Signal transduction inhibitors in treatment of myelodysplastic syndromes

Journal of Hematology and Oncology

Volumn 6, Issue 1, 2013, Pages

  Bachegowda, Lohith ^a,b   Gligich, Oleg ^b,c   Mantzaris, Ionnis ^a,b   Schinke, Carolina ^a,b   Wyville, Dale ^a   Carrillo, Tatiana ^a   Braunschweig, Ira ^a   Steidl, Ulrich ^b   Verma, Amit ^a,b,d  

^a MONTEFIORE MEDICAL CENTER   (United States)

^b ALBERT EINSTEIN COLLEGE OF MEDICINE   (United States)

^c JACOBI MEDICAL CENTER   (United States)

^d Developmental and Molecular Biology   (United States)

Author keywords

ALK; Cytokines; EGFR; FTI; GSTP 1 1; Mek; mTOR; Myelodysplastic syndrome; ON 01910.Na; Signal transduction inhibitors; TGF

Indexed keywords

5 AZA 2' DEOXYCYTIDINE; ARRY 614; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; ERLOTINIB; ETANERCEPT; EVEROLIMUS; EZATIOSTAT; GALUNISERTIB; GEFITINIB; INFLIXIMAB; LENALIDOMIDE; LONAFARNIB; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE P38; N (2,3 DIHYDROXYPROPOXY) 3,4 DIFLUORO 2 (2 FLUORO 4 IODOANILINO)BENZAMIDE; PERIFOSINE; PROTEIN FARNESYLTRANSFERASE INHIBITOR; RIDAFOROLIMUS; RIGOSERTIB; SOTATERCEPT; TALMAPIMOD; TEMSIROLIMUS; TIPIFARNIB; TRAMETINIB; UNCLASSIFIED DRUG;

ANEMIA; ANTIPROLIFERATIVE ACTIVITY; APOPTOSIS; BONE MARROW SUPPRESSION; CELL DIFFERENTIATION; CELL MATURATION; CELL PROLIFERATION; CHRONIC MYELOMONOCYTIC LEUKEMIA; CLINICAL TRIAL (TOPIC); DIARRHEA; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG SAFETY; ERYTHROCYTE TRANSFUSION; FATIGUE; GASTROINTESTINAL SYMPTOM; GLIOMA; HEMATOPOIESIS; HEMATOPOIETIC STEM CELL; HUMAN; MOLECULARLY TARGETED THERAPY; MYELODYSPLASTIC SYNDROME; NAUSEA; NEUTROPHIL COUNT; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); RASH; REVIEW; RHEUMATOID ARTHRITIS; SIDE EFFECT; SIGNAL TRANSDUCTION; THROMBOCYTE DISORDER; WEAKNESS;

ANIMALS; ANTINEOPLASTIC AGENTS; CYTOKINES; ENZYME INHIBITORS; HUMANS; MYELODYSPLASTIC SYNDROMES; SIGNAL TRANSDUCTION;

EID: 84880026724     PISSN: None     EISSN: 17568722     Source Type: Journal    
DOI: 10.1186/1756-8722-6-50     Document Type: Review

References (83)

