Protein kinase inhibitors against malignant lymphoma

Expert Opinion on Pharmacotherapy

Volumn 14, Issue 6, 2013, Pages 707-721

  D'cruz, Osmond J ^a   Uckun, Fatih M ^a,b,c,d  

^a CHILDREN S HOSPITAL LOS ANGELES   (United States)

^b UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

^c UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

^d Children's Center for Cancer and Blood Diseases   (United States)

Author keywords

BTK; Kinase inhibitor; Lymphoma; Protein kinase; SYK

Indexed keywords

8 [4 (1 AMINOCYCLOBUTYL)PHENYL] 9 PHENYL 1,2,4 TRIAZOLO[3,4 F][1,6]NAPHTHYRIDIN 3(2H) ONE; ANAPLASTIC LYMPHOMA KINASE; AURORA KINASE INHIBITOR; BENDAMUSTINE; BORTEZOMIB; BRUTON TYROSINE KINASE INHIBITOR; CYCLOPHOSPHAMIDE; DASATINIB; ENZASTAURIN; EVEROLIMUS; FLUDARABINE; FOSTAMATINIB; IBRUTINIB; IDELALISIB; JANUS KINASE INHIBITOR; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; OFATUMUMAB; PANOBINOSTAT; PERIFOSINE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PROTEIN KINASE B INHIBITOR; PROTEIN KINASE C INHIBITOR; PROTEIN KINASE INHIBITOR; PROTEIN KINASE SYK INHIBITOR; RAPAMYCIN; RIDAFOROLIMUS; RITUXIMAB; SORAFENIB; TEMSIROLIMUS; UNINDEXED DRUG;

ANEMIA; ANTINEOPLASTIC ACTIVITY; AUTOIMMUNE DISEASE; B CELL LYMPHOMA; BONE MARROW SUPPRESSION; BURKITT LYMPHOMA; CELL ACTIVATION; CELL DIFFERENTIATION; CELL MATURATION; CELL PROLIFERATION; CELL SURVIVAL; CHROMOSOME TRANSLOCATION; CHRONIC LYMPHATIC LEUKEMIA; CHRONIC MYELOID LEUKEMIA; DISEASE COURSE; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; FOLLOW UP; GENE EXPRESSION PROFILING; GERMINAL CENTER; GLUCOSE METABOLISM; HUMAN; HYPERTENSION; HYPONATREMIA; IN VITRO STUDY; IN VIVO STUDY; LARGE CELL LYMPHOMA; LUNG NON SMALL CELL CANCER; LYMPHOMA; LYMPHOMA CELL; MANTLE CELL LYMPHOMA; MUCOSA INFLAMMATION; MULTIPLE CYCLE TREATMENT; NEUTROPENIA; OUTCOME ASSESSMENT; PERSONALIZED MEDICINE; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PNEUMONIA; PRE B LYMPHOCYTE; PROGRESSION FREE SURVIVAL; REVIEW; SIGNAL TRANSDUCTION; SKIN TOXICITY; STOMATITIS; T CELL LYMPHOMA; TERATOGENICITY; THROMBOCYTOPENIA; URINARY TRACT INFECTION; WALDENSTROEM MACROGLOBULINEMIA;

ANTINEOPLASTIC AGENTS; APOPTOSIS; DRUG DESIGN; HUMANS; LYMPHOMA, B-CELL; MOLECULAR TARGETED THERAPY; PROTEIN KINASE INHIBITORS; SIGNAL TRANSDUCTION; TUMOR MICROENVIRONMENT;

EID: 84875192776     PISSN: 14656566     EISSN: 17447666     Source Type: Journal    
DOI: 10.1517/14656566.2013.780031     Document Type: Review

References (87)

1. Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2000;103:211-25
2. Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature 2001;411:355-65
3. Niiro H, Clark E. Regulation of B cell fate by antigen-receptor signals. Nat Rev Immunol 2002;2:945-56
4. Gauld S, Dal Porto J, Cambier J. B cell antigen receptor signaling: Roles in cell development and disease. Science 2002;296:1641-2
5. Kuppers R. Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer 2005;5:251-62
6. Portis T, Longnecker R. Epstein-Barr virus (EBV) LMP2A mediates B-lymphocyte survival through constitutive activation of the Ras/PI3K/Akt pathway. Oncogene 2004;23:8619-28
7. Pogue SL, Kurosaki T, Bolen J, et al. B cell antigen receptor-induced activation of Akt promotes B cell survival and is dependent on Syk kinase. J Immunol 2000;165:1300-6
8. Hutchcroft et al.Harrison et al. Geahlen RL. B Lymphocyte activation is accompanied by phosphorylation of a 72 kDa protein-tyrosine kinase. J Biol Chem 1991;266:14846-9
9. Leseux L, Hamdi SM, Al Saati T, et al. Syk-dependent mTOR activation in follicular lymphoma cells. Blood 2006;108:4156-62
10. D'Cruz OJ, Uckun FM. Targeting spleen tyrosine kinase (SYK) for treatment of human disease. J Pharm Drug Deliv Res 2012;1:2
11. Shaffer AL III, Young RM, Staudt LM. Pathogenesis of human B cell lymphomas Annu Rev Immunol. 2012;30:565-610
12. Uckun FM, Qazi S. Spleen tyrosine kinase as a molecular target for treatment of leukemias and lymphomas. Expert Rev Anticancer Ther 2010;10:1407-18
13. Friedberg JW, Sharman J, Sweetenham J, et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 2010;115:2578-5
14. Ye G, Tiwari R, Parang K. Development of Src tyrosine kinase substrate binding site inhibitors. Curr Opin Investig Drugs 2008;9:605-13
15. Uckun FM, Ek RO, Jan ST, Chen CL, Qazi S. Targeting SYK Kinase-Dependent Anti-Apoptotic Resistance Pathway in B-lineage Acute Lymphoblastic Leukemia (ALL) Cells with a Potent SYK Inhibitory Pentapeptide Mimic. British Journal of Haematology 2010;149:508-17
16. Uckun FM, Qazi S. Spleen tyrosine kinase as a molecular target for treatment of leukemias and lymphomas. Expert Rev Anticancer Ther 2010;10:1407-18
17. Schwartzberg PL, Finkelstein LD, Readinger JA. TEC-family kinases: Regulators of T-helper-cell differentiation. Nat Rev Immunol 2005;5:284-95
18. Uckun F, Dibirdik I, Sarkissian A, et al. In vitro and in vivo chemosensitizing activity of LFM-A13, a dual-function inhibitor of Bruton's tyrosine kinase and polo-like kinases, against human leukemic B-cell precursors. Arzneimittelforschung 2011;61:252-9
19. Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci USA 2010;107:13075-80
20. Singh J, Petter RC, Kluge AF. Targeted covalent drugs of the kinase family. Curr Opin Chem Biol 2010;14:1-6
21. Hantschel O, Rix U, Schmidt U, et al. The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib. Proc Natl Acad Sci USA 2007;104:13283-8
22. Burger JA, O'Brien S, Fowler N, et al. The Bruton's tyrosine kinase inhibitor, PCI-32765, is well tolerated and demonstrates promising clinical activity in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL): An update on ongoing Phase 1 studies. Blood 2010;116:32a
23. Advani R, Sharman J, Smith ST, et al. The Btk inhibitor PCI-32765 is highly active and well tolerated in patients with relapsed/refractory. B cell malignancies: Final results from a phase I study. Ann Oncol 2011;22(Suppl 4):iv135-7
24. Fowler N, Sharman JP, Smith SM, et al. The Btk inhibitor, PCI-32765, induces durable responses with minimal toxicity In patients with relapsed/refractory B-cell malignancies: Results from a Phase I study. Blood (ASH Annual Meeting Abstracts) 2010;116-964A
25. Staudt LM, Dunleavy K, Buggy JJ, et al. The Bruton's tyrosine kinase (Btk) inhibitor PCI-32765 modulates chronic active BCR signaling and induces tumor regression in relapsed/refractory ABC DLBCL [abstract 2716]. ASH Annual Meeting; 2011
26. Wang M, Rule SA, Martin P, et al. Interim results of an international, multicenter, Phase 2 study of Bruton's tyrosine kinase (BTK) inhibitor, Ibrutinib (PCI-32765), in relapsed or refractory mantle cell lymphoma (MCL): Durable efficacy and tolerability with longer follow-up [abstract 904]. ASH Annual Meeting; 2012
