Skip to main content
Top
Published in: Investigational New Drugs 5/2015

01-10-2015 | PRECLINICAL STUDIES

P-glycoprotein and breast cancer resistance protein restrict the brain penetration of the CDK4/6 inhibitor palbociclib

Authors: Mark C. de Gooijer, Ping Zhang, Nishita Thota, Isabel Mayayo-Peralta, Levi C. M. Buil, Jos H. Beijnen, Olaf van Tellingen

Published in: Investigational New Drugs | Issue 5/2015

Login to get access

Summary

Introduction Palbociclib is a cyclin dependent kinase (CDK) 4/6 inhibitor with nanomolar potency and was recently approved for treatment of breast cancer. The drug may also be useful in glioblastoma (GBM) and diffuse intrinsic pontine gliomas (DIPG), which often have an activated CDK4/6-retinoblastoma signaling pathway. However, GBM and DIPG spread widely into the surrounding brain, which calls for a CDK4/6 inhibitor with sufficient blood–brain barrier penetration. Methods We first performed in vitro transwell assays and demonstrate that palbociclib is a substrate of both P-gp and BCRP. Next, we conducted pharmacokinetic studies using wildtype, Abcg2−/−, Abcb1a/b−/− and Abcg2; Abcb1a/b−/− mice. Results The plasma levels were about 3000 and 500 nM and similar in all genotypes at 1 and 4 h after i.v. administration of 10 mg/kg. At 4 h the brain-to-plasma ratios were 0.3 in WT and Abcg2−/− mice versus 5.5 and 15 in Abcb1a/b−/− and Abcg2; Abcb1a/b−/− mice, respectively. The oral bioavailability of palbociclib was high (63 %) in WT mice and increased only modestly and non-significantly in Abcg2; Abcb1a/b−/− mice. The plasma level after oral dosing of 150 mg/kg was already much higher than observed in patients (200–400 nM) and exceeded 2500 nM for up to 24 h. This latter dose is commonly used in preclinical studies, which calls into question their predictive value as they were conducted at dose levels causing a clinically non-relevant systemic drug exposure. Conclusion Thus, the brain penetration of palbociclib is restricted by P-gp and BCRP, which may restrict the efficacy against GBM and DIPG. Moreover, preclinical studies with this agent should be conducted at a more clinically relevant dose level.
Literature
1.
go back to reference Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, Albassam M, Zheng X, Leopold WR, Pryer NK, Toogood PL (2004) Specific inhibition of cyclin-dependent kinase 4/6 by Pd 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther 3(11):1427–1438 Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, Albassam M, Zheng X, Leopold WR, Pryer NK, Toogood PL (2004) Specific inhibition of cyclin-dependent kinase 4/6 by Pd 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther 3(11):1427–1438
2.
go back to reference Baughn LB, Di Liberto M, Wu K, Toogood PL, Louie T, Gottschalk R, Niesvizky R, Cho H, Ely S, Moore MA, Chen-Kiang S (2006) 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 66(15):7661–7667. doi:10.1158/0008-5472.Can-06-1098 Baughn LB, Di Liberto M, Wu K, Toogood PL, Louie T, Gottschalk R, Niesvizky R, Cho H, Ely S, Moore MA, Chen-Kiang S (2006) 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 66(15):7661–7667. doi:10.​1158/​0008-5472.​Can-06-1098
3.
