Multi-institutional trial: molecular analysis of margins

描述（由申请人提供）：通过手术切缘的组织学评估来指导癌症的完全切除。边缘的分子检测可以提高治愈率。不幸的是，没有一种标记物足够敏感，可以在临床环境中可靠使用。我们已经确定了原癌基因eIF 4 E在100%的HNSCC中过表达。一项机构研究表明，与eIF 4 E阴性切缘患者相比，组织学无肿瘤手术切缘中eIF 4 E过表达导致无病间期显著缩短。我们将在一项多机构试验中检验我们的假设，即无肿瘤手术切缘中eIF 4 E过表达是复发的独立预测因子。我们将使用来自约翰霍普金斯的Koch博士小组正在进行的ECOG试验中收集的样本，他们目前正在分析p53突变的边缘，以确定这些边缘中eIF 4 E的过度表达是否是复发的重要预测因素。 eIF 4 E的激活导致mRNA翻译增加，如细胞周期蛋白D1，与肿瘤进展相关。我们已经发现在HNSCC患者中过度表达eIF 4 E的边缘中eIF 4 E的激活增加与细胞周期蛋白D1的升高相关。激活的哺乳动物雷帕霉素靶蛋白mTOR磷酸化4 E-BP 1释放结合的eIF 4 E以刺激帽依赖性翻译。因此，雷帕霉素对mTOR的抑制将抑制4 E-BP 1的磷酸化，并将eIF 4 E与4 E-BP 1隔离，从而降低参与肿瘤进展的mRNA的翻译。为了确定CCI-779（一种雷帕霉素类似物）是否可以潜在地用作eIF 4 E阳性边缘患者的辅助治疗，我们将在一项确定性研究中确认磷酸-4 E-BP 1和cyclin D1是否在eIF 4 E阳性边缘中过表达，表明eIF 4 E活性增加。然后，我们将阐明CCI-779在微小残留病模型中对体外和体内具有不同eIF 4 E水平的HNSCC细胞系的抗致瘤特性。我们还将通过研究CCI-779对与eIF 4 E相关的4 E-BP 1的量的影响及其对细胞周期蛋白D1表达的影响来确定这些作用是否是mTOR抑制的结果。如果我们的假设得到证实，我们的长期目标将是进行一项临床试验，CCI-779作为辅助治疗，为eIF 4 E阳性边缘患者可能降低复发率。

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.