Cancer Treatment Reviews
Volume 36, Issue 2 , Pages 142-150 , April 2010

Exploiting cellular pathways to develop new treatment strategies for AML

  • Amir T. Fathi

      Affiliations

    • Division of Hematologic Malignancies, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans Street, Baltimore, MD 21231, United States
    • ,
  • Steven Grant

      Affiliations

    • Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine and Massey Cancer Center, MCV Station Box 230, Richmond, VA 23298, United States
    • Fax: +1 804 225 3788.
    • ,
  • Judith E. Karp

      Affiliations

    • Division of Hematologic Malignancies, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans Street, Baltimore, MD 21231, United States
    • Corresponding Author InformationCorresponding author. Tel.: +1 410 503 5399; fax: +1 410 614 1005.

Received 11 September 2009 ,Revised 1 December 2009 ,Accepted 5 December 2009.

References 

  1. Lowenberg B, Downing JR, Burnett A. Acute myeloid leukemia. N Engl J Med. 1999;341:1051–1062
  2. Karp JE, Smith MA. The molecular pathogenesis of treatment-induced (secondary) leukemias: foundations for treatment and prevention. Semin Oncol. 1997;24:103–113
  3. Bao T, Smith BD, Karp JE. 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 RJ, List AF, Cheson BD. Rational approaches to design of therapeutics targeting molecular markers. Hematol Am Soc Hematol Educ Program. 2001;443–462
  5. Sedlacek HH. Mechanisms of action of flavopiridol. Crit Rev Oncol Hematol. 2001;38:139–170
  6. Chao SH, Price DH. Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo. J Biol Chem. 2001;276:31793–31799
  7. Karp JE, Ross DD, 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 EA, Cloud K, Lahusen T, Varesio L, Senderowicz AM. 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 JC, Shinn C, Waselenko JK, 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 RH, 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 KC, Kaufmann SH. 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 JE, 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 JE, Smith BD, Levis MJ, 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.
  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 JC, Lin TS, Dalton JT, 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 JE. 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 MJ, Cohen GM. Downregulation of Mcl-1 potentiates HDACi-mediated apoptosis in leukemic cells. Leukemia. 2008;22:819–825
  20. Rosato RR, Almenara JA, 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 RG. 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 WD, Haura EB. 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 AA, Ausserlechner MJ, 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 RR, Almenara JA, 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 CS, Wang YC, Yang HC, 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 ET, 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 DP, Leonard H, Parsons PG, Gabrielli BG. 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 SK, 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 LB, Funk VL, 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 AM, 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 DC, Bicaku E, Daud AI, Richon V, Sullivan DM, Munster PN. 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 EE, Bachman KE, Myohanen S, Herman JG, Baylin SB. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet. 1999;21:103–107
  42. Gore SD, 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 HM, 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 RF, 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 PD, Gale RE, Frew ME, 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 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. 2004;103:3669–3676
  49. Stone RM, DeAngelo DJ, 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 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. Blood. 2005;106:121a
  51. Fathi AT, Levis M. Lestaurtinib: a multi-targeted FLT3 inhibitor. Expert Rev Hematol. 2008;2:17–26
  52. 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. 2004;103:3669–3676
  53. 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. Blood. 2005;106:121a
  54. 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. 2006;108:3262–3270
  55. Stone RM, DeAngelo DJ, 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 RM, 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 DJ, Stone RM, Heaney ML, 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 JW, Eder JP, Ryan D, Lathia C, Lenz HJ. 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 EX. Sorafenib (BAY 43-9006): review of clinical development. Curr Clin Pharmacol. 2006;1:223–228
  60. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125–134
  61. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–390
  62. Christiansen DH, Andersen MK, 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 VR, 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 KW, Cortes J, Roboz GJ, 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 PP, Gunawardane RN, Cramer MD, 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 KT, Baird K, Ahn JY, 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 KT, 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 LS, Redkar S, Bearss D, Wierda WG, Gandhi V. Pim kinase inhibitor, SGI-1776, induces apoptosis in chronic lymphocytic leukemia cells. Blood. 2009;114:4150–4157
  79. Witzig TE, Kaufmann SH. 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 AM, 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 DK, Zhang H, Hegedus B, Pelletier CL, Weber JD, Gutmann DH. Nucleophosmin mediates mammalian target of rapamycin-dependent actin cytoskeleton dynamics and proliferation in neurofibromin-deficient astrocytes. Cancer Res. 2007;67:4790–4799
  84. Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 2005;4:988–1004
  85. Xu Q, Simpson SE, Scialla TJ, 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 FE, Spengemen JD, Shelton JG, McCubrey JA. 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 VL, Gale RE, Linch DC, 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 CH, 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 SN. 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 IJ, et al. Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood. 2007;109:3509–3512
  95. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307:1098–1101
  96. Callera F, Lopes CO, Rosa ES, Mulin CC. 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 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. 2006;12:5165–5173
  98. Xu Q, Thompson JE, Carroll M. MTOR regulates cell survival after etoposide treatment in primary AML cells. Blood. 2005;106:4261–4268
  99. Campos L, Rouault JP, 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 CC, 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 RJ, Gillum AM, Klem RE, Frankel SR. Oblimersen Bcl-2 antisense: facilitating apoptosis in anticancer treatment. Antisense Nucleic Acid Drug Dev. 2002;12:193–213
  102. Marcucci G, Byrd JC, 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 EC, Kandimalla ER, 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 BZ, 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 AD, 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 (AEG35156) in combination with chemotherapy in patients with relapsed/refractory AML. Blood, 2008 ASH Annual Meeting Abstracts 2008;112:678.
  110. Ame JC, 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 JC, Spenlehauer C, de Murcia G. The PARP superfamily. Bioessays. 2004;26:882–893
  112. Schreiber V, Ame JC, 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 SW, Wang H, Poitras MF, et al. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science. 2002;297:259–263
  114. de Murcia JM, 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 SY, Cheng YC. 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 CK, Luo Y, Penning TD, 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 ME, 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 JS, 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 LS, Abrams SL, 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 KE, Hadfield-Moorhouse K, Wiggins CM, 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 SM, 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 IJ, 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 JE, Lancet JE. Tipifarnib in the treatment of newly diagnosed acute myelogenous leukemia. Biologics. 2008;2:491–500
  131. Gore SD. 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 DG. Molecular genetics of human leukemias: new insights into therapy. Semin Hematol. 2002;39:6–11
  134. Pedersen-Bjergaard J, Christiansen DH, Desta F, Andersen MK. 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 SB, Singh SS, Dasmahapatra GP, Sausville EA, Roy KK. Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation. Mol Cancer Ther. 2003;2:1093–1103
  137. Rizzieri DA, Feldman E, Dipersio JF, 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 AR, Adickes J, et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008;68:3421–3428
  139. Kang MH, Reynolds CP. 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.

PII: S0305-7372(09)00186-8

doi: 10.1016/j.ctrv.2009.12.004

Cancer Treatment Reviews
Volume 36, Issue 2 , Pages 142-150 , April 2010

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