go back to reference Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, Ginther C, Atefi M, Chen I, Fowst C, Los G, Slamon DJ (2009) Pd 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res 11(5):R77. doi:10.1186/Bcr2419 Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, Ginther C, Atefi M, Chen I, Fowst C, Los G, Slamon DJ (2009) Pd 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res 11(5):R77. doi:10.​1186/​Bcr2419
4.
go back to reference Michaud K, Da S, Oermann E, Kim JS, Zhong WZ, Prados MD, Ozawa T, James CD, Waldman T (2010) Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts. Cancer Res 70(8):3228–3238. doi:10.1158/0008-5472.Can-09-4559 Michaud K, Da S, Oermann E, Kim JS, Zhong WZ, Prados MD, Ozawa T, James CD, Waldman T (2010) Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts. Cancer Res 70(8):3228–3238. doi:10.​1158/​0008-5472.​Can-09-4559
5.
go back to reference Barton KL, Misuraca K, Cordero F, Dobrikova E, Min HD, Gromeier M, Kirsch DG, Becher OJ (2013) Pd-0332991, a Cdk4/6 inhibitor, significantly prolongs survival in a genetically engineered mouse model of brainstem glioma. PLoS ONE 8(10):E77639. doi:10.1371/Journal.Pone.0077639 Barton KL, Misuraca K, Cordero F, Dobrikova E, Min HD, Gromeier M, Kirsch DG, Becher OJ (2013) Pd-0332991, a Cdk4/6 inhibitor, significantly prolongs survival in a genetically engineered mouse model of brainstem glioma. PLoS ONE 8(10):E77639. doi:10.​1371/​Journal.​Pone.​0077639
7.
go back to reference Stupp R, Mason W, Van Den Bent M, Weller M, Fisher B, Taphoorn M, Belanger K, Brandes A, Marosi C, Bogdahn U, Curschmann J, Janzer R, Ludwin S, Gorlia T, Allgeier A, Lacombe D, Cairncross J, Eisenhauer E, Mirimanoff R, European Organisation for R, Treatment of Cancer Brain T Radiotherapy G, National Cancer Institute of Canada Clinical Trials G (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996. doi:10.1056/Nejmoa043330 CrossRefPubMed Stupp R, Mason W, Van Den Bent M, Weller M, Fisher B, Taphoorn M, Belanger K, Brandes A, Marosi C, Bogdahn U, Curschmann J, Janzer R, Ludwin S, Gorlia T, Allgeier A, Lacombe D, Cairncross J, Eisenhauer E, Mirimanoff R, European Organisation for R, Treatment of Cancer Brain T Radiotherapy G, National Cancer Institute of Canada Clinical Trials G (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996. doi:10.​1056/​Nejmoa043330 CrossRefPubMed
8.
go back to reference Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455(7216):1061–1068. doi:10.1038/Nature07385 CrossRef Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455(7216):1061–1068. doi:10.​1038/​Nature07385 CrossRef
9.
go back to reference Brennan CW, Verhaak RG, Mckenna A, Campos B, Noushmehr H, Salama SR, Zheng S, Chakravarty D, Sanborn JZ, Berman SH, Beroukhim R, Bernard B, Wu CJ, Genovese G, Shmulevich I, Barnholtz-Sloan J, Zou L, Vegesna R, Shukla SA, Ciriello G, Yung WK, Zhang W, Sougnez C, Mikkelsen T, Aldape K, Bigner DD, Van Meir EG, Prados M, Sloan A, Black KL, Eschbacher J, Finocchiaro G, Friedman W, Andrews DW, Guha A, Iacocca M, Bp O’n, Foltz G, Myers J, Weisenberger DJ, Penny R, Kucherlapati R, Perou CM, Hayes DN, Gibbs R, Marra M, Mills GB, Lander E, Spellman P, Wilson R, Sander C, Weinstein J, Meyerson M, Gabriel S, Laird PW, Haussler D, Getz G, Chin L, Network TR (2013) The somatic genomic landscape of glioblastoma. Cell 