Emerging cell-cycle inhibitors for pancreatic cancer therapy

Expert Opinion on Emerging Drugs

Volumn 17, Issue 4, 2012, Pages 571-582

  Bayraktar, Soley ^a   Lima, Caio M Rocha ^a,b  

^a UNIVERSITY OF MIAMI   (United States)

^b Mercy Cancer Center   (United States)

Author keywords

Aurora kinase; Cell cycle inhibitors; Cyclin dependent kinase inhibitors; Flavopiridol; MK 1775; Molecular targeted therapy; Pancreatic cancer; Polo like kinase

Indexed keywords

3 METHYL N [1,4,5,6 TETRAHYDRO 6,6 DIMETHYL 5 [(1 METHYL 4 PIPERIDINYL)CARBONYL]PYRROLO[3,4 C]PYRAZOL 3 YL]BUTANAMIDE; 6 ACETYL 8 CYCLOPENTYL 5 METHYL 2 [5 (1 PIPERAZINYL) 2 PYRIDINYLAMINO] 8H PYRIDO[2,3 D]PYRIMIDIN 7 ONE; AT 7519M; AZD 5438; BAY 1000394; BEVACIZUMAB; CETUXIMAB; CYCLIN DEPENDENT KINASE INHIBITOR 2A; CYCLOOXYGENASE 2; DINACICLIB; ERLOTINIB; FLUOROURACIL; GEMCITABINE; MAMMALIAN TARGET OF RAPAMYCIN; MARIMASTAT; MATRIX METALLOPROTEINASE; MILCICLIB; N [5 (5 TERT BUTYL 2 OXAZOLYLMETHYLTHIO) 2 THIAZOLYL]ISONIPECOTAMIDE; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE; P 1446A 05; P 276 00; PROTEIN P53; R 547; SMAD4 PROTEIN; SOMATOMEDIN C RECEPTOR; SONIC HEDGEHOG PROTEIN; TANOMASTAT; TIPIFARNIB; TRANSFERASE; TRANSFORMING GROWTH FACTOR BETA; UNCLASSIFIED DRUG; VASCULOTROPIN; VASCULOTROPIN RECEPTOR 1; VASCULOTROPIN RECEPTOR 2; VASCULOTROPIN RECEPTOR 3;

CANCER COMBINATION CHEMOTHERAPY; CANCER SURVIVAL; CARCINOGENESIS; CELL CYCLE; CELL CYCLE REGULATION; CELL DIVISION; CLINICAL PROTOCOL; CLINICAL TRIAL (TOPIC); ENZYME ACTIVITY; GENE MUTATION; HUMAN; MITOSIS; MOLECULARLY TARGETED THERAPY; ONCOGENE; OVERALL SURVIVAL; PANCREAS CARCINOMA; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROTEIN EXPRESSION; QUALITY OF LIFE; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW;

ANTINEOPLASTIC AGENTS; CELL CYCLE; CYCLIN-DEPENDENT KINASES; DRUG DESIGN; DRUG RESISTANCE, NEOPLASM; HUMANS; MOLECULAR TARGETED THERAPY; PANCREATIC NEOPLASMS; PROTEIN KINASE INHIBITORS;

EID: 84870458846     PISSN: 14728214     EISSN: None     Source Type: Journal    
DOI: 10.1517/14728214.2012.739606     Document Type: Review

References (104)

