319
Views
13
CrossRef citations to date
0
Altmetric
Review

Emerging therapeutic targets for the treatment of human acute myeloid leukemia (part 1) – gene transcription, cell cycle regulation, metabolism and intercellular communication

, , , &

References

  • Döhner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010;115(3):453-74
  • Stapnes C, Gjertsen BT, Reikvam H, Bruserud O. Targeted therapy in acute myeloid leukaemia: current status and future directions. Expert Opin Investig Drugs 2009;18(4):433-55
  • Reikvam H, Hatfield KJ, Fredly H, et al. The angioregulatory cytokine network in human acute myeloid leukemia - from leukemogenesis via remission induction to stem cell transplantation. Eur Cytokine Netw 2012;23(4):140-53
  • Reikvam H, Hatfield KJ, Lassalle P, et al. Targeting the angiopoietin (Ang)/Tie-2 pathway in the crosstalk between acute myeloid leukaemia and endothelial cells: studies of Tie-2 blocking antibodies, exogenous Ang-2 and inhibition of constitutive agonistic Ang-1 release. Expert Opin Investig Drugs 2010;19(2):169-83
  • Hatfield KJ, Olsnes AM, Gjertsen BT, Bruserud O. Antiangiogenic therapy in acute myelogenous leukemia: targeting of vascular endothelial growth factor and interleukin 8 as possible antileukemic strategies. Curr Cancer Drug Targets 2005;5(4):229-48
  • Wellbrock J, Fiedler W. Clinical experience with antiangiogenic therapy in leukemia. Curr Cancer Drug Targets 2011;11(9):1053-68
  • Tsykunova G, Reikvam H, Ahmed AB, et al. Targeting of polo-like kinases and their cross talk with Aurora kinases–possible therapeutic strategies in human acute myeloid leukemia? Expert Opin Investig Drugs 2012;21(5):587-603
  • Reikvam H, Ersvaer E, Bruserud O. Heat shock protein 90 - a potential target in the treatment of human acute myelogenous leukemia. Curr Cancer Drug Targets 2009;9(6):761-76
  • Reikvam H, Hatfield KJ, Ersvaer E, et al. Expression profile of heat shock proteins in acute myeloid leukaemia patients reveals a distinct signature strongly associated with FLT3 mutation status - consequences and potentials for pharmacological intervention. Br J Haematol 2012;156(4):468-80
  • Reikvam H, Nepstad I, Sulen A, et al. Increased antileukemic effects in human acute myeloid leukemia by combining HSP70 and HSP90 inhibitors. Expert Opin Investig Drugs 2013;22(5):551-63
  • Reikvam H, Brenner AK, Nepstad I, et al. Heat shock protein 70 - the next chaperone to target in the treatment of human acute myelogenous leukemia? Expert Opin Ther Targets 2014;18(8):929-44
  • Reikvam H, Olsnes AM, Gjertsen BT, et al. Nuclear factor-kappaB signaling: a contributor in leukemogenesis and a target for pharmacological intervention in human acute myelogenous leukemia. Crit Rev Oncog 2009;15(1-2):1-41
  • Bruserud O, Reikvam H. Therapeutic targeting of NF-kappaB in myelodysplastic syndromes and acute myeloid leukaemia - the biological heterogeneity. Expert Opin Ther Targets 2010;14(11):1139-42
  • Reikvam H, Tamburini J, Skrede S, et al. Antileukaemic effect of PI3K-mTOR inhibitors in acute myeloid leukaemia-gene expression profiles reveal CDC25B expression as determinate of pharmacological effect. Br J Haematol 2014;164(2):200-11
  • Reikvam H, Nepstad I, Tamburini J. Predicting effects of kinase inhibitor in therapy for myeloid malignancies - the challenges in capturing disease heterogeneity. Expert Opin Investig Drugs 2013;22(11):1365-70
  • Martelli AM, Evangelisti C, Chiarini F, et al. Targeting the PI3K/AKT/mTOR signaling network in acute myelogenous leukemia. Expert Opin Invest Drugs 2009;18(9):1333-49