155(2):462–477. doi:10.1016/J.Cell.2013.09.034 Brennan CW, Verhaak RG, Mckenna A, Campos B, Noushmehr H, Salama SR, Zheng S, Chakravarty D, Sanborn JZ, Berman SH, Beroukhim R, Bernard B, Wu CJ, Genovese G, Shmulevich I, Barnholtz-Sloan J, Zou L, Vegesna R, Shukla SA, Ciriello G, Yung WK, Zhang W, Sougnez C, Mikkelsen T, Aldape K, Bigner DD, Van Meir EG, Prados M, Sloan A, Black KL, Eschbacher J, Finocchiaro G, Friedman W, Andrews DW, Guha A, Iacocca M, Bp O’n, Foltz G, Myers J, Weisenberger DJ, Penny R, Kucherlapati R, Perou CM, Hayes DN, Gibbs R, Marra M, Mills GB, Lander E, Spellman P, Wilson R, Sander C, Weinstein J, Meyerson M, Gabriel S, Laird PW, Haussler D, Getz G, Chin L, Network TR (2013) The somatic genomic landscape of glioblastoma. Cell 155(2):462–477. doi:10.​1016/​J.​Cell.​2013.​09.​034
10.
go back to reference Paugh BS, Broniscer A, Qu C, Miller CP, Zhang J, Tatevossian RG, Olson JM, Geyer JR, Chi SN, da Silva NS, Onar-Thomas A, Baker JN, Gajjar A, Ellison DW, Baker SJ (2011) Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma. J Clin Oncol 29(30):3999–4006. doi:10.1200/Jco.2011.35.5677 Paugh BS, Broniscer A, Qu C, Miller CP, Zhang J, Tatevossian RG, Olson JM, Geyer JR, Chi SN, da Silva NS, Onar-Thomas A, Baker JN, Gajjar A, Ellison DW, Baker SJ (2011) Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma. J Clin Oncol 29(30):3999–4006. doi:10.​1200/​Jco.​2011.​35.​5677
11.
go back to reference Wu G, Diaz A, Paugh B, Rankin S, Ju B, Li Y, Zhu X, Qu C, Chen X, Zhang J, Easton J, Edmonson M, Ma X, Lu C, Nagahawatte P, Hedlund E, Rusch M, Pounds S, Lin T, Onar-Thomas A, Huether R, Kriwacki R, Parker M, Gupta P, Becksfort J, Wei L, Mulder H, Boggs K, Vadodaria B, Yergeau D, Russell J, Ochoa K, Fulton R, Fulton L, Jones C, Boop F, Broniscer A, Wetmore C, Gajjar A, Ding L, Mardis E, Wilson R, Taylor MR, Downing JR, Ellison D, Zhang J, Baker SJ, St. Jude Children’s Research Hospital-Washington University Pediatric Cancer Genome P (2014) The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 46(5):444–450. doi:10.1038/Ng.2938 Wu G, Diaz A, Paugh B, Rankin S, Ju B, Li Y, Zhu X, Qu C, Chen X, Zhang J, Easton J, Edmonson M, Ma X, Lu C, Nagahawatte P, Hedlund E, Rusch M, Pounds S, Lin T, Onar-Thomas A, Huether R, Kriwacki R, Parker M, Gupta P, Becksfort J, Wei L, Mulder H, Boggs K, Vadodaria B, Yergeau D, Russell J, Ochoa K, Fulton R, Fulton L, Jones C, Boop F, Broniscer A, Wetmore C, Gajjar A, Ding L, Mardis E, Wilson R, Taylor MR, Downing JR, Ellison D, Zhang J, Baker SJ, St. Jude Children’s Research Hospital-Washington University Pediatric Cancer Genome P (2014) The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 46(5):444–450. doi:10.​1038/​Ng.​2938
12.
go back to reference Van Tellingen O, Yetkin-Arik B, de Gooijer MC, Wesseling P, Wurdinger T, de Vries HE (2015) Overcoming the blood–brain tumor barrier for effective glioblastoma treatment. Drug Resist Updat 19:1–12. doi:10.1016/J.Drup.2015.02.002 Van Tellingen O, Yetkin-Arik B, de Gooijer MC, Wesseling P, Wurdinger T, de Vries HE (2015) Overcoming the blood–brain tumor barrier for effective glioblastoma treatment. Drug Resist Updat 19:1–12. doi:10.​1016/​J.​Drup.​2015.​02.​002
13.
