Drug Discovery, Delivery, and Translational Therapeutics Research Program

项目总结/摘要 Markey癌症中心的药物发现，交付和转化治疗（DT）计划 (MCC)在科学上专注于识别新的目标和生物标志物，并发现和开发 针对这些生物标志物的新药。MCC集水区人口既有高癌症风险， 与过度接触致癌物以及由于地理原因而缺乏尖端临床试验有关 孤立和社会经济地位低下。DT计划的愿景是了解独特的分子和 肯塔基州的癌症表型标记以及获得护理和整合这些知识的障碍 为药物发现、开发和早期临床试验的交付提供信息， 阿巴拉契亚肯塔基州人口。MCC研究人员是生物标志物发现的国际领导者（主题 1)正在进行的转化研究，包括600多名参与者，评估环境的作用， 致癌物和识别肺癌的生物标志物。DT制药科学家致力于发现和 开发针对已识别突变和表型的新型抗癌药物（主题2），与 癌症细胞生物学和信号传导（CS）和基因组不稳定性，表观遗传学和代谢（GEM）程序 成员例如，一种新的4 E-BP 1磷酸化调节剂，一种经验证的结肠癌靶点， 从阿巴拉契亚天然产品储存库中识别出来。DT研究人员领导的临床试验侧重于 与集水区相关的癌症（主题3），并招募了500多名患者， 卵巢介入治疗和诊断试验。他们经常与癌症预防合作， 控制（CP），CS和GEM计划成员，以告知和推进MCC基础科学，例如， 将CS中PAR-4抗癌活性的早期鉴定转化为关注PAR-4的临床试验， 促分泌素DT是一个由来自6所学院和18个部门的47名调查人员组成的跨学科项目， 共同开发新的抗癌疗法，并将这些疗法转化为临床。这 生产性计划每年的外部癌症相关资金总额为850万美元（每年直接成本为590万美元， 其中28%来自NCI）。成员在本资助期内出版了366份出版物，其中99份（27%） 其中84个（23%）为方案内，189个（52%）为机构间。的DT 项目共同负责人Jill Kolesar博士和Jon Thorson博士长期合作， 在生物标志物发现、药物开发和早期临床试验方面的互补专业知识。两个直接键 支持DT计划的资源，MCC精准医学中心和英国中心 医药创新，分别。每位领导者都带来了关键优势，包括地方、国家和 国际合作，企业关系，并积极参与NCI倡议。采取 DT项目拥有一个团结协作的团队，将新的生物标志物转化为靶点 用于有效的抗癌治疗。

PROJECT SUMMARY/ABSTRACT The Drug Discovery, Delivery and Translational Therapeutics (DT) Program at the Markey Cancer Center (MCC) is scientifically focused on identifying novel targets and biomarkers and discovering and developing new drugs targeting these biomarkers. The MCC catchment area population has both a high cancer risk related to excessive carcinogen exposure and lack of access to cutting-edge clinical trials due to geographical isolation and poor socioeconomic status. The DT program vision is to understand the unique molecular and phenotypic markers of cancer in Kentucky as well as barriers to accessing care and integrate that knowledge to inform drug discovery, development, and delivery of early phase clinical trial efforts for a hard-to-reach Appalachian Kentucky population. MCC investigators are international leaders in biomarker discovery (Theme 1) with ongoing translational studies including more than 600 participants, evaluating the role of environmental carcinogens and identifying biomarkers of lung cancer. DT pharmaceutical scientists work to discover and develop new anticancer agents targeting identified mutations and phenotypes (Theme 2), partnering with Cancer Cell Biology and Signaling (CS) and Genomic Instability, Epigenetics, and Metabolism (GEM) program members. For example, a novel modulator of 4E-BP1 phosphorylation, a validated colon cancer target, was identified from the Appalachian natural products repository. DT investigators lead clinical trials focusing on cancers relevant to the catchment area (Theme 3) and have enrolled more than 500 patients to lung, colon and ovarian interventional treatment and diagnostic trials. They regularly partner with Cancer Prevention and Control (CP), CS and GEM program members to inform and advance MCC basic science, for example, translating early identification of the anticancer activity of PAR-4 in CS to clinical trials focused on a PAR-4 secratagogue. DT is a cross-disciplinary program of 47 investigators from 6 colleges and 18 departments who work together to develop novel anticancer therapies and translate these therapies into the clinic. This productive program has total annual external cancer-related funding of $8.5M ($5.9M annual direct costs, of which 28% is from the NCI). Members published 366 publications over the current funding period, 99 (27%) of which are inter-programmatic, 84 (23%) are intra-programmatic, and 189 (52%) are inter-institutional. The DT program Co-leaders, Drs. Jill Kolesar and Jon Thorson, have a long-standing collaboration and bring complementary expertise in biomarker discovery, drug development, and early clinical trials. Both direct key resources supporting the DT program, the MCC Precision Medicine Center and the UK Center for Pharmaceutical Innovation, respectively. Each leader brings critical strengths including local, national and international collaborations, entrepreneurial relationships, and active participation in NCI initiatives. Taken together, the DT program has a cohesive and collaborative team that translates novel biomarkers into targets for effective anticancer treatments.