  • Weisberg E, Barrett R, Liu Q, et al. FLT3 inhibition and mechanisms of drug resistance in mutant FLT3-positive AML. Drug Resist Updat 2009;12(3):81-9
  • Bruserud O, Nepstad I, Hauge M, et al. STAT3 as a possible therapeutic target in human malignancies: Lessions from acute myeloid leukemia. Exp Rev Hematol 2014;6:1-13
  • Seavey MM, Dobrzanski P. The many faces of Janus kinase. Biochem Pharmacol 2012;83(9):1136-45
  • Rozovski U, Wu JY, Harris DM, et al. Stimulation of the B-cell receptor activates the JAK2/STAT3 signaling pathway in chronic lymphocytic leukemia cells. Blood 2014;123(24):3797-802
  • Looyenga BD, Hutchings D, Cherni I, et al. STAT3 is activated by JAK2 independent of key oncogenic driver mutations in non-small cell lung carcinoma. PLoS One 2012;7(2):e30820
  • Eghtedar A, Verstovsek S, Estrov Z, et al. Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia. Blood 2012;119(20):4614-18
  • Yang H, Lawrence HR, Kazi A, et al. Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation. Oncotarget 2014;5(10):2947-61
  • Bruserud O, Hovland R, Wergeland L, et al. Flt3-mediated signaling in human acute myelogenous leukemia (AML) blasts: a functional characterization of Flt3-ligand effects in AML cell populations with and without genetic Flt3 abnormalities. Haematologica 2003;88(4):416-28
  • Ofran Y, Rowe JM. Treatment for relapsed acute myeloid leukemia: what is new? Curr Opin Hematol 2012;19(2):89-94
  • Bruserud O, Gjertsen BT, Foss B, Huang TS. New strategies in the treatment of acute myelogenous leukemia (AML): in vitro culture of aml cells--the present use in experimental studies and the possible importance for future therapeutic approaches. Stem Cells 2001;19(1):1-11
  • Advani AS, Tiu R, Saunthararajah Y, et al. A Phase 1 study of imatinib mesylate in combination with cytarabine and daunorubicin for c-kit positive relapsed acute myeloid leukemia. Leuk Res 2010;34(12):1622-6
  • Mikesch JH, Steffen B, Berdel WE, et al. The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia. Leukemia 2007;21(8):1638-47
  • Dinner SN, Giles FJ, Altman JK. New strategies for relapsed acute myeloid leukemia: fertile ground for translational research. Curr Opin Hematol 2014;21(2):79-86
  • Bruserud O, Nepstad I, Hauge M, et al. STAT3 as a possible therapeutic target in human malignancies: lessons from acute myeloid leukemia. Expert Rev Hematol 2015;8(1):29-41
  • Oku S, Takenaka K, Kuriyama T, et al. JAK2 V617F uses distinct signalling pathways to induce cell proliferation and neutrophil activation. Br J Haematol 2010;150(3):334-44
  • Keeton EK, McEachern K, Dillman KS, et al. AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia. Blood 2014;123(6):905-13
  • Yi S, Wen L, He J, et al. Deguelin, a selective silencer of the NPM1 mutant, potentiates apoptosis and induces differentiation in AML cells carrying the NPM1 mutation. Ann Hematol 2015;94(2):201-10
  • Balusu R, Fiskus W, Rao R, et al. Targeting levels or oligomerization of nucleophosmin 1 induces differentiation and loss of survival of human AML cells with mutant NPM1. Blood 2011;118(11):3096-106
  • Mukherjee H, Chan KP, Andresen V, et al. Interactions of the natural product (+)-avrainvillamide with nucleophosmin and exportin-1 mediate the cellular localization of nucleophosmin and its AML-associated mutants. ACS Chem Biol 2015;10(3):855-63