go back to reference Lin F, de Gooijer MC, Hanekamp D, Brandsma D, Beijnen J, Van Tellingen O (2013) Targeting core (mutated) pathways of high-grade gliomas: challenges of intrinsic resistance and drug efflux. CNS Oncol 2(3):271–288. doi:10.2217/Cns.13.15 Lin F, de Gooijer MC, Hanekamp D, Brandsma D, Beijnen J, Van Tellingen O (2013) Targeting core (mutated) pathways of high-grade gliomas: challenges of intrinsic resistance and drug efflux. CNS Oncol 2(3):271–288. doi:10.​2217/​Cns.​13.​15
14.
go back to reference Sparreboom A, Van Asperen J, Mayer U, Schinkel A, Smit JW, Meijer DK, Borst P, Nooijen WJ, Beijnen J, van Tellingen O (1997) Limited oral bioavailability and active epithelial excretion of paclitaxel (taxol) caused by P-glycoprotein in the intestine. Proc Natl Acad Sci U S A 94(5):2031–2035 Sparreboom A, Van Asperen J, Mayer U, Schinkel A, Smit JW, Meijer DK, Borst P, Nooijen WJ, Beijnen J, van Tellingen O (1997) Limited oral bioavailability and active epithelial excretion of paclitaxel (taxol) caused by P-glycoprotein in the intestine. Proc Natl Acad Sci U S A 94(5):2031–2035
15.
go back to reference Lin F, Buil L, Sherris D, Beijnen J, Van Tellingen O (2013) Dual mTORC1 and mTORC2 inhibitor palomid 529 penetrates the blood–brain barrier without restriction by Abcb1 and Abcg2. Int J Cancer 133(5):1222–1233. doi:10.1002/Ijc.28126 Lin F, Buil L, Sherris D, Beijnen J, Van Tellingen O (2013) Dual mTORC1 and mTORC2 inhibitor palomid 529 penetrates the blood–brain barrier without restriction by Abcb1 and Abcg2. Int J Cancer 133(5):1222–1233. doi:10.​1002/​Ijc.​28126
17.
go back to reference Shukla S, Ohnuma S, Ambudkar SV (2011) Improving cancer chemotherapy with modulators of Abc drug transporters. Curr Drug Targets 12(5):621–630 Shukla S, Ohnuma S, Ambudkar SV (2011) Improving cancer chemotherapy with modulators of Abc drug transporters. Curr Drug Targets 12(5):621–630
20.
go back to reference Dahan A, Miller JM, Amidon GL (2009) Prediction of solubility and permeability class membership: provisional Bcs classification of the world’s top oral drugs. AAPS J 11(4):740–746. doi:10.1208/S12248-009-9144-X Dahan A, Miller JM, Amidon GL (2009) Prediction of solubility and permeability class membership: provisional Bcs classification of the world’s top oral drugs. AAPS J 11(4):740–746. doi:10.​1208/​S12248-009-9144-X
21.
go back to reference Flaherty K, Lorusso PM, Demichele A, Abramson VG, Courtney R, Randolph SS, Shaik MN, Wilner KD, O'Dwyer PJ, 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(2):568–576. doi:10.1158/1078-0432.Ccr-11-0509 Flaherty K, Lorusso PM, Demichele A, Abramson VG, Courtney R, Randolph SS, Shaik MN, Wilner KD, O'Dwyer PJ, 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(2):568–576. doi:10.​1158/​1078-0432.​Ccr-11-0509
22.
go back to reference Niesvizky R, Badros Az, Costa Lj, Ely Sa, Singhal Sb, Stadtmauer Ea, Haideri Na, Yacoub A, Hess G, Lentzsch S, Spicka I, Chanan-Khan Aa, Raab Ms, Tarantolo S, Vij R, Zonder Ja, Huang X, Jayabalan D, Diliberto M, Huang X, Jiang Y, Kim St, Randolph S, Chen-Kiang S (2015) Phase 1/2 Study Of Cdk4/6 inhibitor palbociclib (Pd-0332991) With bortezomib and dexamethasone in relapsed/refractory multiple myeloma. Leuk Lymphoma1–21. Doi:10.3109/10428194.2015.1030641 Niesvizky R, Badros Az, Costa Lj, Ely Sa, Singhal Sb, Stadtmauer Ea, Haideri Na, Yacoub A, Hess G, Lentzsch S, Spicka I, Chanan-Khan Aa, Raab Ms, Tarantolo S, Vij R, Zonder Ja, Huang X, Jayabalan D, Diliberto M, Huang X, Jiang Y, Kim St, Randolph S, Chen-Kiang S (2015) Phase 1/2 Study Of Cdk4/6 inhibitor palbociclib (Pd-0332991) With bortezomib and dexamethasone in relapsed/refractory multiple myeloma. Leuk Lymphoma1–21. Doi:10.​3109/​10428194.​2015.​1030641