1. Revised International Prognostic Scoring System (IPSS-R) for myelodysplastic syndromes. Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, Bennett JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Levis A, Malcovati L, Cazzola M, Cermak J, Fonatsch C, Le Beau MM, Slovak ML, Krieger O, Luebbert M, Maciejewski J, Magalhaes SM, Miyazaki Y, Pfeilstocker M, Sekeres M, Sperr WR, Stauder R, Tauro S, Valent P, et al. Blood 2012 10.1182/blood-2012-03-420489
2. Apoptosis and its role in the myelodysplastic syndromes: implications for disease natural history and treatment. Greenberg PL, Leuk Res 1998 22 1123 1136 10.1016/S0145-2126(98)00112-X 9922076 (Pubitemid 29002986)
3. Correlation of tumor necrosis factor alpha (TNF alpha) with high Caspase 3-like activity in myelodysplastic syndromes. Mundle SD, Reza S, Ali A, Mativi Y, Shetty V, Venugopal P, Gregory SA, Raza A, Cancer Lett 1999 140 201 207 10.1016/S0304-3835(99)00072-5 10403560 (Pubitemid 29251332)
4. Inhibition of the TGF-beta receptor I kinase promotes hematopoiesis in MDS. Zhou L, Nguyen AN, Sohal D, Ying Ma J, Pahanish P, Gundabolu K, Hayman J, Chubak A, Mo Y, Bhagat TD, Das B, Kapoun AM, Navas TA, Parmar S, Kambhampati S, Pellagatti A, Braunchweig I, Zhang Y, Wickrema A, Medicherla S, Boultwood J, Platanias LC, Higgins LS, List AF, Bitzer M, Verma A, Blood 2008 112 3434 3443 10.1182/blood-2008-02-139824 18474728
5. Angiogenesis and survival in patients with myelodysplastic syndrome. Savic A, Cemerikic-Martinovic V, Dovat S, Rajic N, Urosevic I, Sekulic B, Kvrgic V, Popovic S, Pathol Oncol Res 2012 18 681 690 10.1007/s12253-012-9495-y 22270865
6. ALK1 as an emerging target for antiangiogenic therapy of cancer. Cunha SI, Pietras K, Blood 2011 117 6999 7006 10.1182/blood-2011-01-330142 21467543
7. IL-17-producing CD4(+) T cells, pro-inflammatory cytokines and apoptosis are increased in low risk myelodysplastic syndrome. Kordasti SY, Afzali B, Lim Z, Ingram W, Hayden J, Barber L, Matthews K, Chelliah R, Guinn B, Lombardi G, Farzaneh F, Mufti GJ, Br J Haematol 2009 145 64 72 10.1111/j.1365-2141.2009. 07593.x 19210506
8. Protein kinase R as mediator of the effects of interferon (IFN) gamma and tumor necrosis factor (TNF) alpha on normal and dysplastic hematopoiesis. Sharma B, Altman JK, Goussetis DJ, Verma AK, Platanias LC, J Biol Chem 2011 286 27506 27514 10.1074/jbc.M111.238501 21659535
9. Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application. Furqan, et al. Biomarker Research 2013 10.1186/2050-7771-1-2
10. Treatment of myelodysplastic syndrome with agents interfering with inhibitory cytokines. Greenberg P, Ann Rheum Dis 2001 60 Suppl 3 ii41 iii42 11890651
11. Role of plasmapheresis in the management of myeloma kidney: a systematic review. Gupta D, Bachegowda L, Phadke G, Boren S, Johnson D, Misra M, Hemodial Int 2010 14 355 363 10.1111/j.1542-4758.2010.00481.x 20955270
12. Revisiting use of growth factors in myelodysplastic syndromes. Newman K, Maness-Harris L, El-Hemaidi I, Akhtari M, Asian Pac J Cancer Prev 2012 13 1081 1091 10.7314/APJCP.2012.13.4.1081 22799286
13. Cytokine targets in the treatment of myelodysplastic syndromes. Verma A, List AF, Curr Hematol Rep 2005 4 429 435 16232378
