, et al. A phase III randomized trial of intensive induction and consolidation chemotherapy ± oblimersen, a pro-apoptotic Bcl-2 antisense oligonucleotide in untreated acute myeloid leukemia patients >60 years old. J Clin Oncol 2007 ASCO Annual Meeting Proceedings Part 1 2007;25:7012.
105. Lacasse E.C., Kandimalla E.R., Winocour P., et al. Application of XIAP antisense to cancer and other proliferative disorders: development of AEG35156/GEM640. Ann NY Acad Sci 2005, 1058:215-234.
106. Carter B.Z., Gronda M., Wang Z., et al. Small-molecule XIAP inhibitors derepress downstream effector caspases and induce apoptosis of acute myeloid leukemia cells. Blood 2005, 105:4043-4050.
107. Tamm I. AEG-35156, an antisense oligonucleotide against X-linked inhibitor of apoptosis for the potential treatment of cancer. Curr Opin Investig Drugs 2008, 9:638-646.
108. Schimmer A.D., Estey E., Borthakur G., et al. Phase 1/2 trial of AEG35156 in combination with idarubicin and cytarabine in patients with relapsed or refractory AML. J Clin Oncol 2009, 27:4741-4746.
109. Carter BZ, Mak DH, Morris S, et al. Pharmacodynamic study of phase 1/2 trial of the XIAP antisense oligonucleotide () in combination with chemotherapy in patients with relapsed/refractory AML. Blood, 2008 ASH Annual Meeting Abstracts 2008;112:678. ncbi-p:AEG35156.
110. Ame J.C., Rolli V., Schreiber V., et al. PARP-2, A novel mammalian DNA damage-dependent poly(ADP-ribose) polymerase. J Biol Chem 1999, 274:17860-17868.
111. Ame J.C., Spenlehauer C., de Murcia G. The PARP superfamily. Bioessays 2004, 26:882-893.
112. Schreiber V., Ame J.C., Dolle P., et al. Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1. J Biol Chem 2002, 277:23028-23036.
113. Yu S.W., Wang H., Poitras M.F., et al. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 2002, 297:259-263.
114. de Murcia J.M., Niedergang C., Trucco C., et al. Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proc Natl Acad Sci USA 1997, 94:7303-7307.
115. Park S.Y., Cheng Y.C. Poly(ADP-ribose) polymerase-1 could facilitate the religation of topoisomerase I-linked DNA inhibited by camptothecin. Cancer Res 2005, 65:3894-3902.
116. Masutani M., Nozaki T., Nakamoto K., et al. The response of Parp knockout mice against DNA damaging agents. Mutat Res 2000, 462:159-166.
117. O'Shaughnessy J, Osborne C, Pippen J, et al. Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): Results of a randomized phase II trial. J Clin Oncol 2009;27:18s(suppl; abstr 3).
118. Gaymes TJ, Shall S, Farzaneh F, Mufti GJ. Poly ADP ribose polymerase (PARP) inhibitors induce apoptosis alone or synergistically with histone deacetylase inhibitors in primary acute myeloid leukemic patient cells. Blood (ASH Annual Meeting Abstracts 2008);112:Abstract 2974.
119. Donawho C.K., Luo Y., Penning T.D., et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res 2007, 13:2728-2737.
120. Kummar S., Kinders R., Gutierrez M.E., et al. Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor ABT-888 in patients with advanced malignancies. J Clin Oncol 2009, 27:2705-2711.
121. Sebolt-Leopold J.S., Herrera R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer 2004, 4:937-947.
122. Towatari M., Iida H., Tanimoto M., Iwata H., Hamaguchi M., Saito H. Constitutive activation of mitogen-activated protein kinase pathway in acute leukemia cells. Leukemia 1997, 11:479-484.
123. Steelman L.S., Abrams S.L., Whelan J., et al. Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia. Leukemia 2008, 22:686-707.
124. Ewings K.E., Hadfield-Moorhouse K., Wiggins C.M., et al. ERK1/2-dependent phosphorylation of BimEL promotes its rapid dissociation from Mcl-1 and Bcl-xL. Embo J 2007, 26:2856-2867.
125. Milella M., Kornblau S.M., Estrov Z., et al. Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia. J Clin Invest 2001, 108:851-859.
126. Kojima K., Konopleva M., Samudio I.J., Ruvolo V., Andreeff M. Mitogen-activated protein kinase kinase inhibition enhances nuclear proapoptotic function of p53 in acute myelogenous leukemia cells. Cancer Res 2007, 67:3210-3219.
127. Konopleva M., Contractor R., Tsao T., et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 2006, 10:375-388.
128. Carracedo A., Ma L., Teruya-Feldstein J., et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 2008, 118:3065-3074.
129. Martinelli G., Iacobucci I., Paolini S., Ottaviani E. Farnesyltransferase inhibition in hematologic malignancies: the clinical experience with tipifarnib. Clin Adv Hematol Oncol 2008, 6:303-310.
130. Karp J.E., Lancet J.E. Tipifarnib in the treatment of newly diagnosed acute myelogenous leukemia. Biologics 2008, 2:491-500.
131. Gore S.D. Combination therapy with DNA methyltransferase inhibitors in hematologic malignancies. Nat Clin Pract Oncol 2005, 2(Suppl. 1):S30-S35.
132. Plass C., Oakes C., Blum W., Marcucci G. Epigenetics in acute myeloid leukemia. Semin Oncol 2008, 35:378-387.
133. Gilliland D.G. Molecular genetics of human leukemias: new insights into therapy. Semin Hematol 2002, 39:6-11.
134. Pedersen-Bjergaard J., Christiansen D.H., Desta F., Andersen M.K. Alternative genetic pathways and cooperating genetic abnormalities in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia. Leukemia 2006, 20:1943-1949.
135. Park S., Chapuis N., Bardet V., et al. PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML. Leukemia 2008, 22:1698-1706.
136. Kondapaka S.B., Singh S.S., Dasmahapatra G.P., Sausville E.A., Roy K.K. Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation. Mol Cancer Ther 2003, 2:1093-1103.
137. Rizzieri D.A., Feldman E., Dipersio J.F., et al. A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 2008, 14:2756-2762.
138. Tse C., Shoemaker A.R., Adickes J., et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 2008, 68:3421-3428.
139. Kang M.H., Reynolds C.P. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res 2009, 15:1126-1132.
140. Schimmer AD, Brandwein J, O'Brien SM, et al. A phase I trial of the small molecule pan-Bcl-2 family inhibitor obatoclax mesylate (GX15-070) administered by continuous infusion for up to four days to patients with hematological malignancies. Blood (ASH Annual Meeting Abstracts 2007);110:Abstract 892.