Multi-institutional trial: adjuvant mTOR targeted therapy

多机构试验：辅助 mTOR 靶向治疗

基本信息

批准号：
8504714
负责人：
CHERIE-ANN O NATHAN
金额：
$ 20.03万
依托单位：
LOUISIANA STATE UNIV HSC SHREVEPORT
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8504714
关键词：
AKT1 gene AKT2 gene Address Adjuvant Adjuvant Study Adjuvant Therapy Animals Antibodies Apoptosis Biological Markers Blood Vessels Cancer Patient Cancer cell line Cervical lymph node group Cessation of life Chicago Chronic Disease Clinical Clinical Trials Coculture Techniques Collaborations Correlative Study Critiques Cytokeratin Data Disease Disease model Endothelial Cells Enzyme-Linked Immunosorbent Assay Epithelial Epithelial Cells Esophagus Fibroblast Growth Factor 2 Funding Gene Mutation Genetic Gleevec Goals Grant Growth Factor Head and Neck Cancer Head and neck structure Health Care Costs Histologic Human Impairment In Situ Nick-End Labeling In Vitro Incidence Laboratory Study Lung Lymphangiogenesis Lymphatic Lymphatic Spread Lymphovascular Malignant Neoplasms Malignant Squamous Cell Neoplasm Measures Mediating Medical Mission Modeling Mucous Membrane Multi-Institutional Clinical Trial Multiple Myeloma NIH Program Announcements Neoadjuvant Therapy Neoplasm Metastasis Nodal Operative Surgical Procedures Outcome PECAM1 gene PIK3CA gene PTEN gene Pathway interactions Patients Pharmaceutical Preparations Phase Phase II Clinical Trials Placebos Progression-Free Survivals Publishing Randomized Randomized Clinical Trials Recurrence Relative (related person)Residual Neoplasm Resistance Risk Roche brand of trastuzumab SDZ RAD Serum Sirolimus Specimen Squamous cell carcinoma Staging Staining method Stains Surgical margins Surrogate Markers Survival Rate Testing Therapeutic Intervention Time Tissues Toxic effect Tumor Tissue United States National Institutes of Health Universities Vascular Endothelial Growth Factor C Vascular Endothelial Growth Factor D Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factor Receptor-3 Vascular Endothelial Growth Factors Western Blotting Xenograft Model abstracting base cancer recurrence chemoradiation cost functional disability head and neck cancer patient high risk human FRAP1 protein improved in vivo Model lymph nodes mTOR Inhibitor malignant breast neoplasm neoplastic cell novel overexpression pre-clinical preclinical study prognostic response success tumor vector

项目摘要

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.

描述（由申请人提供）：项目摘要/摘要头颈恶性肿瘤是一个严重的问题，仅在美国每年就有约 40,000 例新发头颈鳞状细胞癌 (HNSCC) 和 13,000 例死亡。尽管治疗取得了进展，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，类似于乳腺癌中的赫赛汀(R)和多发性骨髓瘤中的格列卫(R)。该计划公告的使命是使用从多机构临床试验中收集的肿瘤标本进行相关实验室研究，以确定可以促进治疗干预临床结果预测的新生物标志物。该提案的主要目标是确定无肿瘤手术切缘或邻近粘膜中 Akt/mTOR 通路生物标志物的激活程度是否可以预测随机 2 期临床试验的结果，该试验评估依维莫司的 mTOR 靶向治疗对患者的疗效拥有当地先进的 HNSCC。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其成为一种慢性疾病，从而提高 HNSCC 患者的生存率并减少复发和二次原发。目前还没有经过验证的标记物可以预测 mTOR 靶向治疗的反应性，并且识别将从治疗中受益的患者对于靶向药物的成功至关重要。本申请中提出的研究将评估在超过 90% 的 HNSCC 中过度表达并在无肿瘤手术切缘中频繁激活的 Akt/mTOR 通路成分是否与 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瘤手术切缘或邻近正常粘膜进行分析，以确定 Akt/mTOR 通路的表达和基因突变。表达水平和基因突变将与临床试验患者的生存率和复发率相关。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，并可用作药物活性的替代标志物。这些研究有可能确定标记物，用于选择将从 mTOR 靶向治疗中受益的头颈癌患者，这将减少不必要的毒性和医疗费用。这项研究的结果将用于后续头颈癌患者的 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，该疗法还可用于治疗其他上呼吸消化道恶性肿瘤（例如肺癌和食道）的鳞状癌。