  • Zaitseva L, Murray MY, Shafat MS, et al. Ibrutinib inhibits SDF1/CXCR4 mediated migration in AML. Oncotarget 2014;5(20):9930-8
  • Rushworth SA, Murray MY, Zaitseva L, et al. Identification of Bruton’s tyrosine kinase as a therapeutic target in acute myeloid leukemia. Blood 2014;123(8):1229-38
  • Davids MS. Boldly targeting kinases without mutations. Blood 2014;123(8):1119-21
  • Placke T, Faber K, Nonami A, et al. Requirement for CDK6 in MLL-rearranged acute myeloid leukemia. Blood 2014;124(1):13-23
  • van der Linden MH, Willekes M, van Roon E, et al. MLL fusion-driven activation of CDK6 potentiates proliferation in MLL-rearranged infant ALL. Cell Cycle 2014;13(5):834-44
  • Choi YJ, Anders L. Signaling through cyclin D-dependent kinases. Oncogene 2014;33(15):1890-903
  • Musgrove EA, Caldon CE, Barraclough J, et al. Cyclin D as a therapeutic target in cancer. Nat Rev Cancer 2011;11(8):558-72
  • Kozar K, Sicinski P. Cell cycle progression without cyclin D-CDK4 and cyclin D-CDK6 complexes. Cell Cycle 2005;4(3):388-91
  • Wang L, Wang J, Blaser BW, et al. Pharmacologic inhibition of CDK4/6: mechanistic evidence for selective activity or acquired resistance in acute myeloid leukemia. Blood 2007;110(6):2075-83
  • Dickson MA, Tap WD, Keohan ML, et al. Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J Clin Oncol 2013;31(16):2024-8
  • Schwartz GK, LoRusso PM, Dickson MA, et al. Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1). Br J Cancer 2011;104(12):1862-8
  • Flaherty KT, Lorusso PM, Demichele A, et al. Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. Clin Cancer Res 2012;18(2):568-76
  • Chiron D, Martin P, Di Liberto M, et al. Induction of prolonged early G1 arrest by CDK4/CDK6 inhibition reprograms lymphoma cells for durable PI3Kdelta inhibition through PIK3IP1. Cell Cycle 2013;12(12):1892-900
  • Puc J, Keniry M, Li HS, et al. Lack of PTEN sequesters CHK1 and initiates genetic instability. Cancer Cell 2005;7(2):193-204
  • Hirose Y, Katayama M, Mirzoeva OK, et al. Akt activation suppresses Chk2-mediated, methylating agent-induced G2 arrest and protects from temozolomide-induced mitotic catastrophe and cellular senescence. Cancer Res 2005;65(11):4861-9
  • Lavecchia A, Di Giovanni C, Pesapane A, et al. Discovery of new inhibitors of Cdc25B dual specificity phosphatases by structure-based virtual screening. J Med Chem 2012;55(9):4142-58
  • Lavecchia A, Di Giovanni C, Novellino E. CDC25 phosphatase inhibitors: an update. Mini Rev Med Chem 2012;12(1):62-73
  • Lavecchia A, Di Giovanni C, Novellino E. Inhibitors of Cdc25 phosphatases as anticancer agents: a patent review. Expert Opin Ther Pat 2010;20(3):405-25
  • Lavecchia A, Di Giovanni C, Novellino E. CDC25A and B dual-specificity phosphatase inhibitors: potential agents for cancer therapy. Curr Med Chem 2009;16(15):1831-49
  • Lavecchia A, Cosconati S, Limongelli V, Novellino E. Modeling of Cdc25B dual specifity protein phosphatase inhibitors: docking of ligands and enzymatic inhibition mechanism. ChemMedChem 2006;1(5):540-50
  • Lavecchia A, Coluccia A, Di Giovanni C, Novellino E. Cdc25B phosphatase inhibitors in cancer therapy: latest developments, trends and medicinal chemistry perspective. Anticancer Agents Med Chem 2008;8(8):843-56
  • Brenner AK, Reikvam H, Lavecchia A, Bruserud Ø. Therapeutic targeting the cell division cycle 25 (CDC25) phosphatases in human acute myeloid leukemia -The possibility to target several kinases through inhibition of the various CDC25 isoforms. Molecules 2014;19(11):18414-47