1. Cancer Facts and Figures 2012. Available from: http://www.cancer.org/acs/ groups/content/@epidemiologysurveilance/documents/document/acspc-031941.pdf [Last accessed on 5 August 2012]
2. Almhanna K, Philip PA. Defining new paradigms for the treatment of pancreatic cancer. Curr Treat Options Oncol 2011;12:111-25
3. Burris HA III, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J clin Oncol 1997;15:2403-13
4. Casper E, Green M, Kelsen D, et al. Phase II trial of gemcitabine (2,20- difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas. Invest New Drugs 1994;12:29-34
5. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25
6. Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008;321:1801-6
7. Hruban RH, Goggins M, Parsons J, et al. Progression model for pancreatic cancer. Clin Cancer Res 2000;6:2969-72
8. Evans JD SA, Johnson CD, et al. A phase II trial of marimastat in advanced pancreatic cancer. Br J Cancer 2001;85:1865-70
9. Cohen SJ, Ranganathan S, et al. Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma. J Clin Oncol 2003;21:1301-6
10. Van Cutsem E, van de Velde H, Karasek P, et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 2004;22:1430-8
11. Xiong HQ, Kayaleh OR, Goodwin JW, et al. A phase II trial of gemcitabine and celecoxib for metastatic pancreatic cancer. J Clin Oncol 2005;23(Suppl):4174
12. Wolpin BM, Ryan DP, Abrams TA, et al. Phase II study of RAD001 in previously treated patients with metastatic pancreatic cancer. J Clin Oncol 2008;26:2210-13
13. Xiong HQ, Rosenberg A, LoBuglio A, et al. Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II Trial. J Clin Oncol 2004;22:2610-16
14. Fountzilas G, Bobos M, Kalogera-Fountzila A, et al. Gemcitabine combined with gefitinib in patients with inoperable or metastatic pancreatic cancer: a phase II Study of the Hellenic Cooperative Oncology Group with biomarker evaluation. Cancer Invest 2008;26:784-93
15. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007;25:1960-6
16. Fogelman DR, Xiong HQ, Chang DZ, et al. Final results of a bi-institution phase II study of gemcitabine, oxaliplatin, and bevacizumab for advanced pancreatic cancer [abstract 182]. In 2009 ASCO Gastrointestinal Cancers Symposium; 2009
17. Kindler HL, Hollis D. A double-blind placebo-controlled, randomized phase III trial of gemcitabine plus bevacizumab versus gemcitabine plus placebo in patients with advanced pancreatic cancer: A preliminary analysis of Cancer and Leukemia Group B (CALGB) 80303. In 2007 Gastrointestinal Cancers symposium; 2007
18. Kindler HL, Stephenson J, Garbo LE, et al. A placebo-controlled, randomized phase II study of conatumumab (C) or AMG 479 (A) or placebo (P) plus gemcitabine (G) in patients (pts) with metastatic pancreatic cancer (mPC). J Clin Oncol 2010;28:15s (abstract 4035)
19. Javle MM, Shroff RT, Bhosale P, et al. Phase I/II study of MK-0646, the humanized monoclonal IGF-1R antibody in combination with gemcitabine or gemcitabine plus erlotinib (E) for advanced pancreatic cancer. J Clin Oncol 2010;28:15s (abstract 4039)
20. Ogino T, Suzuki H, Yamasaki A, et al. Evaluation of the hedgehog signaling pathway as a therapeutic target for dendritic cell-based immunotherapy against patients with cancer. J Clin Oncol 2010;28:15s (e13061)
21. Ashworth A. Drug resistance caused by reversion mutation. Cancer Res 2008;68:10021-3
22. Boeck SH, Waldschmidt V, Kettner E, et al. Gemcitabine plus erlotinib (GE) followed by capecitabine (C) versus capecitabine plus erlotinib (CE) followed by gemcitabine (G) in advanced pancreatic cancer (APC): a randomized, cross-over phase III trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO). J Clin Oncol 2010;28:18s (abstract LBA4011)
