Translational Studies and Clinical Pharmacology of New Drugs for Chemoprevention

项目3将测试和临床验证项目1-2中探索的机制和药理策略，这些策略针对Akt-mTOR、AMPK-mTOR和Fyn/RSK途径。皮肤癌发生、生物学和病理生理学的高级临床/翻译研究将有助于降低发病率/死亡率，提供 深入了解角质形成细胞信号，并为其他上皮性癌症提供一个容易获得的全谱致癌的人类模型。该计划项目的总体目标是根除上皮内肿瘤(LEN)，并大幅降低鳞状细胞癌的风险。我们的目标是确定临床、组织病理学、核测量和蛋白质/磷蛋白激活。 与人类皮肤癌发生相关的模式，并开发安全、有效的皮肤癌预防药物。该项目的假设是，局部小分子药物可以调节太阳紫外线诱导的信号级联中的特定靶点，从而导致皮肤日光损伤的衰减或逆转。 目的包括：1)展示和交叉验证在慢性日照下的人体皮肤中激活的信号靶点和信号通路；2)验证小分子抑制剂在临床前研究中所展示的信号通路调节，通过将人体皮肤剧烈地暴露在太阳模拟光下；3)展示 新外用药物应用于人体皮肤的安全性和耐受性；4)证明外用药物对日晒损伤皮肤的生物标志物和表皮靶点的调节作用；5)证明外用药物(特别是药物组合)的临床益处，并进一步验证生物标记物的选择 皮肤癌化学预防试验。开发的目标包括：1)进一步开发光学相干断层成像硬件和鉴别图像分析软件；2)开发一种利用定量核酸酶保护分析直接从固定组织中进行mRNA表达阵列分析的“皮肤芯片”。新的 战略包括使用太阳模拟光而不是分离的UVA或UVB；用于分子网络分析的先进的反相蛋白质微阵列技术；以及使用“0期”临床试验更快地验证药物/靶标。新的局部药物/靶向发现的转化将指导新的个体化治疗 皮肤里的晶状体。这个高度互动和临床转化的研究计划项目专注于在创新的小鼠模型中成功地进行靶向化学预防药物的临床前测试(项目1和2)，然后在高危人群中设计和实施临床试验(项目3)。有关决策树选择过程以及项目与核心之间的互动的详细说明，请参阅资源格式页面。

Project 3 will test and clinically validate mechanisms and pharmacologic strategies explored in Projects 1-2, which target Akt-mTOR, AMPK-mTOR, and Fyn/RSK pathways. Advanced clinical/translational study of skin cancer carcinogenesis, biology, and pathophysiology will help reduce morbidity/ mortality, provide insight into keratinocyte signaling, and provide an easily-accessed human model of full-spectrum carcinogenesis for other epithelial cancers. The overall goal of this Program Project is to eradicate intraepithelial neoplasias (lEN) and substantially reduce the risk of squamous cell carcinoma. Our objectives are to determine clinical, histopathologic, karyometric, and protein/phosphoprotein activation patterns associated with human skin carcinogenesis and to develop safe, active drugs for skin cancer prevention. The hypothesis for this project is that topical small molecule drugs can modulate specific targets in solar UV-induced signaling cascades resulting in attenuation or reversal of skin sun damage. Aims include; 1) To demonstrate and cross-validate signaling targets and pathways activated in chronically sun-exposed human skin; 2) To validate signaling pathway modulation demonstrated by small molecule inhibitors in preclinical studies by acutely exposing human skin to solar simulated light; 3) To demonstrate safety and tolerability of new topical drugs when applied to human skin; 4) To demonstrate biomarker and epidermal target modulation by topical drugs applied to sun-damaged human skin; and 5) To demonstrate clinical benefit of topical drugs (especially drug combinations), and further validate biomarker selection in skin cancer chemoprevention trials. Developmental Aims include: 1) To further develop optical coherence tomography hardware and discriminative image-analysis software; and 2) To develop a "skin chip" for mRNA expression array analysis directly from fixed tissue using a quantitative nuclease protection assay. New strategies include use of solar simulated light instead of fractionated UVA or UVB; advanced reverse-phase protein microarray technology for molecular network analysis; and faster drug/target validation using "Phase 0" clinical trials. Translation of new topical drug/target discoveries will direct new individualized treatment of lEN In the skin. This highly interactive and clinically translational research program project focuses on the successful preclinical testing of targeted chemoprevention agents in Innovative mouse models (Projects 1 and 2) followed by the design and implementation of clinical trials in at-risk human populations (Project 3). Detailed descriptions ofthe decision-tree selection process as well as the interactions between Projects and Cores are found on the Resources Format Page.