  • Malumbres M, Barbacid M. Mammalian cyclin-dependent kinases. Trends Biochem Sci 2005;30(11):630-41
  • Salaun P, Rannou Y, Prigent C. Cdk1, Plks, Auroras, and Neks: the mitotic bodyguards. Adv Exper Med Biol 2008;617:41-56
  • Macurek L, Lindqvist A, Medema RH. Aurora-A and hBora join the game of Polo. Cancer Res 2009;69(11):4555-8
  • Hyun SY, Hwang HI, Jang YJ. Polo-like kinase-1 in DNA damage response. BMB Rep 2014;47(5):249-55
  • Moore AS, Blagg J, Linardopoulos S, Pearson AD. Aurora kinase inhibitors: novel small molecules with promising activity in acute myeloid and Philadelphia-positive leukemias. Leukemia 2010;24(4):671-8
  • Janning M, Fiedler W. Volasertib for the treatment of acute myeloid leukemia: a review of preclinical and clinical development. Future Oncol 2014;10(7):1157-65
  • Gjertsen BT, Schoffski P. Discovery and development of the Polo-like kinase inhibitor volasertib in cancer therapy. Leukemia 2015;29(1):11-19
  • Lin CC, Su WC, Yen CJ, et al. A phase I study of two dosing schedules of volasertib (BI 6727), an intravenous polo-like kinase inhibitor, in patients with advanced solid malignancies. Br J Cancer 2014;110(10):2434-40
  • Monti SM, Supuran CT, De Simone G. Anticancer carbonic anhydrase inhibitors: a patent review (2008 - 2013). Expert Opin Ther Pat 2013;23(6):737-49
  • Chen J, Kremer CS, Bender TP. The carbonic anhydrase I locus contains a c-Myb target promoter and modulates differentiation of murine erythroleukemia cells. Oncogene 2006;25(19):2758-72
  • Pastorekova S, Zatovicova M, Pastorek J. Cancer-associated carbonic anhydrases and their inhibition. Curr Pharm Des 2008;14(7):685-98
  • Chow DC, Wenning LA, Miller WM, Papoutsakis ET. Modeling pO(2) distributions in the bone marrow hematopoietic compartment. I. Krogh’s model. Biophys J 2001;81(2):675-84
  • Hatfield KJ, Bedringsaas SL, Ryningen A, et al. Hypoxia increases HIF-1alpha expression and constitutive cytokine release by primary human acute myeloid leukaemia cells. Eur Cytokine Netw 2010;21(3):154-64
  • Abbate F, Casini A, Owa T, et al. Carbonic anhydrase inhibitors: E7070, a sulfonamide anticancer agent, potently inhibits cytosolic isozymes I and II, and transmembrane, tumor-associated isozyme IX. Bioorg Med Chem Lett 2004;14(1):217-23
  • Owa T, Yoshino H, Okauchi T, et al. Discovery of novel antitumor sulfonamides targeting G1 phase of the cell cycle. J Med Chem 1999;42(19):3789-99
  • Ozawa Y, Kusano K, Owa T, et al. Therapeutic potential and molecular mechanism of a novel sulfonamide anticancer drug, indisulam (E7070) in combination with CPT-11 for cancer treatment. Cancer Chemother Pharmacol 2012;69(5):1353-62
  • E7070, idarubicin and cytarabine in relapsed AML and high-risk myelodysplastic syndromes. Available from: https://clinicaltrials.gov/ct2/show/NCT01692197
  • Geng L, Wang X. New insight into hedgehog signaling in hematological malignancies. Leuk Lymphoma 2014. [Epub ahead of print]
  • Kobune M, Iyama S, Kikuchi S, et al. Stromal cells expressing hedgehog-interacting protein regulate the proliferation of myeloid neoplasms. Blood Cancer J 2012;2:e87
  • Bhardwaj G, Murdoch B, Wu D, et al. Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nat Immunol 2001;2(2):172-80
  • Sandhiya S, Melvin G, Kumar SS, Dkhar SA. The dawn of hedgehog inhibitors: vismodegib. J Pharmacol Pharmacother 2013;4(1):4-7
  • Ally MS, Aasi S, Wysong A, et al. An investigator-initiated open-label clinical trial of vismodegib as a neoadjuvant to surgery for high-risk basal cell carcinoma. J Am Acad Dermatol 2014;71(5):904-11. e901