23. Von Hoff DD, Borad M, Laheru D, et al. SPARC correlation with response to gemcitabine (G) plus nab-paclitaxel (nab-P) in patients with advanced metastatic pancreatic cancer: a phase I/II study. J Clin Oncol 2009;27:15s (abstract 4525)
24. Hosein PJ, Gomez CM, Macintyre J, et al. A phase II trial of nab-paclitaxel (NP) in patients with advanced pancreatic cancer (PC) who have progressed on gemcitabine-based therapy. In J Clin Oncol 2010 ASCO Gastrointestinal Cancer Symposium;
25. Malumbres M. Physiological relevance of cell cycle kinases. Physiol Rev 2011;91:973-1007
26. Sherr CJ. Cancer cell cycles. Science 1996;274:1672-7
27. Von Hoff DD. What's new in pancreatic cancer treatment pipeline? Best Pract Res Clin Gastroenterol 2006;20:315-26
28. Al-Aynati MM, Radulovich N, Ho J, Tsao MS. Overexpression of G1-S cyclins and cyclin-dependent kinases during multistage human pancreatic duct cell carcinogenesis. Clin Cancer Res 2004;10:6598-605
29. Yue H, Jiang HY. Expression of cell cycle regulator p57kip2, cyclinE protein and proliferating cell nuclear antigen in human pancreatic cancer: an immunohistochemical study. World J Gastroenterol 2005;11:5057-60
30. Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 2009;9:153-66
31. Poch B, Gansauge F, Schwarz A, et al. Epidermal growth factor induces cyclin D1 in human pancreatic carcinoma: evidence for a cyclin D1-dependent cell cycle progression. Pancreas 2001;23:280-7
32. Wang JC, Thiere M, Henne-Bruns D, et al. Inhibition of pancreatic cancer cell growth in vivo using a tetracyclineinducible cyclin D1 antisense expression system. Pancreas 2012; Epub ahead of print
33. Gansauge S, Gansauge F, Ramadani M, et al. Overexpression of cyclin D1 in human pancreatic carcinoma is associated with poor prognosis. Cancer Res 1997;57:1634-7
34. Kornmann M, Ishiwata T, Itakura J, et al. Increased cyclin D1 in human pancreatic cancer is associated with decreased postoperative survival. Oncology 1998;55:363-9
35. Eggers JP, Grandgenett PM, Collisson EC, et al. Cyclin-dependent kinase 5 is amplified and overexpressed in pancreatic cancer and activated by mutant K-Ras. Clin Cancer Res 2011;17:6140-50
36. Feldmann G, Mishra A, Hong SM, et al. Inhibiting the cyclin-dependent kinase CDK5 blocks pancreatic cancer formation and progression through the suppression of Ras-Ral signaling. Cancer Res 2010;70:4460-9
37. Archambault V, Carmena M. Polo-like kinase-activating kinases: aurora A, Aurora B and what else? Cell Cycle 2012;11:1490-5
38. Hao D, Chu Q, Welch S, et al. A phase I and pharmacokinetic (PK) study of continuous daily administration of P1446A-05, a potent and specific oral Cdk4 inhibitor. In Oncol JC (ed), ASCO Annual Meeting; 2012.
39. Green MR, Woolery JE, Mahadevan D. Update on aurora kinase targeted therapeutics in oncology. Expert Opin Drug Discov 2011;6:291-307
40. Barr FA, Sillje HH, Nigg EA. Polo-like kinases and the orchestration of cell division. Nat Rev Mol Cell Biol 2004;5:429-40
41. Mountzios G, Terpos E, Dimopoulos MA. Aurora kinases as targets for cancer therapy. Cancer Treat Rev 2008;34:175-82
42. Gray PJ Jr, Bearss DJ, Han H, et al. Identification of human polo-like kinase 1 as a potential therapeutic target in pancreatic cancer. Mol Cancer Ther 2004;3:641-6
43. Keen N, Taylor S. Aurora-kinase inhibitors as anticancer agents. Nat Rev Cancer 2004;4:927-36
44. Spankuch B, Heim S, Kurunci-Csacsko E, et al. Down-regulation of Polo-like kinase 1 elevates drug sensitivity of breast cancer cells in vitro and in vivo. Cancer Res 2006;66:5836-46
45. Liu X, Lei M, Erikson RL. Normal cells, but not cancer cells, survive severe Plk1 depletion. Mol Cell Biol 2006;26:2093-108