23.
go back to reference Schwartz GK, LoRusso PM, Dickson MA, Randolph SS, Shaik MN, Wilner KD, Courtney R, O'Dwyer PJ (2011) Phase I study of Pd 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (schedule 2/1). Br J Cancer 104(12):1862–1868. doi:10.1038/Bjc.2011.177 Schwartz GK, LoRusso PM, Dickson MA, Randolph SS, Shaik MN, Wilner KD, Courtney R, O'Dwyer PJ (2011) Phase I study of Pd 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (schedule 2/1). Br J Cancer 104(12):1862–1868. doi:10.​1038/​Bjc.​2011.​177
24.
go back to reference Parrish KE, Pokorny JL, Mittapalli RK, Bakken K, Sarkaria JN, Elmquist WF (2013) Abstract C81: Bbb efflux pump activity limits brain penetration of palbociclib (Pd0332991) in glioblastoma. Mol Cancer Ther 12(11 Supplement):C81. doi:10.1158/1535-7163.Targ-13-C81 Parrish KE, Pokorny JL, Mittapalli RK, Bakken K, Sarkaria JN, Elmquist WF (2013) Abstract C81: Bbb efflux pump activity limits brain penetration of palbociclib (Pd0332991) in glioblastoma. Mol Cancer Ther 12(11 Supplement):C81. doi:10.​1158/​1535-7163.​Targ-13-C81
25.
go back to reference Kemper EM, Leenders W, Kusters B, Lyons S, Buckle T, Heerschap A, Boogerd W, Beijnen J, Van Tellingen O (2006) Development of luciferase tagged brain tumour models in mice for chemotherapy intervention studies. Eur J Cancer 42(18):3294–3303. doi:10.1016/J.Ejca.2006.07.013 Kemper EM, Leenders W, Kusters B, Lyons S, Buckle T, Heerschap A, Boogerd W, Beijnen J, Van Tellingen O (2006) Development of luciferase tagged brain tumour models in mice for chemotherapy intervention studies. Eur J Cancer 42(18):3294–3303. doi:10.​1016/​J.​Ejca.​2006.​07.​013
26.
go back to reference Mcconville P, Hambardzumyan D, Moody JB, Leopold WR, Kreger AR, Woolliscroft MJ, Rehemtulla A, Ross BD, Holland EC (2007) Magnetic resonance imaging determination of tumor grade and early response to temozolomide in a genetically engineered mouse model of glioma. Clin Cancer Res 13(10):2897–2904. doi:10.1158/1078-0432.Ccr-06-3058 Mcconville P, Hambardzumyan D, Moody JB, Leopold WR, Kreger AR, Woolliscroft MJ, Rehemtulla A, Ross BD, Holland EC (2007) Magnetic resonance imaging determination of tumor grade and early response to temozolomide in a genetically engineered mouse model of glioma. Clin Cancer Res 13(10):2897–2904. doi:10.​1158/​1078-0432.​Ccr-06-3058
Metadata
Title
P-glycoprotein and breast cancer resistance protein restrict the brain penetration of the CDK4/6 inhibitor palbociclib
Authors
Mark C. de Gooijer
Ping Zhang
Nishita Thota
Isabel Mayayo-Peralta
Levi C. M. Buil
Jos H. Beijnen
Olaf van Tellingen
Publication date
01-10-2015
Publisher
Springer US
Published in
Investigational New Drugs / Issue 5/2015
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-015-0266-y

Other articles of this Issue 5/2015

Investigational New Drugs 5/2015 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine