Chordoma Foundation, Greensboro, NC, USA, and Division of Medical Oncology, Department of Medicine, Duke University Medical Center and Durham Veterans Affairs Medical Center, Durham, NC, USA.
J Pathol. 2010 Apr;220(5):608-17. doi: 10.1002/path.2679.
Currently there is no effective chemotherapy for chordoma. Recent studies report co-expression of insulin-like growth factor-1 receptor (IGF1R) and its cognate ligand in chordoma, but it is unknown whether this receptor tyrosine kinase is activated in these tumours. Additionally, genetic studies have confirmed frequent deletions of chromosome 9p in chordomas, which encompasses the cyclin-dependent kinase inhibitor 2A (CDKN2A) locus. Another gene in this region, methylthioadenosine phosphorylase (MTAP), is an essential enzyme of the purine salvage pathway and has therapeutic relevance because MTAP-deficient cells are particularly sensitive to inhibitors of de novo purine synthesis. We investigated whether these pathways might be potential therapeutic targets for chordoma. Paraffin-embedded tissue samples from 30 chordomas were analysed by immunohistochemistry for expression of the phosphorylated isoforms of IGF1R or the insulin receptor (pIGF1R/pIR) and selected downstream signalling molecules, including BCL2-associated agonist of cell death protein (BAD). Expression of CDKN2A and MTAP proteins was also assessed. Skeletal chondrosarcomas, benign notochordal cell tumours, and fetal notochord were studied for comparison. Phosphorylated IGF1R/IR was detected in 41% of chordomas, together with activated downstream signalling molecules, and pIGF1R/pIR was absent in benign notochordal cell tumours and fetal notochord. Thirty-nine per cent of chordomas were negative for MTAP immunoreactivity. Patients with pIGF1R/pIR-positive tumours showed significantly decreased median disease-free survival in multivariate survival analysis (p = 0.036), whereas phosphorylation of BAD at serine-99 was found to be associated with a favourable prognosis (p = 0.002). Approximately 40% of chordomas demonstrate evidence of activation of the IGF1R/IR signalling pathway or loss of a key enzyme in the purine salvage pathway. Aberrant signalling cascades and disrupted metabolic pathways such as these may represent opportunities for novel targeted therapeutic approaches for the treatment of chordoma.
目前，针对脊索瘤尚无有效的化疗药物。最近的研究报告称，胰岛素样生长因子-1 受体（IGF1R）及其配体在脊索瘤中共同表达，但尚不清楚该受体酪氨酸激酶是否在这些肿瘤中被激活。此外，遗传研究已证实脊索瘤中染色体 9p 的频繁缺失，该区域包含细胞周期蛋白依赖性激酶抑制剂 2A（CDKN2A）基因座。该区域的另一个基因，即甲基硫代腺苷磷酸化酶（MTAP），是嘌呤补救途径的必需酶，具有治疗相关性，因为 MTAP 缺陷细胞对从头合成嘌呤的抑制剂特别敏感。我们研究了这些途径是否可能成为脊索瘤的潜在治疗靶点。通过免疫组织化学分析 30 例脊索瘤的石蜡包埋组织样本，检测磷酸化 IGF1R 或胰岛素受体（pIGF1R/pIR）及其下游信号转导分子（包括 BCL2 相关细胞死亡促进蛋白）的表达。还评估了 CDKN2A 和 MTAP 蛋白的表达。为了比较，研究了骨软骨肉瘤、良性脊索瘤和胎儿脊索。在 41%的脊索瘤中检测到磷酸化 IGF1R/IR 与激活的下游信号分子，而良性脊索瘤和胎儿脊索中未检测到 pIGF1R/pIR。39%的脊索瘤对 MTAP 免疫反应呈阴性。多变量生存分析显示，pIGF1R/pIR 阳性肿瘤患者的中位无疾病生存时间显著缩短（p = 0.036），而丝氨酸 99 处 BAD 的磷酸化与有利的预后相关（p = 0.002）。大约 40%的脊索瘤显示 IGF1R/IR 信号通路激活或嘌呤补救途径中关键酶缺失的证据。这些异常的信号级联和代谢途径的破坏可能为治疗脊索瘤提供新的靶向治疗方法。
