Iwenofu O Hans, Lackman Richard D, Staddon Arthur P, Goodwin Diana G, Haupt Helen M, Brooks John S J
Department of Pathology, Pennsylvania Hospital of the University of Pennsylvania Health System, Philadelphia, PA, USA.
Mod Pathol. 2008 Mar;21(3):231-7. doi: 10.1038/modpathol.3800995. Epub 2007 Dec 21.
Metastatic sarcomas are commonly resistant to chemotherapy. The serine/threonine kinase, mammalian target of rapamycin (mTOR), is a protein kinase of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway thought to have a key role in controlling cancer growth and thus is an important target for cancer therapy. Several inhibitors of mTOR are in clinical trials, including AP23573, which is being tested on metastatic sarcomas and other tumors. We hypothesized that a marker for the activity of mTOR, phosphorylated S6 ribosomal protein, would be predictive of clinical response to the drug, that is, high tumor expression would signify better response than low expression. This was a blinded study. Of 26 patients treated, 20 remained on study, with available paraffin blocks. Fourteen patients received AP23573 alone and six patients received AP23573 in combination with adriamycin. An antibody to the phosphorylated S6 ribosomal protein was used to stain the tumors, all high-grade sarcomas. Pretreatment biopsy or resection material was tested: the original tumor (n=6) or tumor recurrence/metastasis (n=14); either of these may have been after treatment with other agents. Staining was scored for both quantity/percentage of tumor cells and intensity. Scoring was performed without knowledge of tumor response. Staining quantity could be categorized into two natural groups: high expressors (> or =20% of tumor cells, 11 cases) and low expressors (0-10% of tumor cells, 9 cases). The high-expression group had eight stable and three progressive cases (73% stable disease); the low-expression group had three stable and six progressive cases (67% progressive disease). Chi-square analysis showed statistical significance (P< or =0.05) at this initial cutoff (10%) selected blindly. The level of phosphorylated S6 ribosomal protein expression was predictive of early tumor response to the mTOR inhibitor, suggesting that this is a promising new predictive sarcoma marker for targeted mTOR inhibitor therapy.
转移性肉瘤通常对化疗耐药。丝氨酸/苏氨酸激酶，即哺乳动物雷帕霉素靶蛋白（mTOR），是磷脂酰肌醇3激酶（PI3K）/AKT信号通路中的一种蛋白激酶，被认为在控制癌症生长中起关键作用，因此是癌症治疗的一个重要靶点。几种mTOR抑制剂正在进行临床试验，包括AP23573，它正在转移性肉瘤和其他肿瘤上进行测试。我们假设mTOR活性的一个标志物，即磷酸化S6核糖体蛋白，将可预测对该药物的临床反应，也就是说，肿瘤高表达意味着比低表达有更好的反应。这是一项盲法研究。在接受治疗的26例患者中，20例仍在研究中，并有可用的石蜡块。14例患者单独接受AP23573治疗，6例患者接受AP23573与阿霉素联合治疗。使用针对磷酸化S6核糖体蛋白的抗体对肿瘤进行染色，所有肿瘤均为高级别肉瘤。对治疗前活检或切除材料进行检测：原发肿瘤（n = 6）或肿瘤复发/转移（n = 14）；这些情况中任何一种都可能是在接受其他药物治疗之后。对肿瘤细胞的数量/百分比和强度进行染色评分。评分在不知道肿瘤反应的情况下进行。染色数量可分为两个自然组：高表达组（肿瘤细胞≥20%，11例）和低表达组（肿瘤细胞0 - 10%，9例）。高表达组有8例病情稳定和3例进展性病例（疾病稳定率73%）；低表达组有3例病情稳定和6例进展性病例（疾病进展率67%）。卡方分析显示，在盲目选择的这个初始临界值（10%）时具有统计学意义（P≤0.05）。磷酸化S6核糖体蛋白的表达水平可预测肿瘤对mTOR抑制剂的早期反应，表明这是一种有前景的新的预测性肉瘤标志物，用于靶向mTOR抑制剂治疗。
