Antimitotic agents for the treatment of patients with metastatic castrate-resistant prostate cancer

Expert Opinion on Investigational Drugs

Volumn 22, Issue 5, 2013, Pages 635-661

  Wissing, Michel D ^a   Van Diest, Paul J ^b   Van Der Wall, Elsken ^b   Gelderblom, Hans ^a  

^a LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

^b UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

Author keywords

Aurora kinases; Chemotherapy; Epothilone; Kinesin spindle protein; Metastatic castrate resistant prostate cancer; Mitosis; Polo like kinase 1; Taxane

Indexed keywords

ABIRATERONE ACETATE; AFLIBERCEPT; ANTIMITOTIC AGENT; ATRASENTAN; BEVACIZUMAB; CABAZITAXEL; CALCITRIOL; CUSTIRSEN; DASATINIB; DOCETAXEL; ENZALUTAMIDE; EPOTHILONE B; EPOTHILONE D; EPOTHILONE DERIVATIVE; ESTRAMUSTINE; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR VACCINE; IXABEPILONE; LENALIDOMIDE; MITOXANTRONE; PACLITAXEL; PREDNISONE; RISEDRONIC ACID; SAGOPILONE; TAK 327; TEMOZOLOMIDE; TESETAXEL; UNCLASSIFIED DRUG; UNINDEXED DRUG; VINCRISTINE; ZIBOTENTAN; ZOLEDRONIC ACID;

ADVERSE OUTCOME; ANTINEOPLASTIC ACTIVITY; CANCER RADIOTHERAPY; CASTRATION RESISTANT PROSTATE CANCER; DRUG EFFICACY; DRUG SAFETY; FATIGUE; HUMAN; MICROTUBULE; MITOSIS; MUSCULOSKELETAL DISEASE; NAIL DISEASE; NEUROPATHY; NONHUMAN; REVIEW; TREATMENT RESPONSE;

ANIMALS; ANTIMITOTIC AGENTS; CASTRATION; CELL CYCLE PROTEINS; HUMANS; KINESIN; MALE; PROSTATIC NEOPLASMS; PROTEIN KINASE INHIBITORS; PROTEIN-SERINE-THREONINE KINASES; PROTO-ONCOGENE PROTEINS; TAXOIDS;

EID: 84876226303     PISSN: 13543784     EISSN: 17447658     Source Type: Journal    
DOI: 10.1517/13543784.2013.789858     Document Type: Review

References (244)

1. Siegel R, Naishadham D, Jemal A. Cancer statistics. CA Cancer J Clin 2012;62:10-29
2. Muntzing J, Shukla SK, Chu TM, et al. Pharmacoclinical study of oral estramustine phosphate (Estracyt) in advanced carcinoma of the prostate. Invest Urol 1974;12:65-8
3. Soloway MS, deKernion JB, Gibbons RP, et al. Comparison of estramustine phosphate and vincristine alone or in combination for patients with advanced, hormone refractory, previously irradiated carcinoma of the prostate. J Urol 1981;125:664-7
4. Belotti D, Vergani V, Drudis T, et al. The microtubule-affecting drug paclitaxel has antiangiogenic activity. Clin Cancer Res 1996;2:1843-9
5. Giannakakou P, Nakano M, Nicolaou KC, et al. Enhanced microtubule-dependent trafficking and p53 nuclear accumulation by suppression of microtubule dynamics. Proc Natl Acad Sci USA 2002;99:10855-60
6. Thadani-Mulero M, Nanus DM, Giannakakou P. Androgen receptor on the move: boarding the microtubule expressway to the nucleus. Cancer Res 2012;72:4611-15
7. Poirier TI. Mitoxantrone. Drug Intell Clin Pharm 1986;20:97-105
8. Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol 1996;14:1756-64
9. Khan MA, Carducci MA, Partin AW. The evolving role of docetaxel in the management of androgen independent prostate cancer. J Urol 2003;170:1709-16
10. Tannock IF, de WR, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502-12
11. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513-20
12. Serpa NA, Tobias-Machado M, Kaliks R, et al. Ten years of docetaxel-based therapies in prostate adenocarcinoma: a systematic review and meta-analysis of 2244 patients in 12 randomized clinical trials. Clin Genitourin Cancer 2011;9:115-23
13. Scher HI, Jia X, Chi K, et al. Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer. J Clin Oncol 2011;29:2191-8
14. Kelly WK, Halabi S, Carducci M, et al. Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol 2012;30:1534-40
15. Meulenbeld HJ, van Werkhoven ED, Coenen JL, et al. Randomised phase II/III study of docetaxel with or without risedronate in patients with metastatic Castration Resistant Prostate Cancer (CRPC), the Netherlands Prostate Study (NePro). Eur J Cancer 2012;48:2993-3000
16. Armstrong AJ, Creel P, Turnbull J, et al. A phase I-II study of docetaxel and atrasentan in men with castration-resistant metastatic prostate cancer. Clin Cancer Res 2008;14:6270-6
17. Quinn DI, Tangen CM, Hussain M, et al. SWOG S0421: Phase III study of docetaxel (D) and atrasentan (A) versus docetaxel and placebo (P) for men with advanced castrate resistant prostate cancer (CRPC) [abstract]. J Clin Oncol 2012;30(Suppl); abstract 4511
18. Higano C, Saad F, Somer B, et al. A phase III trial of GVAX immunotherapy for prostate cancer versus docetaxel plus prednisone in asymptomatic, castration-resistant prostate cancer (CRPC) [abstract LBA150]. Genitourinary Cancers Symposium; 26-28 Feb 2009; Orlando, FL
19. Small E, Demkow T, Gerritsen R, et al. A phase III trial of GVAX immunotherapy for prostate cancer in combination with docetaxel versus docetaxel plus prednisone in symptomatic, castration-resistant prostate cancer (CRPC) [abstract 7]. Genitourinary Cancers Symposium; 26-28 Feb 2009; Orlando, FL
20. Nelson JB, Fizazi K, Miller K, et al. Phase 3, randomized, placebo-controlled study of zibotentan (ZD4054) in patients with castration-resistant prostate cancer metastatic to bone. Cancer 2012;118:5709-18
21. Sanofi and Regeneron Announce Regulatory and Clinical Update for Zaltrap (aflibercept). Sanofi, Tarrytown, NY; 2012. Available from: http://en. sanofi. com/Images/30138-20120405-ZALTRAP-BLA- VENICE-en. pdf [Last accessed 11 December 2012]
22. Lenalidomide Plus Docetaxel: phase III Results Fall Short. OncLive, Plainsboro, NJ; 2012. Available from: http://www. onclive. com/publications/ oncology-live/2012/january-2012/Lenalidomide-Plus-Docetaxel-Phase-IIIResults- Fall-Short [Last accessed 11 December 2012]
23. Randomized Study Comparing Docetaxel Plus Dasatinib to Docetaxel Plus Placebo in Castration-Resistant Prostate Cancer (READY). US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/NCT00744497 [Last accessed 12 December 2012]
24. Comparison of Docetaxel/Prednisone to Docetaxel/Prednisone in Combination With OGX-011 in Men With Prostate Cancer (SYNERGY). US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/NCT01188187 [Last accessed 12 December 2012]
25. Araujo JC, Mathew P, Armstrong AJ, et al. Dasatinib combined with docetaxel for castration-resistant prostate cancer: results from a phase 1-2 study. Cancer 2012;118:63-71
26. Chi KN, Hotte SJ, Yu EY, et al. Randomized phase II study of docetaxel and prednisone with or without OGX-011 in patients with metastatic castration-resistant prostate cancer. J Clin Oncol 2010;28:4247-54