  • LoRusso PM, Rudin CM, Reddy JC, et al. Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin Cancer Res 2011;17(8):2502-11
  • Berlin J, Bendell JC, Hart LL, et al. A randomized phase II trial of vismodegib versus placebo with FOLFOX or FOLFIRI and bevacizumab in patients with previously untreated metastatic colorectal cancer. Clin Cancer Res 2013;19(1):258-67
  • Jimeno A, Weiss GJ, Miller WHJr, et al. Phase I study of the Hedgehog pathway inhibitor IPI-926 in adult patients with solid tumors. Clin Cancer Res 2013;19(10):2766-74
  • Rodon J, Tawbi HA, Thomas AL, et al. A phase I, multicenter, open-label, first-in-human, dose-escalation study of the oral smoothened inhibitor Sonidegib (LDE225) in patients with advanced solid tumors. Clin Cancer Res 2014;20(7):1900-9
  • Gal H, Amariglio N, Trakhtenbrot L, et al. Gene expression profiles of AML derived stem cells; similarity to hematopoietic stem cells. Leukemia 2006;20(12):2147-54
  • Essers MA, Trumpp A. Targeting leukemic stem cells by breaking their dormancy. Mol Oncol 2010;4(5):443-50
  • Peled A, Tavor S. Role of CXCR4 in the pathogenesis of acute myeloid leukemia. Theranostics 2013;3(1):34-9
  • Konopleva MY, Jordan CT. Leukemia stem cells and microenvironment: biology and therapeutic targeting. J Clin Oncol 2011;29(5):591-9
  • Bruserud O, Ryningen A, Olsnes AM, et al. Subclassification of patients with acute myelogenous leukemia based on chemokine responsiveness and constitutive chemokine release by their leukemic cells. Haematologica 2007;92(3):332-41
  • Kittang AO, Hatfield K, Sand K, et al. The chemokine network in acute myelogenous leukemia: molecular mechanisms involved in leukemogenesis and therapeutic implications. Curr Top Microbiol Immunol 2010;341:149-72
  • Reikvam H, Nepstad I, Bruserud O, Hatfield KJ. Pharmacological targeting of the PI3K/mTOR pathway alters the release of angioregulatory mediators both from primary human acute myeloid leukemia cells and their neighboring stromal cells. Oncotarget 2013;4(6):830-43
  • Rombouts EJ, Pavic B, Lowenberg B, Ploemacher RE. Relation between CXCR-4 expression, Flt3 mutations, and unfavorable prognosis of adult acute myeloid leukemia. Blood 2004;104(2):550-7
  • Kim HY, Oh YS, Song IC, et al. Endogenous stromal cell-derived factor-1 (CXCL12) supports autonomous growth of acute myeloid leukemia cells. Leuk Res 2013;37(5):566-72
  • Spoo AC, Lubbert M, Wierda WG, Burger JA. CXCR4 is a prognostic marker in acute myelogenous leukemia. Blood 2007;109(2):786-91
  • Uy GL, Rettig MP, Motabi IH, et al. A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia. Blood 2012;119(17):3917-24
  • Kremer KN, Peterson KL, Schneider PA, et al. CXCR4 chemokine receptor signaling induces apoptosis in acute myeloid leukemia cells via regulation of the Bcl-2 family members Bcl-XL, Noxa, and Bak. J Biol Chem 2013;288(32):22899-914
  • Ramsay DM, McAlpine SR. Halting metastasis through CXCR4 inhibition. Bioorg Med Chem Lett 2013;23(1):20-5
  • Portella L, Vitale R, De Luca S, et al. Preclinical development of a novel class of CXCR4 antagonist impairing solid tumors growth and metastases. PLoS One 2013;8(9):e74548
  • Peng SB, Zhang X, Paul D, et al. Identification of LY2510924, a novel cyclic peptide CXCR4 antagonist that exhibits antitumor activities in solid tumor and breast cancer metastatic models. Mol Cancer Ther 2015;14(2):480-90
