Functional characterization of salivary gland cancers and development of patient

2012年，美国唾液腺癌(SGC)的发病率估计为预期的5-6% 40,250例头颈部癌症，发病率为0.9/10万。尽管总体上很少见，但在 SGC是一种毁灭性的疾病，因为大多数原发肿瘤在10年内复发， 都是致命的，而传统的化疗提供了暂时的好处。特别是，缺乏 用于临床前药物测试和探索导致SGC的分子事件的模型已经瘫痪 这一致命疾病的研究进展。本研究的主要目标是开发SGC的临床前平台， 并阐明SGC的分子发病机制，主要目的是为 重点开展靶向治疗。为了实现第一个目标，我们将开发一种人在老鼠中 SGC异种移植平台。在小鼠体内植入肿瘤可以产生大量的肿瘤 便于进行复杂测试的组织，在小的原始人类样本中是不可能的。肿瘤是 在小鼠身上保持活着，以产生用于描述SGC分子损伤的组织，并 验证异种移植模型是否忠实地保留了原始肿瘤的特征。我们希望 开发一个尽可能靠近临床的体内平台，使未来的药物开发和 生物标志物的发现。为了实现第二个目标，我们提出了一个详细的初级 肿瘤和异种移植，辅助系统生物学综合分析。我们的方法将结合静态 利用功能性遗传筛选进行遗传事件分析、转录组分析和磷蛋白质组分析 使用慢病毒为基础的短发夹状RNA(ShRNA)文库，以识别 肿瘤存活率。总而言之，这种多层次的特征将确定未来治疗的功能途径 靶向，产生关于唾液腺癌发病机制的新假说，并促进 用来检验这些假说的体内模型的未来发展。 )

In 2012 the estimated incidence of salivary gland cancers (SGC) in the USA was 5-6% of the expected 40,250 head and neck cancers, representing an incidence of 0.9 per 100,000. Although rare overall, in the patient population affected, SGC is a devastating disease as most primary tumors return within 10 years and are uniformly fatal, and conventional chemotherapy provides transient, if any, benefit. In particular, the lack of models for preclinical drug testing and for exploration of the molecular events leading to SGC has crippled progress on this deadly disease. The primary goals of this study are to develop a preclinical platform of SGC, and to elucidate the molecular pathogenesis of SGC, with the overarching goal of providing a rationale for focused development of targeted treatments. To achieve the first goal, we will develop a human-in-mouse SGC xenograft platform. Implanting tumors in mice allows the generation of substantial amounts of tumor tissue that facilitates complex testing not possible in the small, original human sample. The tumors are maintained alive on mice to generate tissue for the characterization of molecular lesions in SGC, and to validate the xenografts as models that faithfully maintain the features in the originator tumor. We hope to develop an in vivo platform as close to the clinic as possible that will enable future drug development and biomarker discovery. To achieve the second goal we propose a detailed molecular characterization of primary tumors and xenografts, aided by Systems Biology integrative analyses. Our approach will combine static analysis of genetic events, and transcriptome and phosphoproteome analysis, with functional genetic screens using lentiviral based short-hairpin RNA (shRNA) libraries, to identify of genes and pathways essential for tumor survival. Together, this multi-level characterization will identify functional pathways for future therapeutic targeting, generate new hypotheses regarding the pathogenesis of salivary glands cancer, and promote the future development of in vivo models in which to test these hypotheses. )