Brain exposure of two selective dual CDK4 and CDK6 inhibitors and the antitumor activity of CDK4 and CDK6 inhibition in combination with temozolomide in an intracranial glioblastoma xenograft

Drug Metabolism and Disposition

Volumn 43, Issue 9, 2015, Pages 1360-1371

  Raub, Thomas J ^a   Wishart, Graham N ^a   Kulanthaivel, Palaniappan ^a   Staton, Brian A ^a,d   Ajamie, Rose T ^a   Sawada, Geri A ^a   Gelbert, Lawrence M ^a,e   Shannon, Harlan E ^a,c,e   Sanchez Martinez, Concepcion ^b   De Dios, Alfonso ^a  

^a ELI LILLY AND COMPANY   (United States)

^b ELI LILLY AND COMPANY   (Spain)

^c Covance Laboratories ^*  (United States)

^d IQVIA   (United States)

^e INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ABEMACICLIB; BREAST CANCER RESISTANCE PROTEIN; CYCLIN DEPENDENT KINASE 4; CYCLIN DEPENDENT KINASE 6; MULTIDRUG RESISTANCE PROTEIN; PALBOCICLIB; TEMOZOLOMIDE; 5-(4-ETHYLPIPERAZIN-1-YLMETHYL)PYRIDIN-2-YL)-(5-FLUORO-4-(7-FLUORO-3-ISOPROPYL-2-METHYL-3H-BENZIMIDAZOL-5-YL)PYRIMIDIN-2-YL)AMINE; AMINOPYRIDINE DERIVATIVE; ANTINEOPLASTIC AGENT; BENZIMIDAZOLE DERIVATIVE; DACARBAZINE; PIPERAZINE DERIVATIVE; PROTEIN KINASE INHIBITOR; PYRIDINE DERIVATIVE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; AREA UNDER THE CURVE; ARTICLE; BLOOD BRAIN BARRIER; CANCER INHIBITION; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG ABSORPTION; DRUG BRAIN LEVEL; DRUG MECHANISM; DRUG METABOLISM; DRUG PROTEIN BINDING; DRUG RESPONSE; DRUG UPTAKE; ENZYME INHIBITION; FEMALE; GLIOBLASTOMA; IN VITRO STUDY; IN VIVO STUDY; MALE; MOUSE; NONHUMAN; PRIORITY JOURNAL; RAT; TUMOR XENOGRAFT; ANALOGS AND DERIVATIVES; ANIMAL; ANTAGONISTS AND INHIBITORS; BRAIN; BRAIN NEOPLASMS; DOG; DRUG EFFECTS; DRUG SCREENING; MDCK CELL LINE; PATHOLOGY;

ANIMALIA; MUS; RATTUS; RODENTIA;

AMINOPYRIDINES; ANIMALS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; BENZIMIDAZOLES; BRAIN; BRAIN NEOPLASMS; CYCLIN-DEPENDENT KINASE 4; CYCLIN-DEPENDENT KINASE 6; DACARBAZINE; DOGS; FEMALE; GLIOBLASTOMA; MADIN DARBY CANINE KIDNEY CELLS; MALE; MICE; PIPERAZINES; PROTEIN KINASE INHIBITORS; PYRIDINES; RATS; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84940421447     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.114.062745     Document Type: Article

References (68)

