(PQA4) Molecularly Targeted Chemoprevention for Preneoplastic Squamous Epithelia

 描述(申请人提供)：据估计，癌症预防工作有可能将癌症发病率和癌症相关死亡率分别降低50%和30%以上。尽管许多可避免的接触在病因学上与癌症有关，但事实证明，有效的干预措施很难在全球范围内实施。筛查仍然主要基于临床检查，其次是活检的组织学评估，如果存在癌前病变，可能会随后切除它们。然而，与晚期疾病不同，有效的分子驱动干预和风险评估不适用于可能暴露于致癌物或癌前病变的临床正常组织。这是因为我们还没有确定从正常组织到癌前病变再到浸润性癌进展的关键基因组驱动因素。该项目长期目标是使用 了解推动癌症早期进展的关键基因组变化，以确定和验证用于化学预防和风险评估的新分子靶点，从而降低癌症发病率。鳞状细胞癌(SCC)发生在不同的器官部位，每年导致全球90多万人死亡。由于复层鳞状上皮在呼吸道、胃肠道/泌尿生殖道和皮肤中形成环境屏障，大多数是由烟草和太阳辐射等致癌暴露驱动的。重要的是，先前的结果和我们自己的数据表明，来自不同位点的SCC具有深刻的分子共性，包括全球基因表达和TP53、TP63、Noch和SOX2信号的变化。皮肤鳞状细胞癌(CuSCC)是人类所有癌症中最易发生且临床特征最明确的一种，从一种独特的癌前病变，光化性角化病(AK)，到浸润性癌。因此，它是一种理想的建立模型 针对鳞癌的分子靶向癌症化学预防范例。我们的中心假设是，特定的microRNA-mRNA功能对和突变事件是临床正常但致癌物(紫外线、烟草)暴露的组织的关键特性，这些是有效的化学预防靶点，因为它们是CuSCC发生的早期驱动因素。为了验证这一假设，我们使用了下一代测序来对临床病理上定义明确的发育序列进行测试，该序列既可访问又常见。我们的建议在使用(1)来自患者的匹配的等基因正常皮肤、AK和CuSCC以最大限度地减少个体间差异方面具有重大创新，(2)用于比较和功能分析的具有良好特性的紫外线驱动的CuSCC小鼠模型，(3)跨物种基因组分析，以及(4)一种新的基于表面活性物质的非侵入性皮肤采样技术，以测量体内RNA表达和DNA突变。我们的团队包括皮肤科、皮肤病理学、化学工程学、小鼠癌症模型、miRNA生物学和生物信息学方面的专业知识。

 DESCRIPTION (provided by applicant): It is estimated that cancer prevention efforts have the potential to reduce cancer incidence and cancer- related mortality by over 50% and 30% percent, respectively. Although many avoidable exposures are etiologically related to cancer, effective interventions have proven difficult to implement globally. Screening continues to be based primarily on clinical examination followed by histologic assessment of biopsies, perhaps followed by removal of preneoplastic lesions when they exist. However, unlike for advanced disease, effective molecularly driven interventions and risk assessment are not available for clinically normal tissues that may be have been exposed to carcinogens or for preneoplastic lesions. This is because we have not identified the key genomic drivers of progression from normal tissue to preneoplastic lesion to invasive cancer. The long-term goal of this project is use knowledge of key genomic changes that drive early cancer progression to identify and validate novel molecular targets for chemoprevention and risk assessment so that cancer incidences may be decreased. Squamous cell carcinomas (SCC) arising in various organ sites cause over 900,000 deaths worldwide annually. Because stratified squamous epithelia form environmental barriers in the airways, gastrointestinal / genitourinary tracts, and skin, the majority are drivenby carcinogenic exposures such as tobacco and solar radiation. Importantly, previous results and our own data show that SCCs from diverse sites share deep molecular commonalities including alterations in global gene expression and in TP53, TP63, NOTCH, and SOX2 signaling. Cutaneous squamous cell carcinoma (cuSCC) has the most accessible and clinically well-characterized progression sequence of any human cancer, from a distinct precancerous lesion, the actinic keratosis (AK), to invasive carcinoma. Therefore, it is an ideal model for establishing a paradigm of molecularly targeted cancer chemoprevention for SCC. Our central hypothesis is that specific microRNA-mRNA functional pairs and mutational events are key properties of clinically normal, but carcinogen (UV, tobacco) -exposed tissue, and that these are effective chemoprevention targets because they are early drivers of cuSCC development. To test this hypothesis, we have used next generation sequencing to bear on a clinic-pathologically well-defined development sequence that is both accessible and common. Our proposal contains significant innovation in its use of (1) matched isogenic normal skin, AK, and cuSCC from patients to minimize inter-individual variability, (2) a well- characterized UV-driven cuSCC mouse model for comparative and functional analysis, (3) cross-species genomic analysis, and (4) a novel surfactant-based non-invasive skin sampling technology to measure RNA expression and DNA mutations in-vivo. Our team includes expertise in dermatology, dermatopathology, chemical engineering, mouse cancer models, miRNA biology, and bioinformatics.