Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC and Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Department of Neurosurgery, Cancer Center Amsterdam, Amsterdam UMC and Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Clin Cancer Res. 2022 Apr 14;28(8):1595-1602. doi: 10.1158/1078-0432.CCR-21-1933.
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.
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.
The median tumor sunitinib concentration of 1.9 μmol/L (range 1.0-3.4) was 10-fold higher than in concurrent plasma, but three times lower than sunitinib IC50s in GBM cell lines (median 5.4 μmol/L, 3.0-8.5; P = 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.
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.
酪氨酸激酶抑制剂（TKI）在胶质母细胞瘤（GBM）患者中的疗效不佳。在这里，我们研究了这主要是由于血脑屏障渗透受限还是GBM 的生物学特征所致。
在 5 名 GBM 患者中，我们测定了术前治疗 2 周后 TKI 舒尼替尼的肿瘤药物浓度，并将其与 GBM 细胞系中的体外抑制浓度（IC50）进行比较。此外，我们还进行了磷酸酪氨酸（pTyr）定向质谱（MS）-基于蛋白质组学的研究，以评估舒尼替尼治疗与对照 GBM 肿瘤。
中位肿瘤舒尼替尼浓度为 1.9 μmol/L（范围 1.0-3.4），是同时期血浆浓度的 10 倍，但比 GBM 细胞系中的舒尼替尼 IC50 低 3 倍（中位值 5.4 μmol/L，3.0-8.5；P = 0.01）。与 7 例对照患者相比，4 例舒尼替尼治疗患者的肿瘤样本的 pTyr 磷酸化蛋白质组学图谱显示，有 108 个磷酸肽明显上调，23 个磷酸肽下调（P < 0.05），导致 EGFR 为中心的信号网络。作为一种识别个体肿瘤中药物靶点的潜在策略，对激酶活性进行离群值分析，鉴定出包括 MAPK10 和 INSR/IGF1R 在内的 9 种激酶。
GBM 患者的肿瘤舒尼替尼浓度高于血浆，但低于其他肿瘤类型，且不足以显著抑制体外肿瘤细胞生长。因此，增加肿瘤内舒尼替尼浓度的替代 TKI 给药可能会提高 GBM 患者的临床获益。同时，我们发现 GBM 中存在激酶活性的复杂谱，支持（磷酸化）蛋白质组学分析在确定（联合）治疗靶点方面的潜力。