1. Agarwal S, Hartz AM, Elmquist W.F., and Bauer B (2011a) Breast cancer resistance protein and P-glycoprotein in brain cancer: two gatekeepers team up. Curr Pharm Des 17:2793-2802.
2. Agarwal S, Manchanda P, Vogelbaum M.A., Ohlfest JR, and Elmquist WF (2013) Function of the blood-brain barrier and restriction of drug delivery to invasive glioma cells: findings in an orthotopic rat xenograft model of glioma. Drug Metab Dispos 41:33-39.
3. Agarwal S, Sane R, Oberoi R., Ohlfest JR, and Elmquist WF (2011b) Delivery of molecularly targeted therapy to malignant glioma, a disease of the whole brain. Expert Rev Mol Med 13:e17.
4. Blagosklonny MV and Pardee AB (2002) The restriction point of the cell cycle. Cell Cycle 1: 103-110.
5. Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061-1068.
6. Carcaboso AM, Elmeliegy MA, Shen J, Juel S.J., Zhang ZM, Calabrese C, Tracey L, Waters C.M., and Stewart CF (2010) Tyrosine kinase inhibitor gefitinib enhances topotecan penetration of gliomas. Cancer Res 70:4499-4508.
7. Chamberlain MC (2010) Anticancer therapies and CNS relapse: overcoming blood-brain and blood-cerebrospinal fluid barrier impermeability. Expert Rev Neurother 10:547-561.
8. Chu X, Bleasby K, and Evers R (2013) Species differences in drug transporters and implications for translating preclinical findings to humans. Expert Opin Drug Metab Toxicol 9:237-252.
9. Cisternino S, Bourasset F, Archimbaud Y., Sémiond D, Sanderink G., and Scherrmann JM (2003) Nonlinear accumulation in the brain of the new taxoid TXD258 following saturation of P-glycoprotein at the blood-brain barrier in mice and rats. Br J Pharmacol 138:1367-1375.
10. Dantzig AH, Shepard RL, Law K.L., Tabas L., Pratt S, Gillespie JS, Binkley S.N., Kuhfeld MT, Starling JJ, and Wrighton SA (1999) Selectivity of the multidrug resistance modulator, LY335979, for P-glycoprotein and effect on cytochrome P-450 activities. J Pharmacol Exp Ther 290:854-862.
11. de Vries N.A., Beijnen JH, and van Tellingen O (2009) High-grade glioma mouse models and their applicability for preclinical testing. Cancer Treat Rev 35:714-723.
12. Deeken JF and Löscher W (2007) The blood-brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res 13:1663-1674.
13. Dempsey JA, Chan EM, Burke T.F., and Beckmann RP (2013) LY2835219, a selective inhibitor of CDK4 and CDK6, inhibits growth in preclinical models of human cancer (Abstract). Cancer Res 73: LB-122.
14. Desai PV, Sawada GA, Watson I.A., and Raub TJ (2013) Integration of in silico and in vitro tools for scaffold optimization during drug discovery: predicting P-glycoprotein efflux. Mol Pharm 10:1249-1261.
15. Di L, Rong H, and Feng B (2013) Demystifying brain penetration in central nervous system drug discovery. Miniperspective. J Med Chem 56:2-12.
16. Dyson N (1998) The regulation of E2F by pRB-family proteins. Genes Dev 12:2245-2262.
17. Eichler AF and Loeffler JS (2007) Multidisciplinary management of brain metastases. Oncologist 12:884-898.
18. Fattori S, Becherini F, Cianfriglia M., Parenti G, Romanini A, and Castagna M (2007) Human brain tumors: multidrug-resistance P-glycoprotein expression in tumor cells and intratumoral capillary endothelial cells. Virchows Arch 451:81-87.
19. Flaherty KT and Fisher DE (2011) New strategies in metastatic melanoma: oncogene-defined taxonomy leads to therapeutic advances. Clin Cancer Res 17:4922-4928.
20. Flaherty KT, Lorusso PM, Demichele A, Abramson V.G., Courtney R., Randolph SS, Shaik MN, Wilner KD, O'Dwyer PJ, and Schwartz GK (2012) 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 18:568-576.
21. Fortin D (2012) The blood-brain barrier: its influence in the treatment of brain tumors metastases. Curr Cancer Drug Targets 12:247-259.
22. Friedman HS, Kerby T, and Calvert H (2000) Temozolomide and treatment of malignant glioma. Clin Cancer Res 6:2585-2597.
23. Gelbert LM, Cai S, Lin X., Sanchez-Martinez C, Del Prado M, Lallena MJ, Torres R, Ajamie R.T., Wishart GN, and Flack RS, et al. (2014) Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs 32:825-837.
24. Geldof M, Freijer J, van Beijsterveldt L, and Danhof M (2008) Pharmacokinetic modeling of nonlinear brain distribution of fluvoxamine in the rat. Pharm Res 25:792-804.
25. Gerstner ER and Fine RL (2007) Increased permeability of the blood-brain barrier to chemotherapy in metastatic brain tumors: establishing a treatment paradigm. J Clin Oncol 25: 2306-2312.
