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学策略，这些机制和策略针对Akt-mTOR、AMPK-mTOR和Fyn/RSK通路。皮肤癌致癌作用、生物学和病理生理学的高级临床/转化研究将有助于降低发病率/死亡率， 深入了解角质形成细胞信号传导，并为其他上皮癌提供易于获得的全谱致癌作用的人类模型。该计划项目的总体目标是根除上皮内瘤形成（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，核计量学，和蛋白/磷蛋白活化 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，从而减弱或逆转皮肤日光损伤。 目标包括：1）证明和交叉验证在长期暴露于阳光下的人类皮肤中激活的信号传导靶点和途径; 2）通过将人类皮肤急性暴露于太阳模拟光，验证在临床前研究中由小分子抑制剂证明的信号传导途径调节; 3）证明 新的局部药物在应用于人类皮肤时的安全性和耐受性; 4）证明应用于太阳损伤的人类皮肤的局部药物对生物标志物和表皮靶点的调节;和5）证明局部药物（特别是药物组合）的临床益处，并进一步验证生物标志物的选择。 皮肤癌化学预防试验。发展目标包括：1）进一步开发光学相干断层扫描硬件和判别图像分析软件; 2）开发“皮肤芯片”，用于使用定量核酸酶保护测定直接从固定组织进行mRNA表达阵列分析。新 这些策略包括使用太阳模拟光而不是分级UVA或UVB;用于分子网络分析的先进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/靶点发现的转化将指导新的个体化治疗。 在皮肤上。这个高度互动和临床转化的研究计划项目的重点是在创新小鼠模型（项目1和2）中成功进行靶向化学预防剂的临床前测试，然后在高危人群中设计和实施临床试验（项目3）。决策树选择过程的详细描述以及项目和核心之间的交互可以在资源格式页面上找到。

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.