27. Tamaskar I, Mekhail T, Dreicer R, et al. Phase I trial of weekly docetaxel and daily temozolomide in patients with metastatic disease. Invest New Drugs 2008;26:553-9
28. Facchini G, Caraglia M, Morabito A, et al. Metronomic administration of zoledronic acid and taxotere combination in castration resistant prostate cancer patients: phase I ZANTE trial. Cancer Biol Ther 2010;10:543-8
29. Bradshaw DM, Arceci RJ. Clinical relevance of transmembrane drug efflux as a mechanism of multidrug resistance. J Clin Oncol 1998;16:3674-90
30. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010;376:1147-54
31. Heck MM, Hoppner M, Horn T, et al. Compassionate use of abiraterone and cabazitaxel: first experiences in docetaxel-pretreated castration-resistant prostate cancer patients. Urologe A 2012;published online; doi:10. 1007/s00120-012-2804-y
32. De Velasco G, Aparicio LA, Esteban E, et al. Cabazitaxel in patients with advanced CRPC after docetaxel failure: results of expanded program access (EAP) in Spain: Safety and efficacy [abstract]. J Clin Oncol 2012;30(Suppl): abstract e15149
33. Bracarda S, Di Lorenzo G, Gasparro D, et al. Updated safety result of a large Italian early access program (EAP) with cabazitaxel plus prednisone (CbzP) in metastatic castration-resistant prostate cancer (mCRPC) patients who progressed during or after docetaxel (D) therapy [abstract]. J Clin Oncol 2012;30(Suppl):abstract e15185
34. Roth BJ, Yeap BY, Wilding G, et al. Taxol in advanced, hormone-refractory carcinoma of the prostate. A phase II trial of the Eastern Cooperative Oncology Group. Cancer 1993;72:2457-60
35. Hudes GR, Nathan F, Khater C, et al. Phase II trial of 96-hour paclitaxel plus oral estramustine phosphate in metastatic hormone-refractory prostate cancer. J Clin Oncol 1997;15:3156-63
36. Smith DC, Esper P, Strawderman M, et al. Phase II trial of oral estramustine, oral etoposide, and intravenous paclitaxel in hormone-refractory prostate cancer. J Clin Oncol 1999;17:1664-71
37. Smith DC, Chay CH, Dunn RL, et al. Phase II trial of paclitaxel, estramustine, etoposide, and carboplatin in the treatment of patients with hormone-refractory prostate carcinoma. Cancer 2003;98:269-76
38. Berry W, Friedland D, Fleagle J, et al. A phase II study of weekly paclitaxel/estramustine/carboplatin in hormone-refractory prostate cancer. Clin Genitourin Cancer 2006;5:131-7
39. Mackler NJ, Pienta KJ, Dunn RL, et al. Phase II evaluation of oral estramustine, oral etoposide, and intravenous paclitaxel in patients with hormone-sensitive prostate adenocarcinoma. Clin Genitourin Cancer 2007;5:318-22
40. Kelly WK, Halabi S, Elfiky A, et al. Multicenter phase 2 study of neoadjuvant paclitaxel, estramustine phosphate, and carboplatin plus androgen deprivation before radiation therapy in patients with unfavorable-risk localized prostate cancer: results of Cancer and Leukemia Group B 99811. Cancer 2008;113:3137-45
41. Sanfilippo NJ, Taneja SS, Chachoua A, et al. Phase I/II study of biweekly paclitaxel and radiation in androgen-ablated locally advanced prostate cancer. J Clin Oncol 2008;26:2973-8
42. Sella A, Yarom N, Zisman A, Kovel S. Paclitaxel, estramustine and carboplatin combination chemotherapy after initial docetaxel-based chemotherapy in castration-resistant prostate cancer. Oncology 2009;76:442-6
43. Sewak S, Kosmider S, Ganju V, et al. Phase II study of paclitaxel and vinorelbine (Pacl-Vin) in hormone-refractory metastatic prostate cancer: double tubulin targeting. Intern Med J 2010;40:201-8
44. DiPaola RS, Chen YH, Stein M, et al. A randomized phase II trial of mitoxantrone, estramustine and vinorelbine or bcl-2 modulation with 13-cis retinoic acid, interferon and paclitaxel in patients with metastatic castrate-resistant prostate cancer: ECOG 3899. J Transl Med 2010;8:20
45. Beer TM, Ryan C, Alumkal J, et al. A phase II study of paclitaxel poliglumex in combination with transdermal estradiol for the treatment of metastatic castration-resistant prostate cancer after docetaxel chemotherapy. Anticancer Drugs 2010;21:433-8
46. Smith DC, Tangen CM, Van Veldhuizen PJJ, et al. Phase II evaluation of early oral estramustine, oral etoposide, and intravenous paclitaxel combined with hormonal therapy in patients with high-risk metastatic prostate adenocarcinoma: southwest Oncology Group S0032. Urology 2011;77:1172-6
47. Jeske S, Tagawa ST, Olowokure O, et al. Carboplatin plus paclitaxel therapy after docetaxel in men with metastatic castrate resistant prostate cancer. Urol Oncol 2011;29:676-81
48. Desai N, Trieu V, Yao Z, et al. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res 2006;12:1317-24
49. Shepard DR, Dreicer R, Garcia J, et al. Phase II trial of neoadjuvant nab-paclitaxel in high risk patients with prostate cancer undergoing radical prostatectomy. J Urol 2009;181:1672-7
50. Kolevska T, Ryan CJ, Huey V, et al. Phase II trial of nab-paclitaxel as first-line therapy of hormone refractory metastatic prostate cancer (HRPC) [abstr 5152]. J Clin Oncol 2009;27(Suppl):15s
51. Phase I Abraxane Weekly and Three Weekly Schedule With Vandetanib. US National Institute of Health, Bethesda, MD; 2013. Available from: http://clinicaltrial. gov/ct2/show/NCT00667147 [Last accessed 21 January 2013]
52. Shionoya M, Jimbo T, Kitagawa M, et al. DJ-927, a novel oral taxane, overcomes P-glycoprotein-mediated multidrug resistance in vitro and in vivo. Cancer Sci 2003;94:459-66
53. Baas P, Szczesna A, Albert I, et al. Phase I/II study of a 3 weekly oral taxane (DJ-927) in patients with recurrent, advanced non-small cell lung cancer. J Thorac Oncol 2008;3:745-50
54. Saif MW, Sarantopoulos J, Patnaik A, et al. Tesetaxel, a new oral taxane, in combination with capecitabine: a phase I, dose-escalation study in patients with advanced solid tumors. Cancer Chemother Pharmacol 2011;68:1565-73
55. Tesetaxel in chemotherapy-naive patients with progressive, castration-resistant prostate cancer. US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/NCT01296243 [Last accessed 12 December 2012]
56. Daliani DD, Assikis V, Tu SM, et al. Phase II trial of cyclophosphamide, vincristine, and dexamethasone in the treatment of androgen-independent prostate carcinoma. Cancer 2003;97:561-7
57. Sepp-Lorenzino L, Balog A, Su DS, et al. The microtubule-stabilizing agents epothilones A and B and their desoxy-derivatives induce mitotic arrest and apoptosis in human prostate cancer cells. Prostate Cancer Prostatic Dis 1999;2:41-52
