Multi-institutional trial: molecular analysis of margins

多机构试验：边缘的分子分析

• 批准号: 7913476
• 负责人: CHERIE-ANN O NATHAN
• 金额: $ 10.35万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7913476
• 关键词: Adjuvant Therapy; Binding; CCI-779; Cell Line; Cells; Clinical; Clinical Trials; Cyclin D1; Detection; Disease; Eastern Cooperative Oncology Group; Environment; Excision; Goals; Growth; Head and Neck Neoplasms; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Histologic; Image Analysis; Immunohistochemistry; In Vitro; Laboratories; Malignant Neoplasms; Methods; Modeling; Molecular; Molecular Analysis; Mutation; Operative Surgical Procedures; Pathologist; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Prognostic Marker; Property; Proto-Oncogenes; Recurrence; Residual Neoplasm; Role; Sampling; Sirolimus; Surgical margins; Surrogate Markers; TP53 gene; Testing; Translations; base; cancer recurrence; established cell line; head and neck cancer patient; human FRAP1 protein; in vivo; mTOR Inhibitor; mTOR inhibition; mTOR protein; mouse model; olympia; overexpression; preclinical study; response; tumor; tumor progression; tumor xenograft; tumorigenesis; tumorigenic

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.

描述（由申请人提供）：癌症的完全切除以手术切缘的组织学评估为指导。边缘的分子检测可以提高治愈率。不幸的是，没有任何标记物足够敏感，可以在临床环境中可靠地使用。我们确定原癌基因 eIF4E 在 100% 的 HNSCC 中过度表达。一项机构研究表明，与 eIF4E 边缘阴性的患者相比，组织学上无肿瘤的手术边缘中 eIF4E 过度表达会导致无病间隔显着缩短。我们将在多机构试验中检验我们的假设，即无肿瘤手术切缘中的 eIF4E 过度表达是复发的独立预测因子。我们将使用约翰·霍普金斯大学 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 eIF4E 的过度表达是否是复发的重要预测因素。 eIF4E 的激活会导致与肿瘤进展相关的 mRNA 翻译增加，例如细胞周期蛋白 D1。我们已经证明，过度表达 eIF4E 的 HNSCC 患者边缘 eIF4E 的激活增加与细胞周期蛋白 D1 的升高相关。雷帕霉素的激活的哺乳动物靶标 mTOR 磷酸化 4E-BP 1，释放结合的 eIF4E 以刺激帽依赖性翻译。因此，雷帕霉素对 mTOR 的抑制将抑制 4E-BP 1 的磷酸化并隔离 eIF4E，4E-BP 1 会减少参与肿瘤进展的 mRNA 的翻译。为了确定雷帕霉素类似物 CCI-779 是否可以用作 eIF4E 边缘阳性患者的辅助治疗，我们将在一项明确的研究中确认磷酸化 4E-BP1 和细胞周期蛋白 D1 在 eIF4E 阳性边缘中是否过度表达，表明 eIF4E 阳性边缘的活性增加。 eIF4E。然后，我们将在微小残留病模型中，在体外和体内阐明 CCI-779 对具有不同 eIF4E 水平的 HNSCC 细胞系的抗肿瘤特性。我们还将通过研究 CCI-779 对与 eIF4E 相关的 4E-BP1 量的影响及其对细胞周期蛋白 D 1 表达的影响，确定这些影响是否是 mTOR 抑制的结果。如果我们的假设得到证实，我们的长期目标是针对eIF4E阳性切缘患者进行CCI-779辅助治疗的临床试验，以可能降低复发率。