Multi-institutional trial: adjuvant mTOR targeted therapy

描述(申请人提供)：项目摘要/摘要头颈部恶性肿瘤是一个严重的问题，仅在美国每年就有约40,000例新发的头颈部鳞状细胞癌(HNSCC)和13,000例死亡。尽管在治疗方面取得了进步，但高达50%的晚期疾病患者会出现HNSCC复发。因此，需要有针对性的辅助治疗，类似于Herceptin(R)治疗乳腺癌和Gleevec(R)治疗多发性骨髓瘤。该计划公告的任务是使用从多机构临床试验中收集的肿瘤标本进行相关的实验室研究，以确定可以促进预测治疗干预的临床结果的新的生物标记物。这项建议的主要目标是确定在一项评估mTOR靶向治疗局部晚期HNSCC患者的疗效的随机第二阶段临床试验中，是否可以确定Akt/mTOR通路生物标记物在无肿瘤的手术切缘或邻近粘膜中的激活程度是否可以预测结果。我们的长期目标是通过使用mTOR抑制剂作为靶向辅助治疗，使HNSCC患者成为一种慢性病，从而提高存活率，减少复发和二次原发。目前还没有有效的标记物来预测对mTOR靶向治疗的反应性，确定哪些患者将从治疗中受益是靶向药物成功的关键。本申请中提出的研究将评估Akt/mTOR通路成分在90%以上的HNSCC中过度表达，并在无肿瘤的手术切缘中频繁激活，是否与mTOR靶向治疗的疗效相关。为了实现这一目标，将对多达160名临床试验患者的肿瘤组织和无肿瘤手术切缘或邻近正常黏膜进行分析，以确定Akt/mTOR途径的表达和基因突变。表达水平和基因突变将与临床试验患者的存活率和复发率相关。我们还将确定依维莫司治疗后血清生长因子水平的变化是否与临床结果相关，并可作为药物活性的替代标记物。这些研究可能会确定选择头颈部癌症患者的标志物，这些患者将受益于mTOR靶向治疗，这将减少不必要的毒性和医疗成本。这项研究的结果将用于头颈癌患者随后的mTOR抑制剂治疗研究，包括可能的3期随机临床试验。如果成功，这种疗法也可以用于治疗鳞癌和其他上呼吸道恶性肿瘤，如肺和食道。

DESCRIPTION (provided by applicant): Project Summary/Abstract Head and neck malignancies are a serious problem with ~40,000 new head and neck squamous cell cancers (HNSCC) and 13,000 deaths each year in the US alone. Despite advances in therapy, HNSCC recurrences occur in up to 50% of patients with advanced stage disease. Hence, there is a need for targeted adjuvant therapy, similar to Herceptin(R) in breast cancer and Gleevec(R) in multiple myeloma. The mission of this program announcement is to conduct correlative laboratory studies using tumor specimens collected from a multi-institutional clinical trial to identify new biomarkers that can facilitate predictions of clinical outcomes of therapeutic interventions. The main goal of this proposal is to determine whether the degree of Akt/mTOR pathway biomarker activation in tumor-free surgical margins or adjacent mucosa can predict outcomes in a randomized phase 2 clinical trial assessing the efficacy of mTOR-targeted therapy with everolimus in patients with locally advanced HNSCC. Our long-term objectives are to improve survival and to decrease recurrences and second primaries in HNSCC patients by making it a chronic disease using the mTOR inhibitors as targeted adjuvant therapy. There are no validated markers that predict responsiveness to mTOR-targeted therapy and identifying patients that would benefit from therapy is essential to success of targeted agents. The studies proposed in this application will evaluate if the Akt/mTOR pathway components that are over expressed in over 90% of HNSCC and frequently activated in tumor-free surgical margins correlate with the efficacy of mTOR-targeted therapy. To achieve this goal, tumor tissues and tumor-free surgical margins or adjacent normal mucosa of up to 160 clinical trial patients will be analyzed to determine expression and genetic mutations of the Akt/mTOR pathway. Expression levels and genetic mutations will be correlated with the clinical trial patients' survival and recurrence rate. We will also determine whether changes in serum growth factor levels after everolimus therapy correlate with clinical outcomes and can be used as a surrogate marker of drug activity. These studies can potentially identify markers for selecting head and neck cancer patients who will benefit from mTOR-targeted therapy, which would decrease unnecessary toxicity and healthcare costs. Results from this study will be used for subsequent mTOR inhibitor therapy studies in head and neck cancer patients, including a possible phase 3 randomized clinical trial. If successful this therapy could also be used for treatment of squamous carcinomas of other upper aerodigestive tract malignancies such as lung and esophagus.