14. Cutting edge: activation of the p38 mitogen-activated protein kinase signaling pathway mediates cytokine-induced hemopoietic suppression in aplastic anemia. Verma A, Deb DK, Sassano A, Kambhampati S, Wickrema A, Uddin S, Mohindru M, Van Besien K, Platanias LC, J Immunol 2002 168 5984 5988 12055203 (Pubitemid 34620009)
15. Activation of the p38 mitogen-activated protein kinase mediates the suppressive effects of type I interferons and transforming growth factor-beta on normal hematopoiesis. Verma A, Deb DK, Sassano A, Uddin S, Varga J, Wickrema A, Platanias LC, J Biol Chem 2002 277 7726 7735 10.1074/jbc.M106640200 11773065 (Pubitemid 34968219)
16. TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Schmierer B, Hill CS, Nat Rev Mol Cell Biol 2007 8 970 982 10.1038/nrm2297 18000526 (Pubitemid 350174642)
17. Inhibition of overactivated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors. Navas TA, Mohindru M, Estes M, Ma JY, Sokol L, Pahanish P, Parmar S, Haghnazari E, Zhou L, Collins R, Kerr I, Nguyen AN, Xu Y, Platanias LC, List AA, Higgins LS, Verma A, Blood 2006 108 4170 4177 10.1182/blood-2006-05-023093 16940419 (Pubitemid 44913289)
18. Randomized, dose-escalation study of the p38alpha MAPK inhibitor SCIO-469 in patients with myelodysplastic syndrome. Sokol L, Cripe L, Kantarjian H, Sekeres MA, Parmar S, Greenberg P, Goldberg SL, Bhushan V, Shammo J, Hohl R, Verma A, Garcia-Manero G, Li YP, Lowe A, Zhu J, List AF, Leukemia 2012 10.1038/leu.2012.264
19. Regulation of angiogenesis in the bone marrow of myelodysplastic syndromes transforming to overt leukaemia. Keith T, Araki Y, Ohyagi M, Hasegawa M, Yamamoto K, Kurata M, Nakagawa Y, Suzuki K, Kitagawa M, Br J Haematol 2007 137 206 215 10.1111/j.1365-2141.2007.06539.x 17408459 (Pubitemid 46537630)
20. High bone marrow angiopoietin-1 expression is an independent poor prognostic factor for survival in patients with myelodysplastic syndromes. Cheng CL, Hou HA, Jhuang JY, Lin CW, Chen CY, Tang JL, Chou WC, Tseng MH, Yao M, Huang SY, Ko BS, Hsu SC, Wu SJ, Tsay W, Chen YC, Tien HF, Br J Cancer 2011 105 975 982 10.1038/bjc.2011.340 21878936
21. Komrokji RS, et al. Phase 1 Dose- escalation/expansion study of the P38/Tie 2 inhibitor ARRY- 614 in patients with IPSS low-int risk MDS 2011 ASH Abstract 118. Presented on 12/11/2011, San Diego, California
22. Winski SL, et al. Role of P38 MAPK and Tie 2 in the pathogenesis of MDS and their inhibition by dual inhibitor ARRY-614 2012 ASH Abstract 2825. Presented on 12/09/2012 at Atlanta, Georgia
23. Transforming growth factor-beta signaling in normal and malignant hematopoiesis. Isufi I, Seetharam M, Zhou L, Sohal D, Opalinska J, Pahanish P, Verma A, J Interferon Cytokine Res 2007 27 543 552 10.1089/jir.2007.0009 17651015 (Pubitemid 47122713)
24. miR-21 mediates hematopoietic suppression in MDS by activating TGF-beta signaling. Bhagat TD, Zhou L, Sokol L, Kessel R, Caceres G, Gundabolu K, Tamari R, Gordon S, Mantzaris I, Jodlowski T, Yu Y, Jing X, Polineni R, Bhatia K, Pellagatti A, Boultwood J, Kambhampati S, Steidl U, Stein C, Ju W, Liu G, Kenny P, List A, Bitzer M, Verma A, Blood 2013 121 2875 2881 10.1182/blood-2011-12- 397067 23390194