46. Tibes R, Jimeno A, Von Hoff DD, et al. Phase I dose escalation study of the oral multi-CDK inhibitor PHA-848125. In ASCO Meeting Abstracts; 2008
47. Bahleda R, Martinez-Garcia A, Varga A, et al. First-in-human phase I study of oral pan-CDK inhibitor BAY 1000394 in patients with advanced solid tumors: Dose escalation with an intermittent 3 days on/4 days off schedule. In Oncol JC (ed) 2012. ASCO Annual Meeting;
48. Shapiro GI, Bannerji R, Small K, et al. A phase I dose-escalation study of the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the novel cyclin-dependent kinase inhibitor SCH 727965 administered every 3 weeks in subjects with advanced malignancies. In Oncol JC (ed) ASCO 2008 Annual Meeting; 2008
49. Nemunaitis J, Steinberg SM, Rosenberg MA, et al. A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of SCH 727965, a novel cyclin-dependent kinase inhibitor, administered weekly in subjects with advanced malignancies. In Oncol JC (ed) 2009 ASCO Annual Meeting; 2009
50. Scott EN, Thomas AL, Molife LR, et al. A phase I dose escalation study of the pharmacokinetics and tolerability of ZK 304709, an oral multi-targeted growth inhibitor (MTGI), in patients with advanced solid tumours. Cancer Chemother Pharmacol 2009;64:425-9
51. Olmos D, Ventura AA, Sharma R, et al. Phase I first-in-human study of the polo-like kinase-1 selective inhibitor, GSK461364, in patients with advanced solid tumors. In Oncol JC (ed) 2009 ASCO Annual Meeting; 2009
52. Ma WW, Freas A, Dy GK, et al. Final results of a phase I study of the combination of a novel cell cycle inhibitor ON 01910.Na with gemcitabine in patients with advanced pancreatic and other solid tumors. In Oncol JC (ed) 2011 ASCO Annual Meeting;
53. Schellens JHM, Shapiro G, Pavlick AC, et al. Update on a phase I pharmacologic and pharmacodynamic study of MK-1775, a Wee1 tyrosine kinase inhibitor, in monotherapy and combination with gemcitabine, cisplatin, or carboplatin in patients with advanced solid tumors. In Oncol JC (ed) 2011 ASCO Annual Meeting;
54. Daud A, Springett GM, Mendelson DS, et al. A phase I dose-escalation study of SCH 900776, a selective inhibitor of checkpoint kinase 1 (CHK1), in combination with gemcitabine (Gem) in subjects with advanced solid tumors. In Oncol JC (ed) 2010 ASCO Annual Meeting;
55. Karp JE, Garrett-Mayer EL, Estey EH, et al. Randomized phase II study of two schedules of flavopiridol given as timed sequential therapy with cytosine arabinoside and mitoxantrone for adults with newly diagnosed, poor-risk acute myelogenous leukemia. Haematologica 2012; Epub ahead of print
56. Burdette-Radoux S, Tozer RG, Lohmann RC, et al. Phase II trial of flavopiridol, a cyclin dependent kinase inhibitor, in untreated metastatic malignant melanoma. Invest New Drugs 2004;22:315-22
57. Grendys EC Jr, Blessing JA, Burger R, et al. A phase II evaluation of flavopiridol as second-line chemotherapy of endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2005;98:249-53
58. Dispenzieri A, Gertz MA, Lacy MQ, et al. Flavopiridol in patients with relapsed or refractory multiple myeloma: a phase 2 trial with clinical and pharmacodynamic end-points. Haematologica 2006;91:390-3
59. Laffranchi B, De Jonge MJ, Bajetta E, et al. Phase II study of danusertib (D) in advanced/metastatic colorectal and pancreatic cancers. In Oncol JC (ed) 2010 ASCO Annual Meeting;
60. Rizzolio F, Tuccinardi T, Caligiuri I, et al. CDK inhibitors: from the bench to clinical trials. Curr Drug Targets 2010;11:279-90
61. Kreutzer JN, Ruzzene M, Guerra B. Enhancing chemosensitivity to gemcitabine via RNA interference targeting the catalytic subunits of protein kinase CK2 in human pancreatic cancer cells. BMC Cancer 2010;10:440