26. Hammarlund-Udenaes M., Fridén M, Syvänen S, and Gupta A (2008) On the rate and extent of drug delivery to the brain. Pharm Res 25:1737-1750.
27. Jacobs VL, Valdes PA, Hickey W.F., and De Leo JA (2011) Current review of in vivo GBM rodent models: emphasis on the CNS-1 tumour model. ASN Neuro 3:e00063.
28. Jiang Z, Pore N, Cerniglia G.J., Mick R., Georgescu MM, Bernhard EJ, Hahn SM, Gupta A.K., and Maity A (2007) Phosphatase and tensin homologue deficiency in glioblastoma confers resistance to radiation and temozolomide that is reversed by the protease inhibitor nelfinavir. Cancer Res 67:4467-4473.
29. Kalvass JC and Maurer TS (2002) Influence of nonspecific brain and plasma binding on CNS exposure: implications for rational drug discovery. Biopharm Drug Dispos 23:327-338.
30. Kalvass JC, Polli JW, Bourdet D.L., Feng B., Huang SM, Liu X, Smith QR, Zhang L.K., and Zamek-Gliszczynski MJ; International Transporter Consortium (2013) Why clinical modulation of efflux transport at the human blood-brain barrier is unlikely: the ITC evidence-based position. Clin Pharmacol Ther 94:80-94.
31. Kodaira H, Kusuhara H, Ushiki J., Fuse E, and Sugiyama Y (2010) Kinetic analysis of the cooperation of P-glycoprotein (P-gp/Abcb1) and breast cancer resistance protein (Bcrp/Abcg2) in limiting the brain and testis penetration of erlotinib, flavopiridol, and mitoxantrone. J Pharmacol Exp Ther 333:788-796.
32. Landis MW, Pawlyk BS, Li T, Sicinski P., and Hinds PW (2006) Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis. Cancer Cell 9:13-22.
33. Langer CJ and Mehta MP (2005) Current management of brain metastases, with a focus on systemic options. J Clin Oncol 23:6207-6219.
34. Lee J, Lund-Smith C, Borboa A., Gonzalez AM, Baird A, and Eliceiri BP (2009) Glioma-induced remodeling of the neurovascular unit. Brain Res 1288:125-134.
35. Lin NU, Carey LA, Liu M.C., Younger J., Come SE, Ewend M, Harris GJ, Bullitt E, Van den Abbeele AD, and Henson JW, et al. (2008) Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 26: 1993-1999.
36. Liu X, Van Natta K, Yeo H, Vilenski O., Weller PE, Worboys PD, and Monshouwer M (2009) Unbound drug concentration in brain homogenate and cerebral spinal fluid at steady state as a surrogate for unbound concentration in brain interstitial fluid. Drug Metab Dispos 37: 787-793.
37. Lockman PR, Mittapalli RK, Taskar K.S., Rudraraju V., Gril B, Bohn KA, Adkins C.E., Roberts A., Thorsheim HR, and Gaasch JA, et al. (2010) Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clin Cancer Res 16:5664-5678.
38. Lundberg AS and Weinberg RA (1998) Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes. Mol Cell Biol 18:753-761.
39. Malumbres M and Barbacid M (2001) To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer 1:222-231.
40. Malumbres M and Barbacid M (2006) Is cyclin D1-CDK4 kinase a bona fide cancer target? Cancer Cell 9:2-4.
41. Michaud K, Solomon DA, Oermann E, Kim J.S., Zhong WZ, Prados MD, Ozawa T, James C.D., and Waldman T (2010) Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts. Cancer Res 70:3228-3238.
42. Motl S, Zhuang Y, Waters C.M., and Stewart CF (2006) Pharmacokinetic considerations in the treatment of CNS tumours. Clin Pharmacokinet 45:871-903.
43. Ohgaki H and Kleihues P (2005) Epidemiology and etiology of gliomas. Acta Neuropathol 109:93-108.
44. Ortega S, Malumbres M, and Barbacid M (2002) Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim Biophys Acta 1602:73-87.
45. Padowski JM and Pollack GM (2011) Influence of time to achieve substrate distribution equilibrium between brain tissue and blood on quantitation of the blood-brain barrier P-glycoprotein effect. Brain Res 1426:1-17.
46. Pardee AB (1974) A restriction point for control of normal animal cell proliferation. Proc Natl Acad Sci USA 71:1286-1290.
47. Parsons DW, Jones S, Zhang X., Lin JC, Leary RJ, Angenendt P, Mankoo P., Carter H, Siu IM, and Gallia GL, et al. (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807-1812.
48. Patchell RA (2003) The management of brain metastases. Cancer Treat Rev 29:533-540.
49. Polli JW, Olson KL, Chism J.P., John-Williams LS, Yeager RL, Woodard S.M., Otto V., Castellino S, and Demby VE (2009) An unexpected synergist role of P-glycoprotein and breast cancer resistance protein on the central nervous system penetration of the tyrosine kinase inhibitor lapatinib (N-3-chloro-4-[(3-fluorobenzyl) oxy]phenyl-6-[5-([2-(methylsulfonyl) ethyl]aminomethyl)-2-furyl]-4-quinazolinamine; GW572016). Drug Metab Dispos 37:439-442.