25. Reduced SMAD7 leads to overactivation of TGF-beta signaling in MDS that can be reversed by a specific inhibitor of TGF-beta receptor I kinase. Zhou L, McMahon C, Bhagat T, Alencar C, Yu Y, Fazzari M, Sohal D, Heuck C, Gundabolu K, Ng C, Mo Y, Shen W, Wickrema A, Kong G, Friedman E, Sokol L, Mantzaris I, Pellagatti A, Boultwood J, Platanias LC, Steidl U, Yan L, Yingling JM, Lahn MM, List A, Bitzer M, Verma A, Cancer Res 2011 71 955 963 10.1158/0008-5472.CAN-10- 2933 21189329
26. First human dose (FHD) study of the oral transforming growth factor-beta receptor I kinase inhibitor LY2157299 in patients with treatment refractory malignant glioma. Ahnert R, et al. Clin Oncol 2011 29 [suppl; abstr 3011] Chicago: ASCO 2011
27. The role of erythropoietin and erythropoiesis-stimulating agents in tumor progression. Hedley BD, Allan AL, Xenocostas A, Clin Cancer Res 2011 17 6373 6380 10.1158/1078-0432.CCR-10-2577 21750199
28. Lenalidomide in lower-risk myelodysplastic syndromes with karyotypes other than deletion 5q and refractory to erythropoiesis-stimulating agents. Sibon D, Cannas G, Baracco F, Prebet T, Vey N, Banos A, Besson C, Corm S, Blanc M, Slama B, Perrier H, Fenaux P, Wattel E, Groupe Francophone des M, Br J Haematol 2012 156 619 625 10.1111/j.1365-2141.2011.08979.x 22211483
29. Efficacy of a single, weekly dose of recombinant erythropoietin in myelodysplastic syndromes. Musto P, Falcone A, Sanpaolo G, Bodenizza C, La Sala A, Perla G, Carella AM, Br J Haematol 2003 122 269 271 10.1046/j.1365-2141.2003. 04435.x 12846896 (Pubitemid 36859613)
30. MicroRNA miR-24 inhibits erythropoiesis by targeting activin type I receptor ALK4. Wang Q, Huang Z, Xue H, Jin C, Ju XL, Han JD, Chen YG, Blood 2008 111 588 595 10.1182/blood-2007-05-092718 17906079
31. Suragani Rajashekar NVS, et al. ACE-536, A modified type ii activin receptor increases red blood cells in vivo by promoting maturation of late stage erythroblasts 2010 ASH Abstract 4236; Presented on 12/06/2010 at Orlando, Florida
32. NUP98-HOXD13 transgenic mice develop a highly penetrant, severe myelodysplastic syndrome that progresses to acute leukemia. Lin YW, Slape C, Zhang Z, Aplan PD, Blood 2005 106 287 295 10.1182/blood-2004-12-4794 15755899 (Pubitemid 40967204)
33. Suragani RN, RAP-536 Promotes Terminal Erythroid Differentiation and Reduces Anemia in Myelodysplastic Syndromes 2011 ASH Abstract 610; Presented at San Diego, California on 12/12/2011
34. A soluble activin receptor Type IIA fusion protein (ACE-011) increases bone mass via a dual anabolic-antiresorptive effect in Cynomolgus monkeys. Lotinun S, Pearsall RS, Davies MV, Marvell TH, Monnell TE, Ucran J, Fajardo RJ, Kumar R, Underwood KW, Seehra J, Bouxsein ML, Baron R, Bone 2010 46 1082 1088 10.1016/j.bone.2010.01.370 20080223
35. Sotatercept, a soluble activin receptor type 2A IgG-Fc fusion protein for the treatment of anemia and bone loss. Raje N, Vallet S, Curr Opin Mol Ther 2010 12 586 597 20886391
36. Chen N, et al. Exposures and Erythropoietic Responses to Sotatercept (ACE-011) in Healthy Volunteers and Cancer Patients: Implications for Mechanism of Action 2012 ASH Abstract 3454; Presented at Atlanta on 12/10/2012
37. Fan A, et al. A Novel Nano-Immunoassay (NIA) Reveals Inhibition of PI3K and MAPK Pathways in CD34+ Bone Marrow Cells of Patients with Myelodysplastic Syndrome (MDS) Treated with the Multi-Kinase Inhibitor On 01910.Na (Rigosertib) 2011 ASH Abstract 3808; Presented at San Diego, California on 12/12/ 2011
38. ON01910, a non-ATP-competitive small molecule inhibitor of Plk1, is a potent anticancer agent. Gumireddy K, Reddy MV, Cosenza SC, Boominathan R, Baker SJ, Papathi N, Jiang J, Holland J, Reddy EP, Cancer Cell 2005 7 275 286 10.1016/j.ccr.2005.02.009 15766665 (Pubitemid 40568686)
39. Directed therapy for patients with myelodysplastic syndromes (MDS) by suppression of cyclin D1 with ON 01910.Na. Olnes MJ, Shenoy A, Weinstein B, Pfannes L, Loeliger K, Tucker Z, Tian X, Kwak M, Wilhelm F, Yong AS, Maric I, Maniar M, Scheinberg P, Groopman J, Young NS, Sloand EM, Leuk Res 2012 36 982 989 10.1016/j.leukres.2012.04.002 22524974
40. Raza A, et al. Final Phase I/II Results of Rigosertib (ON 01910.Na) Hematological Effects in Patients with Myelodysplastic Syndrome and Correlation with Overall Survival 2011 ASH Abstract 3822, Presented at San Diego, Californiaon 12/12/2011
41. New targets for non-small-cell lung cancer therapy. Alvarez M, Roman E, Santos ES, Raez LE, Expert Rev Anticancer Ther 2007 7 1423 1437 10.1586/14737140.7.10.1423 17944567 (Pubitemid 351826908)
42. The Akt/mammalian target of rapamycin signal transduction pathway is activated in high-risk myelodysplastic syndromes and influences cell survival and proliferation. Follo MY, Mongiorgi S, Bosi C, Cappellini A, Finelli C, Chiarini F, Papa V, Libra M, Martinelli G, Cocco L, Martelli AM, Cancer Res 2007 67 4287 4294 10.1158/0008-5472.CAN-06-4409 17483341 (Pubitemid 46815076)
43. Effect of rapamycin on apoptosis in human myelodysplastic syndrome cell line MUTZ-1 and its possible mechanisms. Chen BG, Guo QY, Zhang Y, Yan WH, Pan YQ, Zheng R, Li BL, Luo WD, Zhongguo Shi Yan Xue Ye Xue Za Zhi 2010 18 300 304 20416156
44. AKT activity regulates the ability of mTOR inhibitors to prevent angiogenesis and VEGF expression in multiple myeloma cells. Frost P, Shi Y, Hoang B, Lichtenstein A, Oncogene 2007 26 2255 2262 10.1038/sj.onc.1210019 17016437 (Pubitemid 46572812)
45. Inducible expression of EVI1 in human myeloid cells causes phenotypes consistent with its role in myelodysplastic syndromes. Konrad TA, Karger A, Hackl H, Schwarzinger I, Herbacek I, Wieser R, J Leukoc Biol 2009 86 813 822 10.1189/jlb.0109042 19605700
46. Evi1 represses PTEN expression and activates PI3K/AKT/mTOR via interactions with polycomb proteins. Yoshimi A, Goyama S, Watanabe-Okochi N, Yoshiki Y, Nannya Y, Nitta E, Arai S, Sato T, Shimabe M, Nakagawa M, Imai Y, Kitamura T, Kurokawa M, Blood 2011 117 3617 3628 10.1182/blood-2009-12-261602 21289308
47. 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. Rizzieri DA, Feldman E, Dipersio JF, Gabrail N, Stock W, Strair R, Rivera VM, Albitar M, Bedrosian CL, Giles FJ, Clin Cancer Res 2008 14 2756 2762 10.1158/1078-0432.CCR-07-1372 18451242
48. Emerging Therapeutic Targets in Diffuse Large B-Cell Lymphoma. Janakiram M, Thirukonda VK, Sullivan M, Petrich AM, Curr Treat Options Oncol 2012 10.1007/s11864-011-0178-9
49. Can EGFR-TKIs be used in first line treatment for advanced non-small cell lung cancer based on selection according to clinical factors?-A literature-based meta-analysis. Xu C, Zhou Q, Wu YL, J Hematol Oncol 2012 5 62 10.1186/1756-8722-5-62 23050865
50. EGFR inhibition in non-small cell lung cancer: current evidence and future directions. Alexander C, Scot R, William T, Bio Marker Research 2013 10.1186/2050-7771-1-2
51. Gefitinib induces myeloid differentiation of acute myeloid leukemia. Stegmaier K, Corsello SM, Ross KN, Wong JS, Deangelo DJ, Golub TR, Blood 2005 106 2841 2848 10.1182/blood-2005-02-0488 15998836 (Pubitemid 41510762)
52. Boehrer S, Increased Proliferation Induced by Constitutive Activation of the Src-Kinase Lyn and Aberrant mTOR Signaling in AML Is Abrogated by the EGFR-Inhibitor Erlotinib 2009 ASH Abstract 3813;Presented at New Orleans on 12/07 2009
53. Erlotinib exhibits antineoplastic off-target effects in AML and MDS: a preclinical study. Boehrer S, Ades L, Braun T, Galluzzi L, Grosjean J, Fabre C, Le Roux G, Gardin C, Martin A, de Botton S, Fenaux P, Kroemer G, Blood 2008 111 2170 2180 10.1182/blood-2007-07-100362 17925489 (Pubitemid 351451531)
54. Komrokji RS, et al. Erlotinib for Treatment of Myelodysplastic Syndromes: A phase II clinical study 2010 ASH Abstract 1854. Presented at Orlando, Florida on 12/4/2010
55. Lainey E, et al. Potentiation of Apoptosis in MDS/AML by Combination of Azacitidine and the EGFR-Tyrosine Kinase Inhibitor (TKI) Erlotinib 2011 ASH Abstract 2790. Presented at San Diego, California on 12/11/2011
56. Lainey E, et al. Erlotinib Antagonizes Efflux Via ABC Transporters and Decreases P-Gp Cell Surface Expression by Inhibiting SRC Kinase and mTOR Pathways in Acute Myeloid Leukemia (AML) 2011 ASH Abstract 2564; Presented at San Diego on 12/11/2011
57. Regulation of JNK signaling by GSTp. Adler V, Yin Z, Fuchs SY, Benezra M, Rosario L, Tew KD, Pincus MR, Sardana M, Henderson CJ, Wolf CR, Davis RJ, Ronai Z, EMBO J 1999 18 1321 1334 10.1093/emboj/18.5.1321 10064598 (Pubitemid 29110316)
58. Prediction of response to therapy with ezatiostat in lower risk myelodysplastic syndrome. Galili N, Tamayo P, Botvinnik OB, Mesirov JP, Brooks MR, Brown G, Raza A, J Hematol Oncol 2012 5 20 10.1186/1756-8722-5-20 22559819
59. A phase 2 randomized multicenter study of 2 extended dosing schedules of oral ezatiostat in low to intermediate-1 risk myelodysplastic syndrome. Raza A, Galili N, Smith SE, Godwin J, Boccia RV, Myint H, Mahadevan D, Mulford D, Rarick M, Brown GL, Schaar D, Faderl S, Komrokji RS, List AF, Sekeres M, Cancer 2012 118 2138 2147 10.1002/cncr.26469 21887679
60. Phase 1-2a multicenter dose-escalation study of ezatiostat hydrochloride liposomes for injection (Telintra, TLK199), a novel glutathione analog prodrug in patients with myelodysplastic syndrome. Raza A, Galili N, Callander N, Ochoa L, Piro L, Emanuel P, Williams S, Burris H, Faderl S, Estrov Z, Curtin P, Larson RA, Keck JG, Jones M, Meng L, Brown GL, J Hematol Oncol 2009 2 20 10.1186/1756-8722-2-20 19439093
