Microenvironmental impact on HNSCC response to targeted therapy

描述(申请人提供)：目前只有一种获得批准的分子靶向治疗HNSCC：抑制酪氨酸激酶受体，EGFR。然而，抑制EGFR只对一小部分患者有好处，而且没有可靠的反应预测因素。 我们研究的基本假设是，在复杂的体外工程微环境(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；ii)允许开发准确的和临床上可操作的靶向治疗药物应答预测指标，以指导选择可能从靶向治疗中受益的患者。作为原则的证明，我们将根据两个目的，重点关注EGF和PI3K/AKT/TORC1，2途径的抑制剂。首先，我们的目标是定义影响个体患者肿瘤细胞生长和靶向治疗反应的间质成分。我们将确定MEMA中支持HNSCC患者肿瘤细胞黏附和生长的底物和可溶性因子组合，测试对EGFR和PI3K/AKT/TORC1，2抑制剂的反应，并验证ME条件下对患者反应影响最大(积极或消极)的患者细胞中抑制剂的预测目标。结果可能揭示有利于或禁止患者使用所测试的抑制剂进行治疗的因素，并为未来的治疗发展提供策略建议。其次，我们的目标是为分子靶向治疗反应开发可预测的HNSCC信号。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到40名患者的结果将被用于开发预测性测试，考虑到间质依赖/独立的肿瘤特性，将患者分层到特别可能使他们受益的药物的临床试验。这些将包括HNSCC特定的微环境微阵列，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的肿瘤标本的(Epi)反应的遗传特征(例如，DNA序列变化、RNA表达和已验证的目标基因途径中的蛋白质激活变化)。我们以患者为中心的科学家和HNSCC医生团队将加快我们的结果的转换，以“实时”指导个别HNSCC患者的治疗，同时开发更广泛适用于活检标本的方案。公共卫生的好处是有可能改变HNSCC患者的护理标准，他们现在面临的5年存活率只有50%，在过去40年里没有变化。HNSCC中活细胞和/或分子反应预测指标原理的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。

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.