Tumor Drug Concentration and Phosphoproteomic Profiles After Two Weeks of Treatment With Sunitinib in Patients with Newly Diagnosed Glioblastoma

被引：17

作者：

van Linde, Myra E. ^{[1
,2
]}

Labots, Mariette ^{[1
,2
]}

Brahm, Cyrillo G. ^{[1
,2
]}

Hovinga, Koos E. ^{[2
,3
]}

Hamer, Philip C. De Witt ^{[2
,3
]}

Honeywell, Richard J. ^{[1
,2
,4
]}

De Goeij-de Haas, Richard ^{[1
,2
]}

Henneman, Alex A. ^{[1
,2
]}

Knol, Jaco C. ^{[1
,2
]}

Peters, Godefridus J. ^{[1
,2
,5
]}

Dekker, Henk ^{[1
,2
]}

Piersma, Sander R. ^{[1
,2
]}

Pham, Thang, V ^{[1
,2
]}

Vandertop, William P. ^{[2
,3
]}

Jimenez, Connie R. ^{[1
,2
]}

Verheul, Henk M. W. ^{[1
,2
,6
]}

机构：

[1] Amsterdam UMC, Canc Ctr Amsterdam, Dept Med Oncol, De Boelelaan 1118, NL-1081 HV Amsterdam, Netherlands

[2] Vrije Univ Amsterdam, De Boelelaan 1118, NL-1081 HV Amsterdam, Netherlands

[3] Amsterdam UMC, Canc Ctr Amsterdam, Dept Neurosurg, Amsterdam, Netherlands

[4] Vrije Univ Amsterdam, Canc Ctr Amsterdam, Dept Pharm, Amsterdam UMC, Amsterdam, Netherlands

[5] Med Univ Gdansk, Dept Biochem, Gdansk, Poland

[6] Radboud UMC, Dept Med Oncol, Geert Grootepl Zuid 10, NL-6525 GA Nijmegen, Netherlands

来源：

CLINICAL CANCER RESEARCH | 2022年 / 28卷 / 08期

关键词：

TYROSINE KINASE INHIBITORS; SIGNALING NETWORKS; PHASE-II; EFFICACY; RESISTANCE; TEMOZOLOMIDE; THERAPIES; MECHANISM; PROMOTES; BARRIER;

D O I：

10.1158/1078-0432.CCR-21-1933

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: Tyrosine kinase inhibitors (TKI) have poor efficacy in patients with glioblastoma (GBM). Here, we studied whether this is predominantly due to restricted blood-brain barrier penetration or more to biological characteristics of GBM. Patients and Methods: Tumor drug concentrations of the TKI sunitinib after 2 weeks of preoperative treatment was determined in 5 patients with GBM and compared with its in vitro inhibitory concentration (IC50) in GBM cell lines. In addition, phosphotyrosine (pTyr)-directed mass spectrometry (MS)-based proteomics was performed to evaluate sunitinib-treated versus control GBM tumors. Results: The median tumor sunitinib concentration of 1.9 mu mol/L (range 1.0-3.4) was 10-fold higher than in concurrent plasma, but three times lower than sunitinib IC(50 zeta)s in GBM cell lines (median 5.4 mmol/L, 3.0-8.5; P 1/4 0.01). pTyr-phosphoproteomic profiles of tumor samples from 4 sunitinib-treated versus 7 control patients revealed 108 significantly up-and 23 downregulated (P < 0.05) phosphopeptides for sunitinib treatment, resulting in an EGFR-centered signaling network. Outlier analysis of kinase activities as a potential strategy to identify drug targets in individual tumors identified nine kinases, including MAPK10 and INSR/IGF1R. Conclusions: Achieved tumor sunitinib concentrations in patients with GBM are higher than in plasma, but lower than reported for other tumor types and insufficient to significantly inhibit tumor cell growth in vitro. Therefore, alternative TKI dosing to increase intratumoral sunitinib concentrations might improve clinical benefit for patients with GBM. In parallel, a complex profile of kinase activity in GBM was found, supporting the potential of (phospho)proteomic analysis for the identification of targets for (combination) treatment.

引用

页码：1595 / 1602

页数：8

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[41] Phase I Dose-Escalation Study of Once Weekly or Once Every Two Weeks Administration of High-Dose Sunitinib in Patients With Refractory Solid Tumors [J].