61. Phase 1 dose-ranging study of ezatiostat hydrochloride in combination with lenalidomide in patients with non-deletion (5q) low to intermediate-1 risk myelodysplastic syndrome (MDS). Raza A, Galili N, Mulford D, Smith SE, Brown GL, Steensma DP, Lyons RM, Boccia R, Sekeres MA, Garcia-Manero G, Mesa RA, J Hematol Oncol 2012 5 18 10.1186/1756-8722-5-18 22546242
62. Renewing the conspiracy theory debate: does Raf function alone to mediate Ras oncogenesis? Repasky GA, Chenette EJ, Der CJ, Trends Cell Biol 2004 14 639 647 10.1016/j.tcb.2004.09.014 15519853 (Pubitemid 39440613)
63. Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies? Reuter CW, Morgan MA, Bergmann L, Blood 2000 96 1655 1669 10961860 (Pubitemid 30661043)
64. Development of farnesyl transferase inhibitors: a review. Appels NM, Beijnen JH, Schellens JH, Oncologist 2005 10 565 578 10.1634/theoncologist.10-8- 565 16177281 (Pubitemid 41429120)
65. Ras protein farnesyltransferase: A strategic target for anticancer therapeutic development. Rowinsky EK, Windle JJ, Von Hoff DD, J Clin Oncol 1999 17 3631 3652 10550163 (Pubitemid 29517936)
66. Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. End DW, Smets G, Todd AV, Applegate TL, Fuery CJ, Angibaud P, Venet M, Sanz G, Poignet H, Skrzat S, Devine A, Wouters W, Bowden C, Cancer Res 2001 61 131 137 11196150 (Pubitemid 32095710)
67. Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: clinical and biologic activities in the phase 1 setting. Kurzrock R, Kantarjian HM, Cortes JE, Singhania N, Thomas DA, Wilson EF, Wright JJ, Freireich EJ, Talpaz M, Sebti SM, Blood 2003 102 4527 4534 10.1182/blood-2002-11-3359 12947010 (Pubitemid 37494120)
68. Phase II study of R115777, a farnesyl transferase inhibitor, in myelodysplastic syndrome. Kurzrock R, Albitar M, Cortes JE, Estey EH, Faderl SH, Garcia-Manero G, Thomas DA, Giles FJ, Ryback ME, Thibault A, De Porre P, Kantarjian HM, J Clin Oncol 2004 22 1287 1292 10.1200/JCO.2004.08.082 15051776 (Pubitemid 41079843)
69. A multicenter phase 2 study of the farnesyltransferase inhibitor tipifarnib in intermediate- to high-risk myelodysplastic syndrome. Fenaux P, Raza A, Mufti GJ, Aul C, Germing U, Kantarjian H, Cripe L, Kerstens R, De Porre P, Kurzrock R, Blood 2007 109 4158 4163 10.1182/blood-2006-07-035725 17264294 (Pubitemid 46743377)
70. On the use of lonafarnib in myelodysplastic syndrome and chronic myelomonocytic leukemia. Feldman EJ, Cortes J, DeAngelo DJ, Holyoake T, Simonsson B, O'Brien SG, Reiffers J, Turner AR, Roboz GJ, Lipton JH, Maloisel F, Colombat P, Martinelli G, Nielsen JL, Petersdorf S, Guilhot F, Barker J, Kirschmeier P, Frank E, Statkevich P, Zhu Y, Loechner S, List A, Leukemia 2008 22 1707 1711 10.1038/leu.2008.156 18548095
71. Farnesyl transferase inhibitor (lonafarnib) in patients with myelodysplastic syndrome or secondary acute myeloid leukaemia: a phase II study. Ravoet C, Mineur P, Robin V, Debusscher L, Bosly A, Andre M, El Housni H, Soree A, Bron D, Martiat P, Ann Hematol 2008 87 881 885 10.1007/s00277-008-0536-2 18641985
