Semi-mechanistic pharmacokinetic/pharmacodynamic modeling of the antitumor activity of LY2835219, a new cyclin-dependent kinase 4/6 inhibitor, in mice bearing human tumor xenografts

Clinical Cancer Research

Volumn 20, Issue 14, 2014, Pages 3763-3774

  Tate, Sonya C ^a   Cai, Shufen ^a   Ajamie, Rose T ^a   Burke, Teresa ^a   Beckmann, Richard P ^a   Chan, Edward M ^a   De Dios, Alfonso ^a   Wishart, Graham N ^a   Gelbert, Lawrence M ^a   Cronier, Damien M ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLIN DEPENDENT KINASE 4; CYCLIN DEPENDENT KINASE 6; CYCLIN DEPENDENT KINASE INHIBITOR; DNA TOPOISOMERASE (ATP HYDROLYSING); HISTONE H3; LY 2835219; RETINOBLASTOMA PROTEIN; UNCLASSIFIED DRUG; 5-(4-ETHYLPIPERAZIN-1-YLMETHYL)PYRIDIN-2-YL)-(5-FLUORO-4-(7-FLUORO-3-ISOPROPYL-2-METHYL-3H-BENZOIMIDAZOL-5-YL)PYRIMIDIN-2-YL)AMINE; AMINOPYRIDINE DERIVATIVE; ANTINEOPLASTIC AGENT; BENZIMIDAZOLE DERIVATIVE; CDK4 PROTEIN, HUMAN; CDK6 PROTEIN, HUMAN; PROTEIN KINASE INHIBITOR; TUMOR MARKER;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER INHIBITION; CELL CYCLE ARREST; CELL DEATH; CELL DENSITY; COLORECTAL CANCER; COMPARTMENT MODEL; CONTROLLED STUDY; CYTOSTASIS; DISEASE MARKER; DOSE RESPONSE; DRUG ABSORPTION; DRUG BLOOD LEVEL; DRUG CYTOTOXICITY; DRUG EFFECT; DRUG MEGADOSE; ENZYME INHIBITION; GROWTH RATE; MELANOMA; MITOSIS RATE; MOUSE; NONHUMAN; PRIORITY JOURNAL; QUANTITATIVE STUDY; SINGLE DRUG DOSE; STEADY STATE; TUMOR GROWTH; TUMOR XENOGRAFT; ANIMAL; ANTAGONISTS AND INHIBITORS; DRUG EFFECTS; DRUG SCREENING; HUMAN; IC50; METABOLISM; NUDE MOUSE; ORAL DRUG ADMINISTRATION; TUMOR CELL LINE; TUMOR VOLUME;

ADMINISTRATION, ORAL; AMINOPYRIDINES; ANIMALS; ANTINEOPLASTIC AGENTS; BENZIMIDAZOLES; CELL LINE, TUMOR; CYCLIN-DEPENDENT KINASE 4; CYCLIN-DEPENDENT KINASE 6; HUMANS; INHIBITORY CONCENTRATION 50; MICE, NUDE; PROTEIN KINASE INHIBITORS; TUMOR BURDEN; TUMOR MARKERS, BIOLOGICAL; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84904402837     PISSN: 10780432     EISSN: 15573265     Source Type: Journal    
DOI: 10.1158/1078-0432.CCR-13-2846     Document Type: Article

References (34)

1. Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 1986;323: 643-6. (Pubitemid 16008560)
2. Paggi MG, Baldi A, Bonetto F, Giordano A. Retinoblastoma protein family in cell cycle and cancer: a review. J Cell Biochem 1996;62:418-30. (Pubitemid 26301541)
3. Harbour JW, Dean DC. The Rb/E2F pathway: expanding roles and emerging paradigms. Genes Dev 2000;14:2393-409.
4. Shan B, Chang CY, Jones D, Lee WH. The transcription factor E2F-1 mediates the autoregulation of RB gene expression. Mol Cell Biol 1994;14:299-309.
5. Sun A, Bagella L, Tutton S, Romano G, Giordano A. From G0 to S phase: a view of the roles played by the retinoblastoma (Rb) family members in the Rb-E2F pathway. J Cell Biochem 2007;102:1400-4.
6. DeCaprio JA, Ludlow JW, Lynch D, Furukawa Y, Griffin J, Piwnica-Worms H, et al. The product of the retinoblastoma susceptibility gene has properties of a cell cycle regulatory element. Cell 1989;58:1085-95. (Pubitemid 19238186)
7. Kitagawa M, Higashi H, Jung HK, Suzuki-Takahashi I, Ikeda M, Tamai K, et al. The consensus motif for phosphorylation by cyclin D1-Cdk4 is different from that for phosphorylation by cyclin A/E-Cdk2. EMBO J 1996;15:7060-9. (Pubitemid 27023276)
8. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100: 57-70. (Pubitemid 30046295)
9. Nevins JR. The Rb/E2F pathway and cancer. Hum Mol Genet 2001; 10:699-703. (Pubitemid 32331578)
10. Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther 2004;3:1427-38.
11. Gelbert LM, Cai S, Lin X, Sanchez-Martinez C, del Prado M, Lallena MJ, et al. Identification and characterization of LY2835219: a potent oral inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6) with broad in vivo antitumor activity [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B233.
12. Sanchez-Martinez C, Gelbert LM, Shannon H, De Dios A, Staton BA, Ajamie RT, et al. LY2835219, a potent oral inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6) that crosses the blood-brain barrier and demonstrates in vivo activity against intracranial human brain tumor xenografts [abstract]. In: Proceedings of the AACR-NCIEORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B234.
13. Leonard JP, LaCasce AS, Smith MR, Noy A, Chirieac LR, Rodig SJ, et al. Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood 2012; 119:4597-607.
14. Shapiro GI, Rosen LS, Tolcher AW, Goldman JW, Gandhi L, Papadopoulos KP, et al. A first-in-human phase 1 study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer. J Clin Oncol 31, 2013 (suppl; abstr 2500).
15. Goswami PC, Roti Roti JL, Hunt CR. The cell cycle-coupled expression of topoisomerase II alpha during S phase is regulated by mRNA stability and is disrupted by heat shock or ionizing radiation. Mol Cell Biol 1996;16:1500-8. (Pubitemid 26095620)
16. Gurley LR, Walters RA, Tobey RA. Cell cycle-specific changes in histone phosphorylation associated with cell proliferation and chromosome condensation. J Cell Biol 1974;60:356-64.
17. Sharma A, Ebling WF, Jusko WJ. Precursor-dependent indirect pharmacodynamic response model for tolerance and rebound phenomena. J Pharm Sci 1998;87:1577-84. (Pubitemid 28559645)
18. Huang WS, Wang JP, Wang T, Fang JY, Lan P, Ma JP. ShRNA-mediated gene silencing of beta-catenin inhibits growth of human colon cancer cells. World J Gastroenterol 2007;13:6581-7.
19. Simeoni M, Magni P, Cammia C, De NG, Croci V, Pesenti E, et al. Predictive pharmacokinetic-pharmacodynamic modeling of tumor growth kinetics in xenograft models after administration of anticancer agents. Cancer Res 2004;64:1094-101. (Pubitemid 38176915)
20. Lam TL, Wong GK, Chow HY, Chong HC, Chow TL, Kwok SY, et al. Recombinant human arginase inhibits the in vitro and in vivo proliferation of human melanoma by inducing cell cycle arrest and apoptosis. Pigment Cell Melanoma Res 2011;24:366-76.
21. Wang Y, Roy A, Sun L, Lau CE. A double-peak phenomenon in the pharmacokinetics of alprazolam after oral administration. Drug Metab Dispos 1999;27:855-9. (Pubitemid 29347583)
22. Shapiro GI, Edwards CD, Ewen ME, Rollins BJ. p16INK4A participates in a G1 arrest checkpoint in response to DNA damage. Mol Cell Biol 1998;18:378-87.
23. Fry DW, Bedford DC, Harvey PH, Fritsch A, Keller PR, Wu Z, et al. Cell cycle and biochemical effects of PD 0183812. A potent inhibitor of the cyclin D-dependent kinases CDK4 and CDK6. J Biol Chem 2001; 276:16617-23.
24. Liliensiek SJ, Schell K, Howard E, Nealey P, Murphy CJ. Cell sorting but not serum starvation is effective for SV40 human corneal epithelial cell cycle synchronization. Exp Eye Res 2006;83:61-8. (Pubitemid 43783228)
25. Chen M, Huang J, Yang X, Liu B, Zhang W, Huang L, et al. Serum starvation induced cell cycle synchronization facilitates human somatic cells reprogramming. PLoS ONE 2012;7:e28203.
26. Sun YN, Jusko WJ. Transit compartments versus gamma distribution function to model signal transduction processes in pharmacodynamics. J Pharm Sci 1998;87:732-7. (Pubitemid 28268573)
27. Cronier D, Gelbert L, Wishart G, De Dios A. A fully integrated PK/IVTI/IVE model in mouse to help design the FHD trial for a cell cycle inhibitor X [abstract]. In: Proceedings of the Annual Meeting of the Population Approach Group in Europe; 2009; St. Petersburg, Russia. p. 18. Abstract nr 1611.
28. Flaherty KT, Lorusso PM, Demichele A, Abramson VG, Courtney R, Randolph SS, et al. Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. Clin Cancer Res 2012;18:568-76.
29. Patnaik A, Rosen LS, Tolaney SM, Tolcher AW, Goldman JW, Gandhi L, et al. Clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with metastatic breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; 2014. Abstract nr CT232.
30. Rosen LS, Shapiro GI, Tolcher AW, Goldman JW, Gandhi L, Papadopoulos KP, et al. Early development of LY2835219, a novel cell cycle inhibitor with activity against CDK4 and CDK6 [abstract]. 12th International congress on Targeted Anticancer Therapies 2014 Mar 5. Abstract nr O4.3.
31. Dempsey JA, Chan EM, Burke TF, Beckmann RP. LY2835219, a selective inhibitor of CDK4 and CDK6, inhibits growth in preclinical models of human cancer [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-122.
32. Kaufmann SH, Desnoyers S, Ottaviano Y, Davidson NE, Poirier GG. Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis. Cancer Res 1993;53: 3976-85. (Pubitemid 23267698)
33. Smith EJ, Leone G, DeGregori J, Jakoi L, Nevins JR. The accumulation of an E2F-p130 transcriptional repressor distinguishes a G0 cell state from a G1 cell state. Mol Cell Biol 1996;16:6965-76.
34. Noble D. Systems biology and the heart. Biosystems 2006;83: 75-80. (Pubitemid 43199808)