  • Kashima K, Watanabe M, Sato Y, et al. Inhibition of metastasis of rhabdomyosarcoma by a novel neutralizing antibody to CXC chemokine receptor-4. Cancer Sci 2014;105(10):1343-50
  • Kuhne MR, Mulvey T, Belanger B, et al. BMS-936564/MDX-1338: a fully human anti-CXCR4 antibody induces apoptosis in vitro and shows antitumor activity in vivo in hematologic malignancies. Clin Cancer Res 2013;19(2):357-66
  • Zhong C, Wang J, Li B, et al. Development and preclinical characterization of a humanized antibody targeting CXCL12. Clin Cancer Res 2013;19(16):4433-45
  • Hoellenriegel J, Zboralski D, Maasch C, et al. The Spiegelmer NOX-A12, a novel CXCL12 inhibitor, interferes with chronic lymphocytic leukemia cell motility and causes chemosensitization. Blood 2014;123(7):1032-9
  • Hafizi S, Dahlback B. Gas6 and protein S. Vitamin K-dependent ligands for the Axl receptor tyrosine kinase subfamily. FEBS J 2006;273(23):5231-44
  • Nagata K, Ohashi K, Nakano T, et al. Identification of the product of growth arrest-specific gene 6 as a common ligand for Axl, Sky, and Mer receptor tyrosine kinases. J Biol Chem 1996;271(47):30022-7
  • Ben-Batalla I, Schultze A, Wroblewski M, et al. Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma. Blood 2013;122(14):2443-52
  • Park IK, Mishra A, Chandler J, et al. Inhibition of the receptor tyrosine kinase Axl impedes activation of the FLT3 internal tandem duplication in human acute myeloid leukemia: implications for Axl as a potential therapeutic target. Blood 2013;121(11):2064-73
  • Whitman SP, Kohlschmidt J, Maharry K, et al. GAS6 expression identifies high-risk adult AML patients: potential implications for therapy. Leukemia 2014;28(6):1252-8
  • Janning M, Ben-Batalla I, Loges S. Axl inhibition: a potential road to a novel acute myeloid leukemia therapy? Expert Rev Hematol 2015;8(2):135-8
  • Rochlitz C, Lohri A, Bacchi M, et al. Axl expression is associated with adverse prognosis and with expression of Bcl-2 and CD34 in de novo acute myeloid leukemia (AML): results from a multicenter trial of the Swiss Group for Clinical Cancer Research (SAKK). Leukemia 1999;13(9):1352-8
  • McCubrey JA, Steelman LS, Chappell WH, et al. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascade inhibitors: how mutations can result in therapy resistance and how to overcome resistance. Oncotarget 2012;3(10):1068-111
  • Kernytsky A, Wang F, Hansen E, et al. IDH2 mutation induced histone and DNA hypermethylation is progressively reversed by small molecule inhibition. Blood 2015;125(2):296-303
  • Rakheja D, Konoplev S, Medeiros LJ, Chen W. IDH mutations in acute myeloid leukemia. Hum Pathol 2012;43(10):1541-51
  • Morin A, Letouze E, Gimenez-Roqueplo AP, Favier J. Oncometabolites-driven tumorigenesis: from genetics to targeted therapy. Int J Cancer 2014;135(10):2237-48
  • Hardie DG. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 2007;8(10):774-85
  • Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001;108(8):1167-74
  • Buzzai M, Jones RG, Amaravadi RK, et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res 2007;67(14):6745-52
  • Mamane Y, Petroulakis E, LeBacquer O, Sonenberg N. mTOR, translation initiation and cancer. Oncogene 2006;25(48):6416-22
  • Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003;115(5):577-90
  • Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 2006;6(9):729-34
  • Green AS, Chapuis N, Maciel TT, et al. The LKB1/AMPK signaling pathway has tumor suppressor activity in acute myeloid leukemia through the repression of mTOR-dependent oncogenic mRNA translation. Blood 2010;116(20):4262-73