50. Radaelli E, Ceruti R, Patton V., Russo M, Degrassi A, Croci V., Caprera F, Stortini G, Scanziani E., and Pesenti E, et al. (2009) Immunohistopathological and neuroimaging characterization of murine orthotopic xenograft models of glioblastoma multiforme recapitulating the most salient features of human disease. Histol Histopathol 24:879-891.
51. Raub TJ, Lutzke BS, Andrus P.K., Sawada GA, and Staton BA (2006) Early preclinical evaluation of brain exposure in support of hit identification and lead optimization, in Optimizing the "Drug-Like" Properties of Leads in Drug Discovery, Biotechnology: Pharmaceutical Aspects Series (Borchardt RT and Middaugh CR, eds) pp 355-410, Springer, New York.
52. Read KD and Braggio S (2010) Assessing brain free fraction in early drug discovery. Expert Opin Drug Metab Toxicol 6:337-344.
53. Reifenberger G, Reifenberger J, Ichimura K., and Collins VP (1995) Amplification at 12q13-14 in human malignant gliomas is frequently accompanied by loss of heterozygosity at loci proximal and distal to the amplification site. Cancer Res 55:731-734.
54. Robey RW, Honjo Y, Morisaki K., Nadjem TA, Runge S, Risbood M, Poruchynsky M.S., and Bates SE (2003) Mutations at amino-acid 482 in the ABCG2 gene affect substrate and antagonist specificity. Br J Cancer 89:1971-1978.
55. Salphati L, Heffron TP, Alicke B, Nishimura M., Barck K, Carano RA, Cheong J, Edgar K.A., Greve J., and Kharbanda S, et al. (2012) Targeting the PI3K pathway in the brain-efficacy of a PI3K inhibitor optimized to cross the blood-brain barrier. Clin Cancer Res 18:6239-6248.
56. Sane R, Agarwal S, and Elmquist WF (2012) Brain distribution and bioavailability of elacridar after different routes of administration in the mouse. Drug Metab Dispos 40:1612-1619.
57. Schmidt EE, Ichimura K, Reifenberger G., and Collins VP (1994) CDKN2 (p16/MTS1) gene deletion or CDK4 amplification occurs in the majority of glioblastomas. Cancer Res 54: 6321-6324.
58. Shapiro G, Rosen LS, Tolcher A.W., Goldman JW, Gandhi L, Papadopoulos KP, Tolaney S.M., Beeram M., Rasco DW, and Kulanthaivel P, et al. (2013) A first-in-human phase I study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer (Abstract). J Clin Oncol 31 (Suppl):2500.
59. Sharom FJ (2008) ABC multidrug transporters: structure, function and role in chemoresistance. Pharmacogenomics 9:105-127.
60. Siena S, Crinò L, Danova M, Del Prete S, Cascinu S, Salvagni S, Schiavetto I, Vitali M, and Bajetta E (2010) Dose-dense temozolomide regimen for the treatment of brain metastases from melanoma, breast cancer, or lung cancer not amenable to surgery or radiosurgery: a multicenter phase II study. Ann Oncol 21:655-661.
61. Steeg PS, Camphausen KA, and Smith QR (2011) Brain metastases as preventive and therapeutic targets. Nat Rev Cancer 11:352-363.
62. Taskar KS, Rudraraju V, Mittapalli R.K., Samala R., Thorsheim HR, Lockman J, Gril B, Hua E., Palmieri D, and Polli JW, et al. (2012) Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer. Pharm Res 29:770-781.
63. Tombline G, Holt JJ, Gannon M.K., Donnelly DJ, Wetzel B, Sawada GA, Raub T.J., and Detty MR (2008) ATP occlusion by P-glycoprotein as a surrogate measure for drug coupling. Biochemistry 47:3294-3307.
64. Vogelbaum M and Thomas T (2007) Small molecular agents, in High-Grade Gliomas: Diagnosis and Treatment (Barnett GH, ed) pp 337-356, Humana Press, Totowa, NJ.
65. Wager TT, Villalobos A, Verhoest P.R., Hou X., and Shaffer CL (2011) Strategies to optimize the brain availability of central nervous system drug candidates. Expert Opin Drug Discov 6: 371-381.
66. Yu Q, Sicinska E, Geng Y., Ahnström M, Zagozdzon A., Kong Y, Gardner H, Kiyokawa H., Harris LN, and Stål O, et al. (2006) Requirement for CDK4 kinase function in breast cancer. Cancer Cell 9:23-32.
67. Zamek-Gliszczynski M.J., Sprague KE, Espada A, Raub T.J., Morton SM, Manro JR, and MolinaMartin M (2012) How well do lipophilicity parameters, MEEKC microemulsion capacity factor, and plasma protein binding predict CNS tissue binding? J Pharm Sci 101:1932-1940.
68. Zhang S, Yang X, and Morris ME (2004) Flavonoids are inhibitors of breast cancer resistance protein (ABCG2)-mediated transport. Mol Pharmacol 65:1208-1216.