MicroRNA marker-based prognosis of oral cancer survival

描述(申请人提供)：全球每年估计有40万人被诊断为口腔鳞状细胞癌(OSCC)，其中包括3万美国人。5年存活率只有50%左右，在美国每小时就有1人死亡。手术切除肿瘤后，辅助治疗的选择在很大程度上取决于肿瘤的临床分期。然而，尽管在治疗方面取得了进步，但在过去的几十年里，存活率并没有显著提高。发现一种策略，以识别预后不良的癌症患者，并有选择地指导这些患者进行额外的辅助化疗/放射治疗，将显著提高癌症存活率。因此，寻找可靠、准确的口腔癌生存预后指标，应用于口腔癌的治疗决策过程，提高口腔癌患者的总体生存率势在必行。这项拟议的研究的目的是开发和验证一种基于microRNA(MiR)标记的口腔癌生存预后模式(5年无病生存与5年内死亡)。那些仅通过手术预后较差的患者可能会被指导进行额外的治疗。在研究的初始阶段，我们建议通过下一代测序对10个口腔鳞状细胞癌组织样本进行全基因组miR表达评估(组1)，这些样本来自5年内无病生存的患者(组1)，而年龄和性别匹配的癌症患者(组2)在5年内死于这种疾病的患者中有10个样本。将进行生物信息学分析，整合测序数据，以确定miR靶基因和miR介导的致癌网络和途径。在AIM 1中，选择最有可能识别预后不良且具有较高敏感性和特异度的MIR候选标记组，然后在AIM 2中，利用RT-qPCR对另外40对组1-组2中的候选标记组进行验证。提出的创新方法以前从未被应用于口腔癌生存的预后；它提供了可扩展性和成本控制，同时允许使用一种不可知性的方法来发现整个基因组的分子变化，然后进行独立验证。培养能够将基础科学转化为可操作的临床信息和方法的新一代牙科科学家是进步的当务之急。NIDCR针对新研究人员的小额资助计划(R03)提案描述了一项为期两年的研究计划，旨在发展口腔鳞癌分子管理方面的高度专业化专业知识。拟议的研究将作为候选人的平台，以发展和微调以患者为导向的研究的实践经验和技能，在口腔癌症研究领域建立独立性，获得可能在不久的将来用于支持R01应用的初步数据，并扩大口腔致癌领域，以更好地了解这种致命疾病。通过这项针对新研究人员的R03计划，候选人将实现她的长期目标，即成为一名拥有口腔癌管理专业知识的独立调查人员。

DESCRIPTION (provided by applicant): Each year an estimated 400,000 people globally, among them 30,000 Americans, are newly diagnosed with oral squamous cell carcinoma (OSCC). The 5-year survival rate is only about 50%, accounting for 1 death every hour in the US. Following the surgical removal of tumor, selection of adjuvant treatment is made largely based on the clinical stage of the tumor. However, despite the advances in treatment, survival rate has not improved significantly over the last several decades. Discovery of a strategy to identify cancer patients with poor prognosis and selectively directing those patients for additional adjuvant chemo/radiation therapy will significantly improve the cancer survival rate. Hence, it is imperative to discover a reliable and accurate prognostic indicator of oral cancer survival to be applied in the treatment decision making process and improve the overall survival of patients with oral cancer. The aim of the proposed study is to develop and validate a microRNA (miR) marker-based prognostic modality for oral cancer survival (5-year disease free survival versus death within 5-years). Those with less favorable prognosis with surgery alone may then be directed for additional treatment. In the initial phase of the study, we propose to perform a genome-wide miR expression assessment via next generation sequencing in 10 OSCC tissue samples from patients who had 5-year disease-free survival (Group 1), compared with 10 of those from age- and gender-matched cancer patients who died of the disease within 5 years (Group 2). Bioinformatics analysis will be performed to integrate sequencing data to identify miR target genes and miR-mediated oncogenic network and pathways. Top miR candidates that can identify those patients with poor prognosis with high sensitivity and specificity will be selected to form a prognostic miR marker panel in Aim 1. The candidate marker panel will then be validated in Aim 2 in additional 40 Group 1-Group 2 pairs using RT-qPCR. The proposed innovative approach has never been applied for prognosis of oral cancer survival before; it offers scalability and cost containment while allowing an agnostic approach to discovery of molecular changes across the genome that is followed by independent validation. Developing a new generation of dental scientists able to translate basic science into actionable clinical information and methods is imperative to progress. This NIDCR Small Grant Program for New Investigators (R03) proposal describes a 2-year research program aimed at developing highly specialized expertise in the molecular management of OSCC. The proposed study will serve as the candidate's platform to develop and fine-tune practical experience and skills in patient-oriented research, to establish independence in the area of oral cancer research, obtain preliminary data that may be used in the near future to support R01 applications and to expand the field of oral carcinogenesis towards a better understanding of this deadly disease. Through this R03 program for the new investigators, the candidate will reach her long-term goal of becoming an independent investigator with expertise in the management of oral cancer.