  • Bao B, Ahmad A, Azmi AS, et al. Overview of cancer stem cells (CSCs) and mechanisms of their regulation: implications for cancer therapy. Curr Prot Pharmacol 2013;Chapter 14:Unit 14.25
  • Vakana E, Altman JK, Glaser H, et al. Antileukemic effects of AMPK activators on BCR-ABL-expressing cells. Blood 2011;118(24):6399-402
  • Huai L, Wang C, Zhang C, et al. Metformin induces differentiation in acute promyelocytic leukemia by activating the MEK/ERK signaling pathway. Biochem Biophys Res Commun 2012;422(3):398-404
  • Kimura T, Takabatake Y, Takahashi A, Isaka Y. Chloroquine in cancer therapy: a double-edged sword of autophagy. Cancer Res 2013;73(1):3-7
  • Slater AF. Chloroquine: mechanism of drug action and resistance in Plasmodium falciparum. Pharmacol Ther 1993;57(2-3):203-35
  • Cheong H, Lu C, Lindsten T, Thompson CB. Therapeutic targets in cancer cell metabolism and autophagy. Nat Biotechnol 2012;30(7):671-8
  • Xie N, Zhong L, Liu L, et al. Autophagy contributes to dasatinib-induced myeloid differentiation of human acute myeloid leukemia cells. Biochem Pharmacol 2014;89(1):74-85
  • Reikvam H, van Hoang T, Bruserud Ø. Emerging therapeutic targets in human acute myeloid leukemia (Part 2) - Bromodomaininhibition should be considered as a possible strategy for various patient subsets. Exp Rev Hematol 2015; In press
  • Walsby E, Lazenby M, Pepper C, Burnett AK. The cyclin-dependent kinase inhibitor SNS-032 has single agent activity in AML cells and is highly synergistic with cytarabine. Leukemia 2011;25(3):411-19
  • Grosjean-Raillard J, Tailler M, Ades L, et al. ATM mediates constitutive NF-kappaB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia. Oncogene 2009;28(8):1099-109
  • Yamauchi T, Uzui K, Nishi R, et al. Gemtuzumab ozogamicin and olaparib exert synergistic cytotoxicity in CD33-positive HL-60 myeloid leukemia cells. Anticancer Res 2014;34(10):5487-94
  • Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015;33(3):244-50
  • Walter RB. Biting back: biTE antibodies as a promising therapy for acute myeloid leukemia. Expert Rev Hematol 2014;7(3):317-19
  • Marin-Hernandez A, Gallardo-Perez JC, Ralph SJ, et al. HIF-1alpha modulates energy metabolism in cancer cells by inducing over-expression of specific glycolytic isoforms. Mini Rev Med Chem 2009;9(9):1084-101
  • Amann T, Hellerbrand C. GLUT1 as a therapeutic target in hepatocellular carcinoma. Expert Opin Ther Targets 2009;13(12):1411-27
  • Barnes K, Ingram JC, Porras OH, et al. Activation of GLUT1 by metabolic and osmotic stress: potential involvement of AMP-activated protein kinase (AMPK). J Cell Sci 2002;115(Pt 11):2433-42
  • Helleday T. Cancer phenotypic lethality, exemplified by the non-essential MTH1 enzyme being required for cancer survival. Ann Oncol 2014;25(7):1253-5
  • Huber KV, Salah E, Radic B, et al. Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. Nature 2014;508(7495):222-7
  • Gad H, Koolmeister T, Jemth AS, et al. MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool. Nature 2014;508(7495):215-21
  • Hatfield KJ, Reikvam H, Bruserud O. Identification of a subset of patients with acute myeloid leukemia characterized by long-term in vitro proliferation and altered cell cycle regulation of the leukemic cells. Expert Opin Ther Targets 2014;18(11):1237-51
  • Available from: www.bergenbio.com/bergenbio-announces-first-patient-dosed-in-bgb324-aml-trial/

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.