Multi-institutional trial: molecular analysis of margins

描述(由申请人提供)：完全切除癌症是由手术切缘的组织学评估指导的。对切缘进行分子检测可以获得更好的治愈率。不幸的是，没有一种标志物足够灵敏，不能在临床环境中可靠地使用。我们已经确定原癌基因eIF4E在100%的HNSCC中高表达。一项单一的机构研究表明，与eIF4E阴性的手术切缘相比，组织学上无肿瘤的手术切缘中eIF4E的过度表达导致无病间期显著缩短。我们将在一项多机构试验中验证我们的假设，即eIF4E在无肿瘤手术切缘中的过度表达是复发的独立预测因素。我们将使用来自约翰霍普金斯大学的科赫博士的团队正在进行的ECOG试验中收集的样本，他们目前正在分析p53突变的边缘，以确定eIF4E在这些边缘的过度表达是否是复发的重要预测因素。 EIF4E的激活导致与肿瘤进展相关的mRNAs的翻译增加，如细胞周期蛋白D1。我们发现，在HNSCC患者的边缘，eIF4E的激活增加与细胞周期蛋白D1的升高有关。激活的哺乳动物靶标雷帕霉素，mTOR，磷酸化4E-BP 1释放结合的eIF4E，刺激帽依赖的翻译。因此，雷帕霉素抑制mTOR将抑制4E-BP 1的磷酸化，并与4E-BP 1隔离eIF4E，从而减少参与肿瘤进展的mRNAs的翻译。为了确定雷帕霉素类似物CCI-779是否可以潜在地用于eIF4E阳性切缘患者的辅助治疗，我们将在一项确凿的研究中证实，磷酸化4E-BP1和细胞周期蛋白D1在eIF4E阳性切缘中是否过度表达，表明eIF4E活性增加。然后，我们将阐明CCI-779在体外和体内具有不同eIF4E水平的HNSCC细胞株上的抗肿瘤特性，在一个微小残留病的模型中。我们还将通过研究CCI-779对eIF4E相关的4E-BP1数量的影响及其对细胞周期蛋白D 1表达的影响来确定这些效应是否是mTOR抑制的结果。如果我们的假设得到证实，我们的长期目标是进行一项临床试验，将CCI-779作为辅助治疗，用于eIF4E阳性边缘患者，以可能降低复发率。

DESCRIPTION (provided by applicant): Complete excision of cancer is guided by histologic assessment of surgical margins. Molecular detection of margins could allow for a better cure rate. Unfortunately, no marker is sensitive enough to be used reliably in a clinical setting. We have determined that the proto-oncogene eIF4E is overexpressed in 100% of HNSCC. A single institutional study showed that eIF4E overexpression in histologically tumor-free surgical margins results in a significant decrease in disease free interval compared to patients with eIF4E-negative margins. We will test our hypothesis that eIF4E overexpression in tumor-free surgical margins is an independent predictor of recurrence in a multi-institutional trial. We will use samples collected in an ongoing ECOG trial by Dr. Koch's group from Johns Hopkins, who are currently analyzing margins for p53 mutations, to determine if overexpression of eIF4E in these margins is a significant predictor of recurrence. Activation of eIF4E results in increased translation of mRNAs such as cyclin D1, associated with tumor progression. We have shown increased activation of eIF4E in margins of HNSCC patients over-expressing eIF4E is associated with elevation of cyclin D1.The activated mammalian target of rapamycin, mTOR, phosphorylates 4E-BP 1 releasing bound eIF4E to stimulate cap-dependent translation. Hence inhibition of mTOR by rapamycin will inhibit phosphorylation of 4E-BP 1 and sequester eIF4E with 4E-BP 1 decreasing translation of mRNAs involved in tumor progression. To determine if CCI-779 a rapamycin analogue can potentially be used as adjuvant therapy for patients with eIF4E-positive margins, we will confirm in a definitive study if phospho-4E-BP1 and cyclin D1 are overexpressed in eIF4E positive margins indicating increased activity of eIF4E. We will then elucidate the anti-tumorigenic properties of CCI-779 on HNSCC cell lines with varying eIF4E levels in vitro and in vivo, in a model of minimal residual disease. We will also determine if these effects are a result of inhibition of mTOR by studying the effects of CCI-779 on the amount of 4E-BP1 associated with eIF4E and its effects on the expression of cyclin D 1. If our hypotheses were proven, our long-term goal would be to conduct a clinical trial with CCI-779 as adjuvant therapy, for eIF4E-positive margin patients to possibly decrease recurrence rates.