Microenvironmental impact on HNSCC response to targeted therapy

微环境对 HNSCC 靶向治疗反应的影响

• 批准号: 8598746
• 负责人: MOLLY F. KULESZ-MARTIN
• 金额: $ 20.1万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-09 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598746
• 关键词: Accounting; Adhesions; Affect; Animal Model; Antibodies; Biomedical Engineering; Biopsy Specimen; Caring; Caspase; Cell Count; Cell Culture Techniques; Cell Survival; Cells; Cessation of life; Cetuximab; Characteristics; Cleaved cell; Clinical Trials; Complex; Cryopreserved Cell; DNA Sequence; Defect; Development; EGF gene; EGFR inhibition; Elements; Engineering; Environment; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epithelial Cells; Extracellular Matrix; Face; Feedback; Future; Gene Targeting; Genetic; Genetic Transcription; Growth; Head and Neck Squamous Cell Carcinoma; Health Benefit; In Situ Hybridization; In Vitro; Individual; Inflammatory; Life; MAP2K1 gene; Malignant Epithelial Cell; Malignant Neoplasms; Molecular; Molecular Target; Monitor; Neoplasm Metastasis; Newly Diagnosed; Oncogenic; Oral cavity; Oropharyngeal; PI3K/AKT; Pathway interactions; Patient Selection; Patients; Phase; Physicians; Property; Protein Array; Proteins; Proto-Oncogene Proteins c-akt; Protocols documentation; Public Health; RNA; RNA analysis; Resistance; Sampling; Scientist; Signal Transduction; Site; Solid Neoplasm; Specimen; Stratification; Survival Rate; Testing; Therapeutic Agents; Time; Tonsil; Translations; Tumor Biology; Tumor Cell Biology; Tumor Tissue; Tyrosine Kinase Receptor Inhibition; United States; Validation; cell growth; cellular engineering; cytokine; design; genetic analysis; in vivo; inhibitor/antagonist; neoplastic cell; patient oriented; prospective; protein activation; public health relevance; response; standard of care; therapeutic development; therapeutic target; tongue root; tumor; tumor growth; tumor microenvironment

DESCRIPTION (provided by applicant): There is currently only one approved molecular targeted HNSCC therapy: inhibition of the tyrosine kinase receptor, EGFR. However, EGFR inhibition benefits only a fraction of patients, and there are no reliable predictors of response. The underlying hypotheses of our study are that patient tumor cells grown on complex engineered in vitro microenvironment (ME) microarrays (MEMA) will: i) sufficiently mimic the tumor cell microenvironment in vivo to ii) allow for the development of accurate and clinically actionable predictors of response to targeted therapeutic agents to guide selection of patients likely to benefit from targeted therapy. As proof of principle, we will focus on inhibitors of EGF and PI3K/AKT/TORC1,2 pathways, according to two aims. First we aim to define stromal elements that impact individual patient tumor cell growth and response to targeted therapy. We will determine substratum and soluble factor combinations in MEMA that support adhesion and growth of HNSCC patient tumor cells, test response to inhibitors of EGFR and PI3K/AKT/TORC1,2, and validate predicted targets of inhibitors in patients' cells under ME conditions that show the highest (positive or negative) impact on patient responses. The results may uncover factors that favor or contraindicate treatment of a patient with the tested inhibitor, and suggest strategies for future therapeutic development. Secondly we aim to develop predictive HNSCC signatures for molecular targeted therapy response. We will evaluate the relevance of selected proteins on MEMA to original tumor biology. Results of 20 to 40 patients will be used to develop predictive tests, taking into account stromal dependent/independent tumor properties for stratification of patients to clinical trials of agents specifically likely tobenefit them. These will include HNSCC-specific microenvironment microarrays for prospective analysis of each HNSCC patient's viable tumor cells to determine response to inhibitors and for (epi)genetic signatures of response potentially applicable to uncultured tumor specimens (e.g., DNA sequence changes, RNA expression, and protein activation changes in validated target gene pathways). Our patient-centered team of scientists and HNSCC physicians will accelerate translation of our results for guiding treatment of individual HNSCC patients in "real- time", whil developing protocols applicable more broadly to biopsy specimens. The public health benefit is the potential to change standards of care for HNSCC patients, who now face only a 50% 5-year survival rate, unchanged over the last four decades. Proof of principle of viable cell and/or molecular predictors of response in HNSCC also has the potential for broader impact on other cancers with similar signaling network defects.

描述（由申请人提供）：目前仅有一种获批的HNSCC分子靶向治疗：抑制酪氨酸激酶受体EGFR。 然而，EGFR抑制仅使一小部分患者受益，并且没有可靠的反应预测因子。 我们研究的基本假设是，在复杂的工程化体外微环境（ME）微阵列（MEMA）上生长的患者肿瘤细胞将：i）充分模拟体内肿瘤细胞微环境，以ii）允许开发对靶向治疗剂的响应的准确且临床上可操作的预测因子，以指导可能受益于靶向治疗的患者的选择。 作为原理的证明，我们将根据两个目标专注于EGF和PI 3 K/AKT/TORC 1，2通路的抑制剂。 首先，我们的目标是定义基质元素，影响个体患者肿瘤细胞的生长和对靶向治疗的反应。 我们将确定MEMA中支持HNSCC患者肿瘤细胞粘附和生长的基质和可溶性因子组合，测试对EGFR和PI 3 K/AKT/TORC抑制剂的反应1，2，并验证在ME条件下患者细胞中抑制剂的预测靶点，这些条件对患者反应的影响最大（阳性或阴性）。 这些结果可能会揭示有利于或禁忌用测试抑制剂治疗患者的因素，并为未来的治疗开发提出策略。 其次，我们的目标是开发用于分子靶向治疗反应的预测性HNSCC特征。 我们将评估MEMA上选定的蛋白质与原始肿瘤生物学的相关性。 20 - 40例患者的结果将用于开发预测测试，考虑到基质依赖性/非依赖性肿瘤特性，用于将患者分层到可能特别有益于他们的药物的临床试验。 这些将包括HNSCC特异性微环境微阵列，用于对每个HNSCC患者的活肿瘤细胞进行前瞻性分析，以确定对抑制剂的反应，以及可能适用于未培养肿瘤标本的反应的（epi）遗传特征（例如，验证的靶基因途径中的DNA序列变化、RNA表达和蛋白质活化变化）。 我们以患者为中心的科学家和HNSCC医生团队将加速我们的结果的转化，以指导“真实的”治疗个体HNSCC患者，同时开发更广泛适用于活检标本的方案。 公共卫生福利是改变HNSCC患者护理标准的潜力，HNSCC患者现在面临的5年生存率只有50%，在过去四十年中没有变化。 HNSCC中活细胞和/或反应分子预测因子的原理证明也有可能对具有类似信号网络缺陷的其他癌症产生更广泛的影响。