72. Novel targets in solid tumors: MEK inhibitors. Messersmith WA, Hidalgo M, Carducci M, Eckhardt SG, Clin Adv Hematol Oncol 2006 4 831 836 17143253 (Pubitemid 44883551)
73. Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy. McCubrey JA, Steelman LS, Abrams SL, Bertrand FE, Ludwig DE, Basecke J, Libra M, Stivala F, Milella M, Tafuri A, Lunghi P, Bonati A, Martelli AM, Leukemia 2008 22 708 722 10.1038/leu.2008.27 18337766 (Pubitemid 351565619)
74. MEK inhibitors: a therapeutic approach to targeting the Ras-MAP kinase pathway in tumors. Sebolt-Leopold JS, Curr Pharm Des 2004 10 1907 1914 10.2174/1381612043384439 15180527 (Pubitemid 38647576)
75. Potential prognostic value of mitogen-activated protein kinase activity for disease-free survival of primary breast cancer patients. Mueller H, Flury N, Eppenberger-Castori S, Kueng W, David F, Eppenberger U, Int J Cancer 2000 89 384 388 10.1002/1097-0215(20000720)89:4<384::AID-IJC11>3.0.CO;2-R 10956414 (Pubitemid 30620293)
76. Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia. Milella M, Kornblau SM, Estrov Z, Carter BZ, Lapillonne H, Harris D, Konopleva M, Zhao S, Estey E, Andreeff M, J Clin Invest 2001 108 851 859 11560954 (Pubitemid 32880294)
77. MEK blockade converts AML differentiating response to retinoids into extensive apoptosis. Milella M, Konopleva M, Precupanu CM, Tabe Y, Ricciardi MR, Gregorj C, Collins SJ, Carter BZ, D'Angelo C, Petrucci MT, Foa R, Cognetti F, Tafuri A, Andreeff M, Blood 2007 109 2121 2129 10.1182/blood-2006-05-024679 17077328 (Pubitemid 46348214)
78. A MEK inhibitor abrogates myeloproliferative disease in Kras mutant mice. Lyubynska N, Gorman MF, Lauchle JO, Hong WX, Akutagawa JK, Shannon K, Braun BS, Sci Transl Med 2011 3 76ra27 10.1126/scitranslmed.3001069 21451123
79. Borthakur GLP, Kirschbaum MH, Foran JM, Kadia TM, Jabbour E, Boyiadzis M, Verma A, et al. Phase I/II trial of the MEK1/2 inhibitor GSK1120212 (GSK212) in patients (pts) with relapsed/refractory myeloid malignancies: Evidence of activity in pts with RAS mutation 2011 ASCO abstract 6506, presented at ASCO 2011 meeting, Chicago
80. Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Feldmann M, Maini RN, Annu Rev Immunol 2001 19 163 196 10.1146/annurev.immunol. 19.1.163 11244034 (Pubitemid 32368033)
81. Detection of TNFalpha expression in the bone marrow and determination of TNFalpha production of peripheral blood mononuclear cells in myelodysplastic syndrome. Molnar L, Berki T, Hussain A, Nemeth P, Losonczy H, Pathol Oncol Res 2000 6 18 23 10.1007/BF03032653 10749583 (Pubitemid 30262774)
82. Soluble TNF receptor fusion protein (etanercept) for the treatment of myelodysplastic syndrome: a pilot study. Deeg HJ, Gotlib J, Beckham C, Dugan K, Holmberg L, Schubert M, Appelbaum F, Greenberg P, Leukemia 2002 16 162 164 10.1038/sj.leu.2402356 11840280 (Pubitemid 34145131)
83. Remicade as TNF suppressor in patients with myelodysplastic syndromes. Raza A, Candoni A, Khan U, Lisak L, Tahir S, Silvestri F, Billmeier J, Alvi MI, Mumtaz M, Gezer S, Venugopal P, Reddy P, Galili N, Leuk Lymphoma 2004 45 2099 2104 10.1080/10428190410001723322 15370256 (Pubitemid 39232860)