58. Lee FY, Borzilleri R, Fairchild CR, et al. BMS-247550: a novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy. Clin Cancer Res 2001;7:1429-37
59. Chou TC, O'Connor OA, Tong WP, et al. The synthesis, discovery, and development of a highly promising class of microtubule stabilization agents: curative effects of desoxyepothilones B and F against human tumor xenografts in nude mice. Proc Natl Acad Sci USA 2001;98:8113-18
60. Dorff TB, Gross ME. The epothilones: new therapeutic agents for castration-resistant prostate cancer. Oncologist 2011;16:1349-58
61. Hortobagyi GN, Gomez HL, Li RK, et al. Analysis of overall survival from a phase III study of ixabepilone plus capecitabine versus capecitabine in patients with MBC resistant to anthracyclines and taxanes. Breast Cancer Res Treat 2010;122:409-18
62. Sparano JA, Vrdoljak E, Rixe O, et al. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 2010;28:3256-63
63. Roche H, Conte P, Perez EA, et al. Ixabepilone plus capecitabine in metastatic breast cancer patients with reduced performance status previously treated with anthracyclines and taxanes: a pooled analysis by performance status of efficacy and safety data from 2 phase III studies. Breast Cancer Res Treat 2011;125:755-65
64. Jassem J, Fein L, Karwal M, et al. Ixabepilone plus capecitabine in advanced breast cancer patients with early relapse after adjuvant anthracyclines and taxanes: a pooled subset analysis of two phase III studies. Breast 2012;21:89-94
65. Withdrawal of IXEMPRA, (ixabepilone) EMEA/H/C/000930. European Medicines Agency, London, UK, 2009. Available from: http://www. ema. europa. eu/docs/en-GB/document-library/Other/2010/01/WC500062430. pdf [Last accessed 12 December 2012]
66. Smaletz O, Galsky M, Scher HI, et al. Pilot study of epothilone B analog (BMS-247550) and estramustine phosphate in patients with progressive metastatic prostate cancer following castration. Ann Oncol 2003;14:1518-24
67. Rosenberg JE, Ryan CJ, Weinberg VK, et al. Phase I study of ixabepilone, mitoxantrone, and prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-based therapy: a study of the department of defense prostate cancer clinical trials consortium. J Clin Oncol 2009;27:2772-8
68. Galsky MD, Small EJ, Oh WK, et al. Multi-institutional randomized phase II trial of the epothilone B analog ixabepilone (BMS-247550) with or without estramustine phosphate in patients with progressive castrate metastatic prostate cancer. J Clin Oncol 2005;23:1439-46
69. Rosenberg JE, Weinberg VK, Kelly WK, et al. Activity of second-line chemotherapy in docetaxel-refractory hormone-refractory prostate cancer patients : randomized phase 2 study of ixabepilone or mitoxantrone and prednisone. Cancer 2007;110:556-63
70. Liu G, Chen YH, Dipaola R, et al. Phase II trial of weekly ixabepilone in men with metastatic castrate-resistant prostate cancer (E3803): a trial of the Eastern Cooperative Oncology Group. Clin Genitourin Cancer 2012;10:99-105
71. Layton JL, Plette AM, Renzulli JF, et al. The impact of neoadjuvant weekly ixabepilone for high-risk prostate cancer: a phase I/II clinical trial. [abstract]. J Clin Oncol 2012;30(Suppl 5; abstract 158
72. Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008;26:1148-59
73. Hussain A, DiPaola RS, Baron AD, et al. Phase II trial of weekly patupilone in patients with castration-resistant prostate cancer. Ann Oncol 2009;20:492-7
74. Chi KN, Beardsley E, Eigl BJ, et al. A phase 2 study of patupilone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel: canadian Urologic Oncology Group study P07a. Ann Oncol 2012;23:53-8
75. Beer TM, Higano CS, Saleh M, et al. Phase II study of KOS-862 in patients with metastatic androgen independent prostate cancer previously treated with docetaxel. Invest New Drugs 2007;25:565-70
76. Beer TM, Smith DC, Hussain A, et al. Phase II study of first-line sagopilone plus prednisone in patients with castration-resistant prostate cancer: a phase II study of the Department of Defense Prostate Cancer Clinical Trials Consortium. Br J Cancer 2012;107:808-13
77. Roberts K. Cytoplasmic microtubules and their functions. Prog Biophys Mol Biol 1974;28:371-420
78. Mayer TU, Kapoor TM, Haggarty SJ, et al. Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 1999;286:971-4
79. Kapitein LC, Peterman EJ, Kwok BH, et al. The bipolar mitotic kinesin Eg5 moves on both microtubules that it crosslinks. Nature 2005;435:114-18
80. Sarli V, Giannis A. Targeting the kinesin spindle protein: basic principles and clinical implications. Clin Cancer Res 2008;14:7583-7
81. Vijapurkar U, Wang W, Herbst R. Potentiation of kinesin spindle protein inhibitor-induced cell death by modulation of mitochondrial and death receptor apoptotic pathways. Cancer Res 2007;67:237-45
82. Tao W, South VJ, Diehl RE, et al. An inhibitor of the kinesin spindle protein activates the intrinsic apoptotic pathway independently of p53 and de novo protein synthesis. Mol Cell Biol 2007;27:689-98
83. Liu M, Aneja R, Liu C, et al. Inhibition of the mitotic kinesin Eg5 up-regulates Hsp70 through the phosphatidylinositol 3-kinase/Akt pathway in multiple myeloma cells. J Biol Chem 2006;281:18090-7
84. Chin GM, Herbst R. Induction of apoptosis by monastrol, an inhibitor of the mitotic kinesin Eg5, is independent of the spindle checkpoint. Mol Cancer Ther 2006;5:2580-91
85. Lad L, Luo L, Carson JD, et al. Mechanism of inhibition of human KSP by ispinesib. Biochemistry 2008;47:3576-85
86. Blagden SP, Molife LR, Seebaran A, et al. A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours. Br J Cancer 2008;98:894-9
87. Burris HA III, Jones SF, Williams DD, et al. A phase I study of ispinesib, a kinesin spindle protein inhibitor, administered weekly for three consecutive weeks of a 28-day cycle in patients with solid tumors. Invest New Drugs 2011;29:467-72
88. Chu QS, Holen KD, Rowinsky EK, et al. Phase I trial of novel kinesin spindle protein (KSP) inhibitor SB-715992 IV Q 21 days [abstract 2078]. J Clin Oncol 2004;22(Suppl):14S
89. Heath EI, Alousi A, Eder JP, et al. A phase I dose escalation trial of ispinesib (SB-715992) administered days 1-3 of a 21-day cycle in patients with advanced solid tumors [abstrac 2026]. J Clin Oncol 2006;24(Suppl):18S
90. Beer TM, Goldman B, Synold TW, et al. Southwest Oncology Group phase II study of ispinesib in androgen-independent prostate cancer previously treated with taxanes. Clin Genitourin Cancer 2008;6:103-9
91. Xing ND, Ding ST, Saito R, et al. A potent chemotherapeutic strategy in prostate cancer: S-(methoxytrityl)-Lcysteine, a novel Eg5 inhibitor. Asian J Androl 2011;13:236-41
92. Holen KD, Belani CP, Wilding G, et al. A first in human study of SB-743921, a kinesin spindle protein inhibitor, to determine pharmacokinetics, biologic effects and establish a recommended phase II dose. Cancer Chemother Pharmacol 2011;67:447-54
93. Holen K, Dipaola R, Liu G, et al. A phase I trial of MK-0731, a Kinesin Spindle Protein (KSP) inhibitor, in patients with solid tumors. Invest New Drugs 2011; published online; doi:10. 1007/s10637-011-9653-1
94. Esaki T, Seto T, Ariyama H, et al. Phase I study to assess the safety, tolerability and pharmacokinetics of AZD4877 in Japanese patients with solid tumors. Arch Drug Inf 2011;4:23-31
95. Infante JR, Kurzrock R, Spratlin J, et al. A Phase I study to assess the safety, tolerability, and pharmacokinetics of AZD4877, an intravenous Eg5 inhibitor in patients with advanced solid tumors. Cancer Chemother Pharmacol 2012;69:165-72
96. Stephenson JJ, Lewis N, Martin JC, et al. Phase I multicenter study to assess the safety, tolerability, and pharmacokinetics of AZD4877 administered twice weekly in adult patients with advanced solid malignancies [abstract]. J Clin Oncol 2008;26(Suppl); abstract 2516
97. Goncalves PH, Sausville EA, Edelman MJ, et al. A phase I study of ARRY-520 in solid tumors [abstract 2570]. J Clin Oncol 2010;28(Suppl):15s
98. Nakai R, Iida S, Takahashi T, et al. K858, a novel inhibitor of mitotic kinesin Eg5 and antitumor agent, induces cell death in cancer cells. Cancer Res 2009;69:3901-9
99. Wiltshire C, Singh BL, Stockley J, et al. Docetaxel-resistant prostate cancer cells remain sensitive to S-trityl-L-cysteinemediated Eg5 inhibition. Mol Cancer Ther 2010;9:1730-9
100. Carmena M, Earnshaw WC. The cellular geography of aurora kinases. Nat Rev Mol Cell Biol 2003;4:842-54
101. Dar AA, Goff LW, Majid S, et al. Aurora kinase inhibitors-rising stars in cancer therapeutics? Mol Cancer Ther 2010;9:268-78
102. Hirota T, Kunitoku N, Sasayama T, et al. Aurora-A and an interacting activator, the LIM protein Ajuba, are required for mitotic commitment in human cells. Cell 2003;114:585-98
103. Marumoto T, Hirota T, Morisaki T, et al. Roles of aurora-A kinase in mitotic entry and G2 checkpoint in mammalian cells. Genes Cells 2002;7:1173-82
104. Marumoto T, Honda S, Hara T, et al. Aurora-A kinase maintains the fidelity of early and late mitotic events in HeLa cells. J Biol Chem 2003;278:51786-95
105. Berdnik D, Knoblich JA. Drosophila Aurora-A is required for centrosome maturation and actin-dependent asymmetric protein localization during mitosis. Curr Biol 2002;12:640-7
106. Terada Y, Tatsuka M, Suzuki F, et al. AIM-1: a mammalian midbody-associated protein required for cytokinesis. EMBO J 1998;17:667-76
107. Slattery SD, Mancini MA, Brinkley BR, Hall RM. Aurora-C kinase supports mitotic progression in the absence of Aurora-B. Cell Cycle 2009;8:2984-94
108. Khan J, Ezan F, Cremet JY, et al. Overexpression of active Aurora-C kinase results in cell transformation and tumour formation. PLoS ONE 2011;6:e26512
109. Chieffi P, Cozzolino L, Kisslinger A, et al. Aurora B expression directly correlates with prostate cancer malignancy and influence prostate cell proliferation. Prostate 2006;66:326-33
110. Beltran H, Rickman DS, Park K, et al. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov 2011;1:487-95
111. Mosquera JM, Beltran H, Park K, et al. Concurrent AURKA and MYCN gene amplifications are harbingers of lethal treatment-related neuroendocrine prostate cancer. Neoplasia 2013;15:1-10
112. Jeet V, Russell PJ, Verma ND, Khatri A. Targeting aurora kinases: a novel approach to curb the growth & chemoresistance of androgen refractory prostate cancer. Curr Cancer Drug Targets 2011; published online; doi:EPub-Abstract-CCDT-188 [pii]
113. Shu SK, Liu Q, Coppola D, Cheng JQ. Phosphorylation and activation of androgen receptor by Aurora-A. J Biol Chem 2010;285:33045-53
114. Jeong NY, Yoon YG, Rho JH, et al. The novel resveratrol analog HS-1793-induced polyploid LNCaP prostate cancer cells are vulnerable to downregulation of Bcl-xL. Int J Oncol 2011;38:1597-604
115. Moretti L, Niermann K, Schleicher S, et al. MLN8054, a small molecule inhibitor of aurora kinase a, sensitizes androgen-resistant prostate cancer to radiation. Int J Radiat Oncol Biol Phys 2011;80:1189-97
116. Fancelli D, Moll J, Varasi M, et al. 1, 4, 5, 6-tetrahydropyrrolo[3, 4-c]pyrazoles: identification of a potent Aurora kinase inhibitor with a favorable antitumor kinase inhibition profile. J Med Chem 2006;49:7247-51
117. Carpinelli P, Ceruti R, Giorgini ML, et al. PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer. Mol Cancer Ther 2007;6:3158-68
118. Steeghs N, Eskens FA, Gelderblom H, et al. Phase I pharmacokinetic and pharmacodynamic study of the aurora kinase inhibitor danusertib in patients with advanced or metastatic solid tumors. J Clin Oncol 2009;27:5094-101
119. Cohen RB, Jones SF, Aggarwal C, et al. A phase I dose-escalation study of danusertib (PHA-739358) administered as a 24-hour infusion with and without granulocyte colony-stimulating factor in a 14-day cycle in patients with advanced solid tumors. Clin Cancer Res 2009;15:6694-701
120. Meulenbeld HJ, Bleuse JP, Vinci EM, et al. Randomized phase II study of danusertib in patients with metastatic castration-resistant prostate cancer after docetaxel failure. BJU Int 2012;published online; doi:10. 1111/j. 1464-410X. 2012. 11404. x
121. Sells T, Ecsedy JA, Stroud S, et al. MLN8237: an orally active small molecule inhibitor of aurora A kinase in phase I clinical trials [abstract]. Proc Am Assoc Cancer Res (AACR) 2008;49;abstract 2997
122. Manfredi MG, Ecsedy JA, Chakravarty A, et al. Characterization of Alisertib (MLN8237), an investigational small-molecule inhibitor of aurora A kinase using novel in vivo pharmacodynamic assays. Clin Cancer Res 2011;17:7614-24
123. Maris JM, Morton CL, Gorlick R, et al. Initial testing of the aurora kinase A inhibitor MLN8237 by the Pediatric Preclinical Testing Program (PPTP). Pediatr Blood Cancer 2010;55:26-34
124. Dees EC, Cohen RB, von MM, et al. Phase I study of aurora A kinase inhibitor MLN8237 in advanced solid tumors: safety, pharmacokinetics, pharmacodynamics, and bioavailability of two oral formulations. Clin Cancer Res 2012;18:4775-84
125. A Phase 1 study of MLN8237 in patients with advanced solid tumors including castration-resistant prostate cancer receiving a standard docetaxel regimen. US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/NCT01094288 [Last accessed 12 December 2012]
126. Mortlock AA, Foote KM, Heron NM, et al. Discovery, synthesis, and in vivo activity of a new class of pyrazoloquinazolines as selective inhibitors of aurora B kinase. J Med Chem 2007;50:2213-24
127. Wilkinson RW, Odedra R, Heaton SP, et al. AZD1152, a selective inhibitor of Aurora B kinase, inhibits human tumor xenograft growth by inducing apoptosis. Clin Cancer Res 2007;13:3682-8
128. Niermann KJ, Moretti L, Giacalone NJ, et al. Enhanced radiosensitivity of androgen-resistant prostate cancer: AZD1152-mediated Aurora kinase B inhibition. Radiat Res 2011;175:444-51
129. Boss DS, Witteveen PO, van der Sar J, et al. Clinical evaluation of AZD1152, an i. v. inhibitor of Aurora B kinase, in patients with solid malignant tumors. Ann Oncol 2011;22:431-7
130. Schwartz GK, Carvajal RD, Midgley R, et al. Phase I study of barasertib (AZD1152), a selective inhibitor of Aurora B kinase, in patients with advanced solid tumors. Invest New Drugs 2012;published online; doi:10. 1007/s10637-012-9825-7
131. Sawyers CL. Finding the next Gleevec: FLT3 targeted kinase inhibitor therapy for acute myeloid leukemia. Cancer Cell 2002;1:413-15
132. Fletcher GC, Brokx RD, Denny TA, et al. ENMD-2076 is an orally active kinase inhibitor with antiangiogenic and antiproliferative mechanisms of action. Mol Cancer Ther 2011;10:126-37
133. Diamond JR, Bastos BR, Hansen RJ, et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of ENMD-2076, a novel angiogenic and Aurora kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res 2011;17:849-60
134. Matulonis UA, Lee J, Lasonde B, et al. ENMD-2076, an oral inhibitor of angiogenic and proliferation kinases, has activity in recurrent, platinum resistant ovarian cancer. Eur J Cancer 2012;published online; doi:S0959-8049 (12)00603-X [pii];10. 1016/j. ejca. 2012. 07. 020
135. Study of ENMD-2076 in patients with advanced/metastatic soft tissue sarcoma. US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrials. gov/ct2/show/NCT01719744 [Last accessed 12 December 2012]
136. A Phase II study of the aurora and angiogenic kinase inhibitor ENMD-2076 in previously treated locally advanced and metastatic triple-negative breast cancer. US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrials. gov/ct2/show/NCT01639248 [Last accessed 12 December 2012]
137. Harrington EA, Bebbington D, Moore J, et al. VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat Med 2004;10:262-7
138. Traynor AM, Hewitt M, Liu G, et al. Phase I dose escalation study of MK-0457, a novel Aurora kinase inhibitor, in adult patients with advanced solid tumors. Cancer Chemother Pharmacol 2011;67:305-14
139. Howard S, Berdini V, Boulstridge JA, et al. Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity. J Med Chem 2009;52:379-88
140. Dawson MA, Curry JE, Barber K, et al. AT9283, a potent inhibitor of the Aurora kinases and Jak2, has therapeutic potential in myeloproliferative disorders. Br J Haematol 2010;150:46-57
141. Jani JP, Arcari J, Bernardo V, et al. PF-03814735, an orally bioavailable small molecule aurora kinase inhibitor for cancer therapy. Mol Cancer Ther 2010;9:883-94
142. Gürtler U, Tontsch-Grunt U, Jarvis M, et al. Effect of BI 811283, a novel inhibitor of Aurora B kinase, on tumor senescence and apoptosis [abstract]. J Clin Oncol 2010;28(Suppl):abstract e13632
143. VanderPorten EC, Taverna P, Hogan JN, et al. The Aurora kinase inhibitor SNS-314 shows broad therapeutic potential with chemotherapeutics and synergy with microtubule-targeted agents in a colon carcinoma model. Mol Cancer Ther 2009;8:930-9
144. Arkenau HT, Plummer R, Molife LR, et al. A phase I dose escalation study of AT9283, a small molecule inhibitor of aurora kinases, in patients with advanced solid malignancies. Ann Oncol 2011;published online; doi:mdr451 [pii];10 1093/annonc/mdr451
145. Mross KB, Scheulen ME, Frost A, et al. A phase I dose-escalation study of BI 811283, an Aurora B inhibitor, administered every three weeks in patients with advanced solid tumors J Clin Oncol 2010;28(Suppl):15s
146. Scheulen ME, Mross KB, Richly H, et al. A phase I dose-escalation study of BI 811283, an Aurora B inhibitor, administered days 1 and 15, every four weeks in patients with advanced solid tumors [abstract]. J Clin Oncol 2010;28(Suppl):abstract e13065
147. Schoffski P, Jones SF, Dumez H, et al. Phase I, open-label, multicentre, dose-escalation, pharmacokinetic and pharmacodynamic trial of the oral aurora kinase inhibitor PF-03814735 in advanced solid tumours. Eur J Cancer 2011;47:2256-64
148. Minton SE, LoRusso P, Lockhart AC, et al. A phase I study of MK-5108, an oral aurora A kinase inhibitor, in both monotherapy and in combination with docetaxel in patients with advanced solid tumors [abstract]. J Clin Oncol 2010;28(Suppl):abstract e13026
149. Robert F, Verschraegen C, Hurwitz H, et al. A phase I trial of sns-314, a novel and selective pan-aurora kinase inhibitor, in advanced solid tumor patients J Clin Oncol 2009;27(Suppl):15s
150. Xie H, Lee MH, Zhu F, et al. Identification of an Aurora kinase inhibitor specific for the Aurora B isoform. Cancer Res 2012;published online; doi:0008-5472. CAN-12-2784 [pii];10. 1158/0008-5472. CAN-12-2784
151. Payton M, Bush TL, Chung G, et al. Preclinical evaluation of AMG 900, a novel potent and highly selective pan-aurora kinase inhibitor with activity in taxane-resistant tumor cell lines. Cancer Res 2010;70:9846-54
152. Anderson K, Lai Z, McDonald OB, et al. Biochemical characterization of GSK1070916, a potent and selective inhibitor of Aurora B and Aurora C kinases with an extremely long residence time1. Biochem J 2009;420:259-65
153. Carducci MA, Shaheen MF, Paller CJ, et al. First-in-human study of AMG 900, an oral pan-Aurora kinase inhibitor, in adult patients (pts) with advanced solid tumors. [abstract]. J Clin Oncol 2012;30(Suppl); abstract 3009
154. Adams ND, Adams JL, Burgess JL, et al. Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase. J Med Chem 2010;53:3973-4001
155. Hardwicke MA, Oleykowski CA, Plant R, et al. GSK1070916, a potent Aurora B/C kinase inhibitor with broad antitumor activity in tissue culture cells and human tumor xenograft models. Mol Cancer Ther 2009;8:1808-17
156. Aurora B/C kinase inhibitor GSK1070916A in treating patients with advanced solid tumors. US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrials. gov/ct2/show/NCT01118611 [Last accessed 12 December 2012]
157. de CG, Manning G, Malumbres M. From Plk1 to Plk5: functional evolution of polo-like kinases. Cell Cycle 2011;10:2255-62
158. Chopra P, Sethi G, Dastidar SG, Ray A. Polo-like kinase inhibitors: an emerging opportunity for cancer therapeutics. Expert Opin Investig Drugs 2010;19:27-43
159. Strebhardt K. Multifaceted polo-like kinases: drug targets and antitargets for cancer therapy. Nat Rev Drug Discov 2010;9:643-60
160. Takaki T, Trenz K, Costanzo V, Petronczki M. Polo-like kinase 1 reaches beyond mitosis-cytokinesis, DNA damage response, and development. Curr Opin Cell Biol 2008;20:650-60
161. Liu XS, Song B, Liu X. The substrates of Plk1, beyond the functions in mitosis. Protein Cell 2010;1:999-1010
162. Weichert W, Schmidt M, Gekeler V, et al. Polo-like kinase 1 is overexpressed in prostate cancer and linked to higher tumor grades. Prostate 2004;60:240-5
163. Deeraksa A, Pan J, Sha Y, et al. Plk1 is upregulated in androgen-insensitive prostate cancer cells and its inhibition leads to necroptosis. Oncogene 2012;published online; doi:onc2012309 1038/onc. 2012. 309 [doi]
164. Takagi M, Honmura T, Watanabe S, et al. In vivo antitumor activity of a novel sulfonamide, HMN-214, against human tumor xenografts in mice and the spectrum of cytotoxicity of its active metabolite, HMN-176. Invest New Drugs 2003;21:387-99
165. Garland LL, Taylor C, Pilkington DL, et al. A phase I pharmacokinetic study of HMN-214, a novel oral stilbene derivative with polo-like kinase-1-interacting properties, in patients with advanced solid tumors. Clin Cancer Res 2006;12:5182-9
166. Patnaik A, Forero L, Goetz A, et al. HMN-214, a novel oral antimicrotubular agent and inhibitor of pololike-and cyclin-dependent kinases: clinical, pharmacokinetic (PK) and pharmacodynamic (PD) relationships observed in a phase I trial of a daily x 5 schedule every 28 days [abstract]. J Clin Oncol 2003;22(Suppl); abstract 514
167. Steegmaier M, Hoffmann M, Baum A, et al. BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr Biol 2007;17:316-22
168. Rudolph D, Steegmaier M, Hoffmann M, et al. BI 6727, a Polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity. Clin Cancer Res 2009;15:3094-102
169. Wissing MD, Rosmus N, Gonzalez M, et al. Targeting prostate cancer through a combination of Polo-like kinase inhibitors and histone deacetylase inhibitors [abstract]. Proc Am Assoc Cancer Res (AACR) 2010;abstract 5414
170. Mross K, Frost A, Steinbild S, et al. Phase I dose escalation and pharmacokinetic study of BI 2536, a novel Polo-like kinase 1 inhibitor, in patients with advanced solid tumors. J Clin Oncol 2008;26:5511-17
171. Hofheinz RD, Al-Batran SE, Hochhaus A, et al. An open-label, phase I study of the polo-like kinase-1 inhibitor, BI 2536, in patients with advanced solid tumors. Clin Cancer Res 2010;16:4666-74
172. Pandha HS, Protheroe A, Wylie J, et al. An open label phase II trial of BI 2536, a novel Plk1 inhibitor, in patients with metastatic hormone refractory prostate cancer (HRPC) [abstract]. J Clin Oncol 2008;26(Suppl); abstract 14547 . This is the most extensive study with Plk1-inhibitors in mCRPC patients.
173. Schoffski P, Awada A, Dumez H, et al. A phase I, dose-escalation study of the novel Polo-like kinase inhibitor volasertib (BI 6727) in patients with advanced solid tumours. Eur J Cancer 2012;48:179-86
174. Dumez H, Gombos A, Schoffski P, et al. Phase I trial of the polo-like kinase (Plk) inhibitor volasertib (BI 6727) combined with cisplatin or carboplatin in patients with advanced solid tumors [abstract]. J Clin Oncol 2012;30(Suppl):abstract 3018
175. Stadler WM, Vaughn DJ, Sonpavde G, et al. Phase II study of single-agent volasertib (BI 6727) for second-line treatment of urothelial cancer (UC) J Clin Oncol 2011;29(Suppl 7); abstract 253
176. Combination of BI6727 (Volasertib) and BIBF1120 in Solid Tumors. US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/NCT01022853 [Last accessed 12 December 2012]
177. BI 6727 (Volasertib) Randomised Trial in Ovarian Cancer. US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/NCT01121406 [Last accessed 12 December 2012]
178. An Open label phase i dose escalation trial of intravenous BI 6727 (Volasertib) in combination with oral BIBW 2992 (Afatinib) in patients with advanced solid tumours. US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/NCT01206816 [Last accessed 12 December 2012]
179. BI 6727 (Volasertib) Monotherapy Phase I Trial in Japanese Patients With Advanced Solid Tumours. US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/NCT01348347 [Last accessed 12 December 2012]
180. Gilmartin AG, Bleam MR, Richter MC, et al. Distinct concentration- dependent effects of the polo-like kinase 1-specific inhibitor GSK461364A, including differential effect on apoptosis. Cancer Res 2009;69:6969-77
181. Laquerre S, Sung C, Gilmartin A, et al. A potent and selective Polo-like kinase 1 (Plk1) Inhibitor (GSK461364) induces cell cycle arrest and growth inhibition of cancer cell [abstract]. Proc Am Assoc Cancer Res (AACR) 2007;abstract 5389
182. Olmos D, Barker D, Sharma R, et al. Phase I study of GSK461364, a specific and competitive Polo-like kinase 1 inhibitor, in patients with advanced solid malignancies. Clin Cancer Res 2011;17:3420-30
183. Study of NMS-1286937 in adult patients with advanced/metastatic solid tumors. US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/NCT01014429 [Last accessed 12 December 2012]
184. Dose escalation study to determine safety, pharmacokinetics, and pharmacodynamics of intravenous TKM-080301. US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/ NCT01262235 [Last accessed 12 December 2012]
185. Study of orally administered TAK-960 in patients with advanced nonhematologic malignancies. US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/NCT01179399 Last accessed 12 December 2012]
186. Beria I, Bossi RT, Brasca MG, et al. NMS-P937, a 4, 5-dihydro-1H-pyrazolo [4, 3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor Bioorg Med Chem Lett 2011;21:2969-74
187. Valsasina B, Beria I, Alli C, et al. NMSP937, an orally available, specific, small molecule Polo-Like Kinase 1 inhibitor with antitumor activity in solid and haematological malignancies. Mol Cancer Ther 2012;published online; doi:1535-7163. MCT-11-0765 [pii];10. 1158/1535-7163. MCT-11-0765
188. Hikichi Y, Honda K, Hikami K, et al. TAK-960, a novel, orally available, selective inhibitor of Polo-like kinase 1, shows broad-spectrum preclinical antitumor activity in multiple dosing regimens. Mol Cancer Ther 2011;published online; doi:1535-7163. MCT-11-0762 [pii];10. 1158/1535-7163. MCT-11-0762
189. Judge AD, Robbins M, Tavakoli I, et al. Confirming the RNAi-mediated mechanism of action of siRNA-based cancer therapeutics in mice. J Clin Invest 2009;119:661-73
190. Semple SC, Judge AD, Robbins M, et al. Preclinical characterization of TKM-080301, a lipid nanoparticle formulation of a small interfering RNA directed against polo-like kinase 1 [abstract]. Proc Am Assoc Cancer Res (AACR) 2011;71(Suppl 8); abstract 2829
191. Gumireddy K, Reddy MV, Cosenza SC, et al. ON01910, a non-ATP-competitive small molecule inhibitor of Plk1, is a potent anticancer agent. Cancer Cell 2005;7:275-86
192. Chapman CM, Sun X, Roschewski M, et al. ON 01910. Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress. Clin Cancer Res 2012;18:1979-91
193. Ma WW, Messersmith WA, Dy GK, et al. Phase I study of Rigosertib, an inhibitor of the phosphatidylinositol 3-kinase and Polo-like kinase 1 pathways, combined with gemcitabine in patients with solid tumors and pancreatic cancer. Clin Cancer Res 2012;18:2048-55
194. Riggs BL, Hartmann LC. Selective estrogen-receptor modulators -mechanisms of action and application to clinical practice. N Engl J Med 2003;348:618-29
195. Valabrega G, Montemurro F, Aglietta M. Trastuzumab: mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer. Ann Oncol 2007;18:977-84
196. Qi W, Liu X, Cooke LS, et al. AT9283, a novel aurora kinase inhibitor, suppresses tumor growth in aggressive B-cell lymphomas. Int J Cancer 2011;published online; doi:10. 1002/ijc. 26324 [doi]
197. Qi W, Cooke LS, Liu X, et al. Aurora inhibitor MLN8237 in combination with docetaxel enhances apoptosis and anti-tumor activity in mantle cell lymphoma. Biochem Pharmacol 2011;81:881-90
198. Feng B, Wang R, Chen LB. MiR-100 resensitizes docetaxel-resistant human lung adenocarcinoma cells (SPCA1) to docetaxel by targeting Plk1. Cancer Lett 2012;317:184-91
199. Kachhap SK, Rosmus N, Collis SJ, et al. Downregulation of homologous recombination DNA repair genes by HDAC inhibition in prostate cancer is mediated through the E2F1 transcription factor. PLoS ONE 2010;5:e11208
200. Paller C, Wissing M, Kim E, et al. Preclinical profile of AMG900 in combination with HDACIs in prostate cancer [abstract]. Proc Am Assoc Cancer Res (AACR) 2012;abstract 2049
201. Marin-Aguilera M, Codony-Servat J, Kalko SG, et al. Identification of docetaxel resistance genes in castration-resistant prostate cancer. Mol Cancer Ther 2012;11:329-39
202. Domingo-Domenech J, Vidal SJ, Rodriguez-Bravo V, et al. Suppression of acquired docetaxel resistance in prostate cancer through depletion of notch-and hedgehog-dependent tumor-initiating cells. Cancer Cell 2012;22:373-88
203. Madan RA, Pal SK, Sartor O, Dahut WL. Overcoming chemotherapy resistance in prostate cancer. Clin Cancer Res 2011;17:3892-902
204. Beer TM, Javle MM, Ryan CW, et al. Phase I study of weekly DN-101, a new formulation of calcitriol, in patients with cancer. Cancer Chemother Pharmacol 2007;59:581-7
205. Coleman RL, Duska LR, Ramirez PT, et al. Phase 1-2 study of docetaxel plus aflibercept in patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer. Lancet Oncol 2011;12:1109-17
206. Isambert N, Freyer G, Zanetta S, et al. Phase I dose-escalation study of intravenous aflibercept in combination with docetaxel in patients with advanced solid tumors. Clin Cancer Res 2012;18:1743-50
207. Demetri GD, Lo RP, MacPherson IR, et al. Phase I dose-escalation and pharmacokinetic study of dasatinib in patients with advanced solid tumors. Clin Cancer Res 2009;15:6232-40
208. Eisenberger MA, Hardy-Bessard A, Mourey L, et al. Comparison of two doses of cabazitaxel plus prednisone in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) previously treated with a docetaxel (D)-containing regimen J Clin Oncol 2012;30(Suppl):abstract TPS4692
209. Study of Weekly Cabazitaxel for Advanced Prostate Cancer. US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/NCT01518283 [Last accessed 21 December 2012]
210. A study looking at novel scheduling of cabazitaxel for patients with metastatic prostate cancer (ConCab). US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/NCT01541007 [Last accessed 21 December 2012]
211. Second-line chemotherapy in castration resistant prostate cancer (ProstyII). US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/NCT01558219 [Last accessed 21 December 2012]
212. Cabazitaxel plus prednisone with octreotide for Castration-Resistant Prostate Cancer (CRPC) previously treated with docetaxel. us national institute of health. Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/NCT01469338 [Last accessed 21 December 2012]
213. Cabaresc NL. Stichting DUOS; Rotterdam, NL: 2012. Available from: http://www. stichtingduos. nl/studies/cabaresc-nl/
214. Cabazitaxel versus docetaxel both with prednisone in patients with metastatic castration resistant prostate cancer (FIRSTANA). US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/NCT01308567 [Last accessed 21 December 2012]
215. Comparison of Cabazitaxel/Prednisone Alone or in Combination With Custirsen for 2nd Line Chemotherapy in Prostate Cancer (AFFINITY). US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/NCT01578655 [Last accessed 21 December 2012]
216. The CATCH prostate cancer trial: cabazitaxel and tasquinimod in men with prostate cancer. US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/NCT01513733 [Last accessed 21 December 2012]
217. Cabazitaxel and abiraterone acetate in patients with metastatic castrate-resistant prostate cancer. US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/NCT01511536 [Last accessed 21 December 2012]
218. Ph Ib/IIa Study of Cabazitaxel Plus Bavituximab in Castration-resistant Prostate Cancer. US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/NCT01335204 [Last accessed 21 December 2012]
219. Cabazitaxel with or without carboplatin in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-based therapy. US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/NCT01505868 Last accessed 21 December 2012]
220. De Souza PL, Mellado B, Pfister C, et al. Randomized phase II trial of patupilone plus prednisone versus docetaxel plus prednisone in patients with chemotherapy-naive, metastatic, castrate-resistant prostate cancer (CRPC) J Clin Oncol 2010;28(Suppl):15s
221. Gerecitano JF, Stephenson JJ, Lewis NL, et al. A Phase I trial of the kinesin spindle protein (Eg5) inhibitor AZD4877 in patients with solid and lymphoid malignancies. Invest New Drugs 2012;published online; doi:10. 1007/s10637-012-9821-y [doi]
222. Macarulla T, Cervantes A, Elez E, et al. Phase I study of the selective Aurora A kinase inhibitor MLN8054 in patients with advanced solid tumors: safety, pharmacokinetics, and pharmacodynamics. Mol Cancer Ther 2010;9:2844-52
223. Dees EC, Infante JR, Cohen RB, et al. Phase 1 study of MLN8054, a selective inhibitor of Aurora A kinase in patients with advanced solid tumors. Cancer Chemother Pharmacol 2011;67:945-54
224. Cervantes A, Elez E, Roda D, et al. Phase I pharmacokinetic/ pharmacodynamic study of MLN8237, an investigational, oral, selective aurora a kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res 2012;18:4764-74
225. Mosse YP, Lipsitz E, Fox E, et al. Pediatric phase I trial and pharmacokinetic study of MLN8237, an investigational oral selective small-molecule inhibitor of aurora kinase a: a children's oncology group phase I consortium study. Clin Cancer Res 2012;18:6058-64
226. Matulonis UA, Sharma S, Ghamande S, et al. Phase II study of MLN8237 (alisertib), an investigational Aurora A kinase inhibitor, in patients with platinum-resistant or -refractory epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Gynecol Oncol 2012;127:63-9
227. Lee P, Alvarez RH, Melichar B, et al. Phase I/II study of the investigational aurora A kinase (AAK) inhibitor MLN8237 (alisertib) in patients (pts) with non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), breast cancer (BrC), head/neck cancer (H&N), and gastroesophageal (GE) adenocarcinoma: Preliminary phase II results [abstract]. J Clin Oncol 2012;30(Suppl):abstract 3010
228. Falchook GS, Goff BA, Kurzrock R, et al. Phase I/II study of weekly paclitaxel with or without MLN8237 (alisertib), an investigational aurora A kinase inhibitor, in patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (OC), or breast cancer (BrC): Phase I results [abstract]. J Clin Oncol 2012;30(Suppl): abstract 5021
229. Frost A, Mross K, Steinbild S, et al. Phase i study of the Plk1 inhibitor BI 2536 administered intravenously on three consecutive days in advanced solid tumours. Curr Oncol 2012;19:e28-35
230. Ellis PM, Chu QS, Leighl N, et al. A phase I open-label dose-escalation study of intravenous BI 2536 together with pemetrexed in previously treated patients with non-small-cell lung cancer. Clin Lung Cancer 2012;published online; doi:S1525-7304 (12)00080-0 [pii];10. 1016/j. cllc. 2012. 04. 003
231. Schoffski P, Blay JY, De GJ, et al. Multicentric parallel phase II trial of the polo-like kinase 1 inhibitor BI 2536 in patients with advanced head and neck cancer, breast cancer, ovarian cancer, soft tissue sarcoma and melanoma. The first protocol of the European Organization for Research and Treatment of Cancer (EORTC) Network Of Core Institutes (NOCI). Eur J Cancer 2010;46:2206-15
232. Sebastian M, Reck M, Waller CF, et al. The efficacy and safety of BI 2536, a novel Plk-1 inhibitor, in patients with stage IIIB/IV non-small cell lung cancer who had relapsed after, or failed, chemotherapy: results from an open-label, randomized phase II clinical trial. J Thorac Oncol 2010;5:1060-7
233. Mross K, Dittrich C, Aulitzky WE, et al. A randomised phase II trial of the Polo-like kinase inhibitor BI 2536 in chemo-naive patients with unresectable exocrine adenocarcinoma of the pancreas -a study within the Central European Society Anticancer Drug Research (CESAR) collaborative network. Br J Cancer 2012;107:280-6
234. BI 6727 (Volasertib) Human ADME Trial in Various Solid Tumours. US National Institute of Health. Bethesda, MD; 2012. Available from: http://clinicaltrials. gov/ct2/show/NCT01145885 [Last accessed 21 December 2012]
235. Dose Finding Study of BI 6727 (Volasertib) in Patients With Various Solid Cancers. US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/NCT00969553 [Last accessed 21 December 2012]
236. Trial of BI 6727 (Volasertib) Monotherapy and BI 6727 in Combination With Pemetrexed Compared to Pemetrexed Monotherapy in Advanced NSCLC. US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/NCT00824408 [Last accessed 21 December 2012]
237. Jimeno A, Li J, Messersmith WA, et al. Phase I study of ON 01910. Na, a novel modulator of the Polo-like kinase 1 pathway, in adult patients with solid tumors. J Clin Oncol 2008;26:5504-10
238. Ohnuma T, Holland JF, Goel S, et al. Final results of a phase I dose-escalation study of ON 01910. Na in combination with oxaliplatin in patients with advanced solid tumors [abstract]. J Clin Oncol 2011;29(Suppl):abstract e13584
239. Bowles DW, Diamond JR, Lam ET, et al. Phase I study of oral rigosertib in patients with advanced solid tumors J Clin Oncol 2012;30(Suppl); abstract 3017
240. Vainshtein JM, Ghalib MH, Kumar M, et al. Phase I study of ON 01910. Na, a novel polo-like kinase 1 pathway modulator, administered as a weekly 24-hour continuous infusion in patients with advanced cancer [abstract]. J Clin Oncol 2008;26(Suppl); abstract 2515
241. Ohnuma T, Cho SY, ROboz J, et al. Phase I study of ON 01910. Na by 3-day continuous infusion (CI) in patients (pts) with advanced cancer [abstract 13137]. J Clin Oncol 2006;24(Suppl):18S
242. Safety, Pharmacokinetics and Clinical Activity of Oral Rigosertib in Solid Tumors. US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/NCT01168011 [Last accessed 21 December 2012]
243. Effect of 2-h Infusion of ON 01910. Na in Ovarian Cancer Patients. US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/NCT00856791 [Last accessed 21 December 2012]
244. Gemcitabine and ON 01910. Na in Previously Untreated Metastatic Pancreatic Cancer (ONTRAC). US National Institute of Health, Bethesda, MD; 2012. Available from: http://clinicaltrial. gov/ct2/show/NCT01360853 [Last accessed 21 December 2012]