27. Wilson WH, Gerecitano JF, Goy A, et al. The Bruton's tyrosine kinase (BTK) inhibitor, Ibrutinib, has preferential activity in the ABC subtype of relapsed/rRefractory de novo diffuse large B-cell lymphoma (DLBCL): Interim results of a multicenter, open-label, Phase 2 study [abstract 686]. ASH Annual Meeting; 2012
28. O'Brien S, Burger JA, Blum KA, et al. The Bruton's tyrosine kinase inhibitor PCI-32765 induces durable responses in relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): Follow-up of a Phase Ib/II study [abstract 983]. Blood (ASH Annual Meeting Abstracts) 2011;118:983
29. O'Brien S, Furman RF, Coutre SE, et al. The Bruton's tyrosine kinase inhibitor Ibrutinib (PCI-32765) is highly active and tolerable in relapsed or refractory and treatment naive chronic lymphocytic leukemia patients, updated results of a Phase Ib/II study [ abstract 1970]. 17th Congress of European Hematology Association; 2012
30. Byrd JC, Furman RR, Coutre SE, et al. The Bruton's tyrosine kinase (BTK) inhibitor PCI-32765 (P) in treatment-naive (TN) chronic lymphocytic leukemia (CLL) patients (pts): Interim results of a phase Ib/II study. J Clin Oncol 2012;30(Suppl):abstract 6507
31. Byrd JC, Furman RR, Coutre S, et al. The Bruton's tyrosine kinase (BTK) inhibitor Ibrutinib promotes high response rate, durable remissions, and is tolerable in treatment naive (TN) and relapsed or refractory (RR) CLL or SLL patients including patients with high-risk (HR) disease: New and updated results of 116 patients in a Phase Ib/II Study [abstract 189]. ASH Annual Meeting; 2012
32. Burger JA, Keating MJ, Wierda WG, et al. The Btk inhibitor Ibrutinib (PCI-32765) in combination with Rituximab is well tolerated and displays profound activity in high-risk chronic lymphocytic leukemia (CLL) patients [abstract 187]. 2012 ASH Annual Meeting
33. Brown JR, Barrientos J, Flinn IW, et al. Combination of the Bruton's tyrosine kinase inhibitor PCI-32765 with bendamustine/rituximab (BR) in patients with relapsed/refractory chronic lymphocytic leukemia: Interim results of a phase Ib/II study [abstract 1590]. 17th Congress of European Hematology Association; 2012
34. Jaglowski SM, Jones JA, Flynn JM, et al. A phase Ib/II study evaluating activity and tolerability of BTK inhibitor PCI-32765 and ofatumumab in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and related diseases. 2012 ASCO Annual Meeting, Abstract No: 6508. J Clin Oncol 2012;30(Suppl): Abstract 6508
35. O'Brien SM, Barrientos JC, Flinn IW, et al. Combination of the Bruton's tyrosine kinase (BTK) inhibitor PCI-32765 with bendamustine (B)/rituximab (R) (BR) in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): Interim results of a phase Ib/II study. 2012 ASCO Annual Meeting. J Clin Oncol 2012;30(Suppl):abstract 6515
36. Kuo AH, Stoica GE, Riegel AT, Wellstein A. Recruitment of insulin receptor substrate-1 and activation of NF-kappaB essential for midkine growth signaling through anaplastic lymphoma kinase. Oncogene 2007;26:859-69
37. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of tumors of haematopoietic and lymphoid tissues. 4th edition. IARC, Lyon; 2008
38. Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 1995;267:316-17
39. Gascoyne RD, Aoun P, Wu D, et al. Prognostic significance of anaplastic lymphoma kinase (ALK) protein expression in adults with anaplastic large cell lymphoma. Blood 1999;93:3913-21
40. Christensen JG, Zou HY, Arango ME, et al. Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther 2007;6:3314-22
41. Furman RR, Byrd JC, Brown JR, et al. CAL-101, An isoform-selective inhibitor of phosphatidylinositol 3-kinase P110 {delta}, demonstrates clinical activity and pharmacodynamic effects in patients with relapsed or refractory chronic lymphocytic leukemia. Blood 2010;116:31a
42. Meadows SA, Vega F, Kashishian A, et al. PI3Kdelta inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma. Blood 2012;119:1897-900
43. Lannutti BJ, Meadows SA, Herman SE, et al. CAL-101, a p110{delta} selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood 2011;117:591-4
