Tatman Philip D, Osbun Joshua, Yakkioui Youssef, Kaur Sumanpret, Parada Carolina, Busald Tina, Born Donald, Ahmad Owais, Zhang Jing, Ferreira Manuel
Medical Scientist Training Program, University of Colorado, Aurora, Colorado, USA; Department of Neurological Surgery, University of Washington, Seattle, Washington, USA.
Department of Neurological Surgery, University of Washington, Seattle, Washington, USA; Department of Neurological Surgery, Emory, Atlanta, Georgia, USA.
World Neurosurg. 2017 Nov;107:75-81. doi: 10.1016/j.wneu.2017.06.106. Epub 2017 Jun 21.
Chordomas and chondrosarcomas can occur in the skull base. Currently, 45% of chordomas and 56% of chondrosarcomas recur within 5 years of surgery. The role of adjuvant therapy is highly debated. No pharmacotherapies have been approved by the U.S. Food and Drug Administration for chordomas or chondrosarcomas. High propensity for recurrence and lack of definitive adjuvant therapy necessitate additional basic science research to identify molecular anomalies associated with recurrent disease.
We pooled tumor lysates from patients based on clinical criteria into 4 groups: primary chordomas, primary chordomas that recurred, primary chondrosarcomas, and primary chondrosarcomas that recurred. We used a peptide labeling method, isobaric tags for relative and absolute quantitation, to uniquely identify each tumor group. Phosphorylated peptides were identified and quantified via mass spectroscopy to determine and predict active kinases.
Six groups of phosphorylated peptides were associated with primary tumors that later recurred. Specific kinases associated with primary chordomas that recurred were FES and FER. Specific kinases associated with primary chondrosarcomas that recurred were FES, FER, SRC family kinases, PKC, ROCK, and mitogen-activated protein kinase signaling (JNK, ERK1, p38).
These data provide clinicians with a means to screen skull base chordomas and chondrosarcomas to help identify tumors with a propensity to recur. Many of these kinases can be efficaciously inhibited by Food and Drug Administration-approved drugs that have not yet been used in clinical trials for treatment of skull base chordomas or chondrosarcomas. Validation of kinases identified in this study may advance treatment options for patients with these tumors.
脊索瘤和软骨肉瘤可发生于颅底。目前，45%的脊索瘤和56%的软骨肉瘤在手术后5年内复发。辅助治疗的作用存在高度争议。美国食品药品监督管理局尚未批准任何药物疗法用于治疗脊索瘤或软骨肉瘤。复发倾向高且缺乏明确的辅助治疗方法，因此需要开展更多基础科学研究来确定与复发性疾病相关的分子异常。
我们根据临床标准将患者的肿瘤裂解物汇集为4组：原发性脊索瘤、复发性原发性脊索瘤、原发性软骨肉瘤和复发性原发性软骨肉瘤。我们使用一种肽标记方法，即相对与绝对定量的等压标记，来唯一识别每个肿瘤组。通过质谱鉴定和定量磷酸化肽，以确定和预测活性激酶。
六组磷酸化肽与后来复发的原发性肿瘤相关。与复发性原发性脊索瘤相关的特定激酶是FES和FER。与复发性原发性软骨肉瘤相关的特定激酶是FES、FER、SRC家族激酶、PKC、ROCK和丝裂原活化蛋白激酶信号通路（JNK、ERK1、p38）。
这些数据为临床医生提供了一种筛选颅底脊索瘤和软骨肉瘤的方法，以帮助识别有复发倾向的肿瘤。许多这些激酶可被美国食品药品监督管理局批准的药物有效抑制，这些药物尚未用于颅底脊索瘤或软骨肉瘤的临床试验。本研究中鉴定出的激酶的验证可能会推进这些肿瘤患者的治疗选择。