62. Baughn LB, Di Liberto M, Wu K, et al. A novel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6. Cancer Res 2006;66:7661-7
63. Walsby E, Lazenby M, Pepper C, et al. The cyclin-dependent kinase inhibitor SNS-032 has single agent activity in AML cells and is highly synergistic with cytarabine. Leukemia 2011;25:411-19
64. Iseki H, Ko TC, Xue XY, et al. A novel strategy for inhibiting growth of human pancreatic cancer cells by blocking cyclin-dependent kinase activity. J Gastrointest Surg 1998;2:36-43
65. Dickson MA, Carvajal G, Shah MA, et al. A phase I study of FOLFOX administered with flavopiridol (F) in patients with refractory solid tumors. In Oncol JC (ed) 2008 ASCO Annual Meeting; 2008
66. Rathkopf D, Dickson MA, Feldman DR, et al. Phase I study of flavopiridol with oxaliplatin and fluorouracil/leucovorin in advanced solid tumors. Clin Cancer Res 2009;15:7405-11
67. Dickson MA, Shah MA, Rathkopf D, et al. A phase I clinical trial of FOLFIRI in combination with the pan-cyclindependent kinase (CDK) inhibitor flavopiridol. Cancer Chemother Pharmacol 2010;66:1113-21
68. Fekrazad HM, Verschraegen CF, Royce M, et al. A phase I study of flavopiridol in combination with gemcitabine and irinotecan in patients with metastatic cancer. Am J Clin Oncol 2010;33:393-7
69. George S, Kasimis BS, Cogswell J, et al. Phase I study of flavopiridol in combination with Paclitaxel and Carboplatin in patients with non-small-cell lung cancer. Clin Lung Cancer 2008;9:160-5
70. Dickson MA, Rathkopf D, Grant S, et al. Phase I trial of pulse-dose vorinostat with flavopiridol in solid tumors. In Oncol JC (ed) 2010 ASCO Annual Meeting;
71. Carvajal RD, Tse A, Shah MA, et al. A phase II study of flavopiridol (Alvocidib) in combination with docetaxel in refractory, metastatic pancreatic cancer. Pancreatology 2009;9:404-9
72. Meinhart A, Kamenski T, Hoeppner S, et al. A structural perspective of CTD function. Genes Dev 2005;19:1401-15
73. Feldmann G, Mishra A, Bisht S, et al. Cyclin-dependent kinase inhibitor dinaciclib (SCH727965) inhibits pancreatic cancer growth and progression in murine xenograft models. Cancer Biol Ther 2011;12:598-609
74. de Bruijn P, Moghaddam-Helmantel IM, de Jonge MJ, et al. Validated bioanalytical method for the quantification of RGB-286638, a novel multi-targeted protein kinase inhibitor, in human plasma and urine by liquid chromatography/tandem triple-quadrupole mass spectrometry. J Pharm Biomed Anal 2009;50:977-82
75. Siemeister G, Luecking U, Wagner C, et al. Molecular and pharmacodynamic characteristics of the novel multi-target tumor growth inhibitor ZK 304709. Biomed Pharmacother 2006;60:269-72
76. Albanese C, Alzani R, Amboldi N, et al. Dual targeting of CDK and tropomyosin receptor kinase families by the oral inhibitor PHA-848125, an agent with broad-spectrum antitumor efficacy. Mol Cancer Ther 2010;9:2243-54
77. Bahleda R, Spreafico A, Soria J, et al. Phase I study of the oral CDK-TRKA inhibitor PHA-848125 in combination with gemcitabine in advanced solid tumors. In Oncol JC (ed) 2010 ASCO Annual Meeting;
78. Mendoza N, Fong S, Marsters J, et al. Selective cyclin-dependent kinase 2/cyclin A antagonists that differ from ATP site inhibitors block tumor growth. Cancer Res 2003;63:1020-4
79. Canela N, Orzaez M, Fucho R, et al. Identification of an hexapeptide that binds to a surface pocket in cyclin A and inhibits the catalytic activity of the complex cyclin-dependent kinase 2-cyclin A. J Biol Chem 2006;281:35942-53
