(PQA4) Molecularly Targeted Chemoprevention for Preneoplastic Squamous Epithelia

(PQA4) 癌前鳞状上皮的分子靶向化学预防

• 批准号: 8876969
• 负责人: Kenneth Y Tsai
• 金额: $ 47.43万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-10 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8876969
• 关键词: Actinic keratosis; Address; Bioinformatics; Biological Markers; Biology; Biopsy; Cancer Model; Carcinogens; Carcinoma; Cells; Cessation of life; Chemical Engineering; Chemoprevention; Clinic; Clinical; Collaborations; DNA; DNA Sequence Alteration; Data; Dermatology; Dermatopathology; Development; Epidermis; Event; Excision; Gene Expression; Genetic Transcription; Genitourinary system; Genomics; Goals; Grant; Histologic; Human; Incidence; Individual; Intervention; Knowledge; Lesion; Malignant Neoplasms; Measures; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Target; Mus; Mutation; Normal tissue morphology; Nucleic Acids; Organ; Outcome; Papilloma; Patients; Premalignant; Property; RNA; Recording of previous events; Recovery; Risk; Risk Assessment; Sampling; Signal Transduction; Site; Skin; Skin Cancer; Solar Energy; Squamous Epithelium; Squamous cell carcinoma; Stratified Squamous Epithelium; TP53 gene; Technology; Testing; The Sun; Time; Tissues; Tobacco; UV induced; Ultrasonography; Ursidae Family; advanced disease; base; cancer chemoprevention; cancer prevention; cancer risk; chemotherapy; comparative; effective intervention; gastrointestinal; in vivo; innovation; keratinocyte; killings; mRNA Expression; mortality; mouse model; next generation sequencing; novel; prevent; public health relevance; screening; skin squamous cell carcinoma; surfactant; targeted treatment; tumor progression; ultraviolet damage

 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.

 描述（由适用提供）：据估计，预防癌症的工作有可能分别将癌症的发病率和相关死亡率降低超过50％和30％。尽管许多可避免的暴露与癌症有关，但事实证明，有效的干预措施在全球范围内很难实施。筛查继续主要基于临床检查，然后对活检进行组织学评估，然后在存在时去除肿瘤性病变。但是，与晚期疾病不同，有效的分子驱动的干预措施和风险评估对于可能暴露于致癌物或产前肿瘤病变的临床正常时间表不可用。这是因为我们尚未确定从正常组织到肿瘤性病变到侵袭性癌症的关键基因组驱动因素。使用该项目的长期目标 了解主要基因组变化的知识，这些变化推动了早期癌症的进展，以识别和验证新型分子靶标，以进行化学预防和风险评估，从而可以改善癌症肠。在各种器官部位出现的方形细胞癌（SCC）每年在全球造成900,000多人死亡。由于分层的正方形上皮在气道中形成环境障碍，胃肠道 /泌尿生殖道和皮肤，因此大多数是通过致癌暴露（例如烟草和太阳辐射）驱动的。重要的是，先前的结果和我们自己的数据表明，来自不同站点的SCC具有深厚的分子共同点，包括全球基因表达的改变以及TP53，TP63，Notch和Sox2信号传导。皮肤鳞状细胞癌（CUSCC）具有任何人类癌症的最易于访问和临床良好的进展序列，从明显的预制病变，即活化性角化病（AK）到入侵性癌。因此，它是建立的理想模型 SCC的分子靶向癌症化学预防范围。我们的中心假设是，特定的microRNA -MRNA功能对和突变事件是临床上正常的关键特性，但致癌（UV，烟草）暴露的组织是有效的化学预防靶标，因为它们是CUSCC发育的早期驱动因素。为了检验这一假设，我们已经使用了下一代测序来进行既可以访问又常见的临床病理学良好的发展序列。我们的建议在使用（1）匹配的等源性正常皮肤（AK和CUSCC）从患者使用以最小化个体间的可变性时包含了重大创新，（2）用于比较和功能分析的特征性的UV驱动的CUSCC小鼠模型，以进行比较和功能分析；体内。我们的团队包括皮肤病学，皮肤病理学，化学工程，小鼠癌模型，miRNA生物学和生物信息学方面的专业知识。