44. Ikeda H, Hideshima T, Fulciniti M, et al. PI3K/p110{delta} is a novel therapeutic target in multiple myeloma. Blood 2010;116:1460-8
45. Coutre SE, Byrd JC, Furman RR, et al. Phase 1 study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3 kinase p110d,in patients with previously treated chronic lymphocytic leukemia. J Clin Oncol 2011;29(Suppl):abstract 6631
46. Furman RR, Barrientos JC, Sharman JP, et al. A phase I/II study of the selective phosphatidylinositol 3-kinase-delta (PI3Kdelta) inhibitor, GS-1101 (CAL-101), with ofatumumab in patients with previously treated chronic lymphocytic leukemia (CLL). Meeting: 2012 ASCO Annual Meeting Abstracts. J Clin Oncol 2012;30(Suppl):abstract 6518
47. Hay N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell 2005;8:179-83
48. Ghobrial IM, Leleu X, Rubin N, et al. Phase II trial of the novel oral Akt inhibitor perifosine in relapsed and/or refractory Waldenstrom macroglobulinemia (WM). J Clin Oncol 2008;26(Suppl):abstract No. 8546
49. Guidetti A, Viviani S, Marchiano A, et al. Dual targeted therapy with the AKT inhibitor Perifosine and the multikinase inhibitor Sorafenib in patients with relapsed/refractory lymphomas: Final results of a Phase II trial [abstract No. 3679]. 54th ASH Annual Meeting; 2012
50. Witzig TE, Reeder CB, LaPlant BR, et al. A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma. Leukemia 2011;25:341-7
51. Johnston PB, Inwards DJ, Colgan JP, et al. A phase II trial of the oral mTOR inhibitor everolimus in relapsed Hodgkin lymphoma. Am J Hematol 2010;85:320-4
52. Zent CS, LaPlant BR, Johnston PB, et al. The treatment of recurrent/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) with everolimus results in clinical responses and mobilization of CLL cells into the circulation. Cancer 2010;116:2201-7
53. Ghobrial IM, Gertz M, Laplant B, et al. Phase II trial of the oral mammalian target of rapamycin inhibitor everolimus in relapsed or refractory Waldenstrom macroglobulinemia. J Clin Oncol 2010;28:1408-14
54. O'Connor OA, Popplewell L, Winter JN, et al. PILLAR-1: Preliminary results of a phase II study of mTOR inhibitor everolimus in patients with mantle cell lymphoma (MCL) who are refractory or intolerant to bortezomib. Blood 2010;116; abstract 3963
55. Younes A, Copeland A, Fanale MA, et al. Phase I/II study of the novel combination of panobinostat (LBH589) and everolimus (RAD001) in relapsed/refractory Hodgkin and non-Hodgkin lymphoma. Blood 2010;116; abstract 3964
56. Witzig TE, Geyer SM, Ghobrial I, et al. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 2005;23:5347-56
57. Ansell SM, Inwards DJ, Rowland KM, et al. Low-dose, single-agent temsirolimus for relapsed mantle cell lymphoma: A phase 2 trial in the North Central Cancer Treatment Group. Cancer 2008;113:508-14
58. Hess G, Herbrecht R, Romaguera J, et al. Phase III study to evaluate temsirolimus compared with investigator's choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol 2009;27:3822-9
59. Ansell SM, Tang H, Kurtin P, et al. Temsirolimus and rituximab in patients with relapsed or refractory mantle cell lymphoma: A phase 2 study. Lancet Oncol 2011;12:361-8
60. Smith SM, van Besien K, Karrison T, et al. Temsirolimus has activity in non-mantle cell non-Hodgkin's lymphoma subtypes: The University of Chicago phase II consortium. J Clin Oncol 2010;28:4740-6
61. Rizzieri D, Feldman E, Dipersio J, 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;14:2756-62
62. Mita M, Mita A, Chu Q, et al. A phase I trial of the novel mTOR inhibitor deforolimus (AP23573) administered intraveneously daily for 5 days every two weeks to patients with advanced malignancies. J Clin Oncol 2008;26:361-7
63. Wander SA, Hennessy BT, Slingerland JM. Next-generation mTOR inhibitors in clinical oncology: How pathway complexity informs therapeutic strategy. J Clin Invest 2011;121:1231-41
64. Yeatman TJ. A renaissance for SRC. Nat Rev Cancer 2004;4:470-80
65. Alvarez RH, Kantarjian HM, Cortes JE. The role of Src in solid and hematologic malignancies: Development of new-generation Src inhibitors. Cancer 2006;107:918-29
66. Lombardo LJ, Lee FY, Chen P, et al. Discovery of N-(2-chloro-6- methylphenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin- 4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 2004;47:6658-61
67. William BM, Hohenstein M, Loberiza FR Jr, et al. Phase I/II study of Dasatinib in relapsed or refractory non-Hodgkin's lymphoma (NHL) [abstract No. 288]. 53rd ASH Annual Meeting; 2011
68. Carter CA, Kane CJ. Therapeutic potential of natural compounds that regulate the activity of protein kinase C. Curr Med Chem 2004;11:2883-902
69. Teicher BA, Alvarez E, Menon K, et al. Antiangiogenic effects of a protein kinase Cbeta-selective small molecule. Cancer Chemother Pharmacol 2002;49:69-77
70. Morschhauser F, Seymour JF, Kluin-Nelemans HC, et al. A phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory mantle cell lymphoma. Ann Oncol 2008;19:247-53
71. Robertson MJ, Kahl BS, Vose JM, et al. Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol 2005;25:1741-6
72. Schwartzberg L, Hermann RC, Flinn IW, et al. Enzastaurin in patients with follicular lymphoma: Results of a Phase II study. J Clin Oncol 2010;28(Suppl):15s . One of the first study of Enzastaurin in indolent NHL, with measurable responses.
73. Forsyth CJ, Gomez D, Eliadis P, et al. Enzastaurin in patients with non-Hodgkin lymphomas: A multicenter, open-label, screening study. Blood (ASH Annual Meeting Abstracts) 2009;114:3719
74. Ghobrial IM, Harousseau JL, Treon SP, et al. Enzastaurin in previously treated Waldenstrom's macroglobulinemia: An open-label, multicenter, Phase II study. Blood (ASH Annual Meeting Abstracts) 2009;114:3867
75. Reuter CW, Morgan MA, Bergmann L. Targeting the Ras signaling pathway: A rational, mechanism-based treatment for hematologic malignancies? Blood 2000;96:1655-69
76. Steinbrunn T, Stuhmer T, Gattenlohner S, et al. Mutated RAS and constitutively activated Akt delineate distinct oncogenic pathways, which independently contribute to multiple myeloma cell survival. Blood 2011;117:1998-2004
77. Braun T, Fenaux P. Farnesyltransferase inhibitors and their potential role in therapy for myelodysplastic syndromes and acute myeloid leukaemia. Br J Haematol 2008;141:576-86
78. Witzig TE, Maurer MJ, Johnston PB, et al. Oral tipifarnib (R115777) has single agent anti-tumor activity in patients with relapsed aggressive non-Hodgkin lymphoma (NHL): Results of a phase II trial in the University of Iowa/Mayo Clinic Lymphoma SPORE (CA97274) [abstract]. Blood 2006;108:530
79. Rolland D, Ribrag V, Haioun C, et al. Phase II trial and prediction of response of single agent tipifarnib in patients with relapsed/refractory mantle cell lymphoma: A Groupe d'Etude des Lymphomes de l'Adulte trial. Cancer Chemother Pharmacol 2009;65:781-90
80. Mori S, Cortes J, Kantarjian H, et al. Potential role of sorafenib in the treatment of acute myeloid leukemia. Leuk Lymphoma 2008;49:2246-55
81. Leonard WJ, O'Shea JJ. Jaks and STATs: Biological implications. Annu Rev Immunol 1998;16:293-322
82. Younes A, Romaguera J, Fanale M, et al. Phase I study of a novel oral Janus kinase 2 inhibitor, SB1518, in patients with relapsed lymphoma: Evidence of clinical and biologic activity in multiple lymphoma subtypes. J Clin Oncol 2012;4161:7
83. Friedberg J, Mahadevan D, Jung JA, et al. Phase 2 Trial of Alisertib (MLN8237), an investigational, potent inhibitor of Aurora A kinase (AAK), in patients with aggressive B- and T-cell non-Hodgkin lymphoma [abstract No. 95]. 53rd ASH Meeting; 2011
84. Peripheral T-Cell Lymphoma. ClinicalTrials.gov. Available from: Http://clinicaltrials.gov/ct2/show/NCT01482962? term=nct01482962&rank=1
85. Infante J, Dees EC, Cohen RB, et al. Phase I study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of MLN8237, a selective aurora A kinase inhibitor, in the United States. Eur J Cancer Suppl 2008;6:abstract 280
86. De Jonge M, Steeghs N, Verweij J, et al. Phase I study of the aurora kinases (AKs) inhibitor PHA-739358 administered as a 6 and 3-h IV infusion on days 1, 8, 15 every 4 wks in patients with advanced solid tumors. J Clin Oncol 2008;26:abstract 3507
87. Carpinelli P, Moll J. Aurora kinase inhibitors: Identification and preclinical validation of their biomarkers. Expert Opin Ther Targets 2008;12:69-80