80. Bagella L, Sun A, Tonini T, et al. A small molecule based on the pRb2/ p130 spacer domain leads to inhibition of cdk2 activity, cell cycle arrest and tumor growth reduction in vivo. Oncogene 2007;26:1829-39
81. Jordan MA, Wilson L. Microtubules as a target for anticancer drugs. Nat Rev Cancer 2004;4:253-65
82. Taylor S, Peters JM. Polo and Aurora kinases: lessons derived from chemical biology. Curr Opin Cell Biol 2008;20:77-84
83. Carducci MA, ÓBrien SM, 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. In Oncol JC (ed) 2012 ASCO Annual Meeting;
84. 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. In Oncol JC (ed) 2012 ASCO Annual Meeting;
85. Mazumdar A, Henderson YC, El-Naggar AK, et al. Aurora kinase A inhibition and paclitaxel as targeted combination therapy for head and neck squamous cell carcinoma. Head Neck 2009;31:625-34
86. Anand S, Penrhyn-Lowe S, Venkitaraman AR. AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol. Cancer Cell 2003;3:51-62
87. Squire CJ, Dickson JM, Ivanovic I, et al. Structure and inhibition of the human cell cycle checkpoint kinase, Wee1A kinase: an atypical tyrosine kinase with a key role in CDK1 regulation. Structure 2005;13:541-50
88. Bridges KA, Hirai H, Buser CA, et al. MK-1775, a novel Wee1 kinase inhibitor, radiosensitizes p53-defective human tumor cells. Clin Cancer Res 2011;17:5638-48
89. Hirai H, Arai T, Okada M, et al. MK- 1775, a small molecule Wee1 inhibitor, enhances anti-tumor efficacy of various DNA-damaging agents, including 5-fluorouracil. Cancer Biol Ther 2010;9:514-22
90. Lapenna S, Giordano A. Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov 2009;8:547-66
91. http://www.clinicaltrials.gov
92. Konecny GE, Winterhoff B, Kolarova T, et al. Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer. Clin Cancer Res 2011;17:1591-602
93. Perini RF, DeMichele A, Vaughn DJ, et al. Phase II/pharmacodynamic trial of PD0332991 in patients with breast, colon, germ cell, and epithelial tumors containing amplification of CCND1. In Oncol JC (ed) 2011 ASCO Annual Meeting;
94. Goto H, Izawa I, Li P, et al. Novel regulation of checkpoint kinase 1: is checkpoint kinase 1 a good candidate for anti-cancer therapy? Cancer Sci 2012; [Epub ahead of print]
95. Chandana S, Mahadevan D. Translational advances and novel therapies for pancreatic ductal adenocarcinoma: hope or hype? Expert Rev Mol Med 2009;11:e34
96. Byrd JC, Lin TS, Dalton JT, et al. Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Blood 2007;109:399-404
97. Berthet C, Aleem E, Coppola V, et al. Cdk2 knockout mice are viable. Curr Biol 2003;13:1775-85
98. Santamaria D, Barriere C, Cerqueira A, et al. Cdk1 is sufficient to drive the mammalian cell cycle. Nature 2007;448:811-15
99. Wang L, Wang J, Blaser BW, et al. Pharmacologic inhibition of CDK4/6: mechanistic evidence for selective activity or acquired resistance in acute myeloid leukemia. Blood 2007;110:2075-83
100. Bramhall SR, Rosemurgy A, Brown PD, et al. Marimastat as firstline therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol 2001;19:3447-55
101. Bramhall SR, Rosemurgy A, Brown PD, et al. A double-blind placebocontrolled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 2002;87:161-7
102. Moore MJ, Hamm J, Dancey J, et al. Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2003;21:3296-302
103. Philip PA, Fenoglio-Preiser M, et al. Phase III study of gemcitabine plus cetuximab versus gemcitabine in patients with locally advanced or metastatic pancreatic adenocarcinoma: SWOG S0205 study. J Clin Oncol 2007;25:18s (abstract LBA 4509)
104. Stone A, Sutherland RL, Musgrove EA. Inhibitors of cell cycle kinases: recent advances and future prospects and cancer therapeutics. Crit Rev Oncog 2012;17:175-98