Development of a companion diagnostic to predict response to cetuximab in patients with head and neck squamous cell carcinoma

开发伴随诊断来预测头颈鳞状细胞癌患者对西妥昔单抗的反应

• 批准号: 9465203
• 负责人: Greg Bertenshaw
• 金额: $ 29.93万
• 依托单位: BIOMARKER STRATEGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-22 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9465203
• 关键词: Accounting; Adverse reactions; Biological; Biological Markers; Biopsy; Cancer Etiology; Cancer Patient; Cardiopulmonary Arrest; Cell Line; Cells; Cetuximab; Classification; Clinical; Collection; Complex; Conditioned Reflex; Decision Making; Development; Diagnosis; Diagnostic tests; Disease; Dose; Embolism; Epidermal Growth Factor Receptor; Exposure to; FDA approved; Feasibility Studies; Functional disorder; Future; Genetic; Goals; Head and Neck Squamous Cell Carcinoma; Histologic; Human; Human Papillomavirus; Immunotherapy; In Vitro; Individual; Interruption; Kidney Failure; Lung; Lung diseases; MAP Kinase Gene; Malignant Neoplasms; Measures; Medical Oncologist; Methods; Modeling; Molecular; Molecular Target; Monoclonal Antibodies; Oncogenic; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phosphoproteins; Platinum; Predictive Value; Process; Proteins; Radiation; Reagent; Research; Resistance; Risk; Sample Size; Sampling; Sepsis; Signal Transduction; Signal Transduction Pathway; Solid Neoplasm; Standardization; Technology; Testing; Therapeutic; Time; Xenograft Model; Xenograft procedure; actionable mutation; base; clinically actionable; clinically relevant; companion diagnostics; cost; disease classification; drug testing; high risk; improved; indexing; instrument; mortality; neoplastic cell; outcome forecast; outcome prediction; predict clinical outcome; predicting response; predictive marker; receptor binding; response; sample collection; targeted agent; therapy outcome; tissue processing; tumor

ABSTRACT Head and neck squamous cell carcinoma (HNSCC) is the world’s 6th leading cause of cancer, accounting for 5% of cancer mortality. For many other cancers, molecular characterization has led to sub-classification of disease based on the status of oncogenic drivers in signal transduction pathways, leading to the development of molecularly-targeted agents (MTAs), targeting specific dysregulated proteins in these pathways. HNSCC genetics are highly complex with no clinically actionable mutations or classification beyond HPV-positive and HPV-negative tumors. Classification to improve therapeutic decision-making is needed for HNSCC. Cetuximab (CTX), an epidermal growth factor receptor (EGFR)-binding monoclonal antibody (mAb), is FDA- approved for HNSCC as a monotherapy or combined with radiation or platinum-based therapy. Though having a substantial clinical impact in a small proportion (~13%) of patients, treatment with CTX is associated with serious adverse reactions, resulting in interrupted therapy in 3-10% of patients. Due to this high risk, along with a high cost and the low response rate, a companion diagnostic (CDx) to identify patients most likely to respond to CTX is urgently required. We propose to develop a live tumor cell based CDx to guide the identification of CTX-responsive patients based on tumor ex vivo functional responses which are predictive of clinical outcomes. Since traditional tissue processing strips tumor cells of their biological integrity it is only suitable for histologic review, not allowing analysis of dynamic biomarkers. BioMarker Strategies is developing the SnapPath® Process and Pathology Multi Analyte Profiles (PathMAP®) technologies for live tissue processing of solid tumors using a single-use cartridge, which holds the sample and all the necessary reagents and consumables, automating and standardizing tumor processing and treatment to enable highly predictive and standardized tests. The tumor cells' responses are scored against PathMAP, a locked classification model. PathMAP tests can help guide medical oncologists in their treatment decisions for cancer patients. The proposed CDx will measure the pharmacodynamic response upon exposure to CTX of specific phosphoproteins in MAPK, JAK/STAT, and PI3K pathways, the key pathways in HNSCC pathophysiology. We propose to: 1) Optimize Conditions and Response Profile to Predict CTX Sensitivity to detect strong pharmacodynamic responses in sensitive cells and minimal responses in resistant cells; 2) Evoke Functional Signaling Profiles (FSP) Against CTX in Complex Samples by first using clinically- relevant patient derived xenograft (PDX) samples and then human clinical samples. The proposed research will serve as a feasibility study determining percent suppression cut-off values for predictive biomarkers and confirming operationalization of the test in complex samples. It will also determine the sample size for a future larger multisite sample collection in Phase II.

摘要 头颈部鳞状细胞癌（HNSCC）是世界上第六大癌症病因，占 5%的癌症死亡率。对于许多其他癌症，分子表征已经导致了以下分类： 疾病的基础上的状态致癌驱动程序的信号转导途径，导致发展 分子靶向药物（MTA），靶向这些途径中的特定失调蛋白。HNSCC 遗传学是高度复杂的，没有临床上可操作的突变或HPV阳性以外的分类， HPV阴性肿瘤。HNSCC需要分类以改善治疗决策。 西妥昔单抗（CTX）是一种表皮生长因子受体（EGFR）结合单克隆抗体（mAb），是FDA- 批准作为单一疗法或与放射或铂类治疗联合用于HNSCC。虽然具有 在一小部分（约13%）患者中具有实质性临床影响，CTX治疗与 严重不良反应，导致3-10%的患者中断治疗。由于这种高风险，沿着 高成本和低反应率，伴随诊断（CDx），以确定最有可能反应的患者 CTX是迫切需要的。 我们建议开发一种基于活肿瘤细胞的CDx，以指导对CTX敏感的肿瘤细胞的鉴定。 基于肿瘤离体功能反应的患者，其可预测临床结果。 由于传统的组织处理剥夺了肿瘤细胞的生物完整性，因此其仅适用于组织学检查。 审查，不允许分析动态生物标志物。BioMarker Strategies正在开发SnapPath® 用于固体活组织处理的过程和病理学多分析物图谱（PathMAP®）技术 肿瘤使用一次性使用的盒，其中包含样品和所有必要的试剂和消耗品， 自动化和标准化肿瘤处理和治疗， 试验.肿瘤细胞的反应根据锁定分类模型PathMAP进行评分。PathMAP测试 可以帮助指导医学肿瘤学家为癌症患者做出治疗决策。建议的CDx将 测量暴露于CTX后MAPK中特异性磷蛋白的药效学反应， JAK/STAT和PI 3 K通路是HNSCC病理生理学中的关键通路。我们建议： 1)优化条件和响应曲线以预测CTX敏感性以检测强药效学 敏感细胞中的反应和抗性细胞中的最小反应; 2)在复杂样品中通过首先使用临床- 相关患者来源的异种移植物（PDX）样品，然后是人临床样品。 拟议的研究将作为一个可行性研究，确定百分比抑制截止值， 预测性生物标志物和确认测试在复杂样品中的可操作性。它也将决定 在第二阶段，未来更大规模的多中心样本采集的样本量。