Targets, Modulators and Delivery Program

项目摘要/摘要：目标、调制器和交付计划（TMDP） 目标、调节剂和传递计划（TMDP;以前称为癌症基因）的使命 和分子调控计划）的目的是验证靶点，开发调节癌症靶点的小分子， 并开发将调节剂有效递送至肿瘤细胞的方法。组织TMDP是为了促进 合作，并促进弗雷德和帕梅拉巴菲特癌症中心的科学发现的转化 (BCC)基础研究计划成员，同时提供BCC转化研究计划访问 经验证的靶标、小分子调节剂和用于临床转化的递送方法。TMDP集成了 18名医生-科学家（包括成人和儿童血液学家/肿瘤学家、放射肿瘤学家） 和外科肿瘤学家）和23名具有癌症专业知识的研究者 靶向开发、药物化学、药理学和纳米递送。节目组成员 开发工具和技术，促进基础科学发现从实验室到床边的转化 BCC研究计划中的连续体。TMDP开发的资源用于支持新的化学实体 (NCE)TMDP和BCC中的发现/开发包括合成和药物化学 资源，蛋白质水解靶向嵌合体（PROTAC）合成和计算化学资源。的 TMDP教师的转化研究工作延伸到所有的恶性肿瘤，是至关重要的 对内布拉斯加州人口的重要性，包括肺癌，卵巢癌，多发性骨髓瘤，淋巴瘤， 急性白血病、乳腺癌、胰腺癌和髓母细胞瘤。TMDP教师的研究兴趣 围绕三个互动主题组织-目标验证，小分子调节剂，传递方法 - 这有助于通过内部和内部的bench-to-bedside研究翻译的总体目标， 方案合作。这些主题与TMDP的具体目标相一致，即：1）制定概念性的 和技术方法来验证癌症靶点; 2）识别和表征靶点和机制特异性 针对经验证的癌症靶点的小分子;以及3）探索用于有效递送 小分子或RNAi针对验证的癌症靶点。TMDP中的临床医师科学家 试验专业知识促进了推定靶点、化学调节剂和递送方法的翻译， 治疗潜力TMDP成员之间的互动，他们与其他BCC计划的互动， 他们的机构间合作促进了有影响力的转化研究。这些互动有 导致425万美元（直接）的癌症相关同行评审资金给TMDP研究人员，其中317万来自 NCI在资助期间，TMDP研究者报告了647篇癌症相关出版物（平均 期刊影响因子= 7），方案内占37%，方案间占28%，方案内和方案间均占18%， 方案出版物和41%的机构间出版物。

Project Summary/Abstract: Targets, Modulators, and Delivery Program (TMDP) The mission of the Targets, Modulators, and Delivery Program (TMDP; formerly known as the Cancer Genes and Molecular Regulation Program) is to validate targets, develop small molecules that modulate cancer targets, and develop methods for efficient delivery of modulators to tumor cells. The TMDP is organized to promote collaboration and catalyze the translation of scientific discoveries from Fred & Pamela Buffett Cancer Center (BCC) basic research program members while providing BCC translational research programs access to validated targets, small molecule modulators, and delivery methods for clinical translation. The TMDP integrates the efforts of 18 physician-scientists (including adult and pediatric hematologist/oncologists, radiation oncologists and surgical oncologists) with expertise in clinical trial development and 23 investigators with expertise in cancer target development, medicinal chemistry, pharmacology, and nanodelivery. Together, the program members develop tools and technology to facilitate translation of basic science discoveries by the bench-to-bedside continuum within BCC research programs. Resources developed by the TMDP to support novel chemical entity (NCE) discovery/development within the TMDP and the BCC include the Synthetic and Medicinal Chemistry Resource, PROteolysis Targeting Chimera (PROTAC) synthesis and Computational Chemistry Resource. The translational research efforts of the TMDP faculty extend across the full range of malignancies that are of critical importance to the population of Nebraska, including lung cancer, ovarian cancer, multiple myeloma, lymphoma, acute leukemia, breast cancer, pancreatic cancer and medulloblastoma. The research interests of TMDP faculty are organized around three interactive themes – Target Validation, Small Molecule Modulators, Delivery Methods – that contribute to the overarching goal of bench-to-bedside research translation through intra- and inter- programmatic collaboration. These themes exemplify the specific aims of the TMDP to 1) develop conceptual and technical approaches to validate cancer targets; 2) identify and characterize target- and mechanism-specific small molecules directed at validated cancer targets; and 3) explore novel technologies for efficient delivery of small molecules or RNAi against validated cancer targets. Physician scientists within the TMDP with clinical trials expertise facilitate the translation of putative targets, chemical modulators, and delivery methods with therapeutic potential. The interactions between TMDP members, their interactions with other BCC Programs, and their inter-institutional collaborations promote impactful and translational studies. These interactions have resulted in $4.25M (direct) of cancer-relevant peer-reviewed funding to TMDP investigators, with 3.17M from the NCI. During the funding period, the TMDP investigators reported 647 cancer-relevant publications (average journal impact factor = 7), with 37% intra-programmatic, 28% inter-programmatic, 18% both intra- and inter- programmatic and 41% inter-institutional publications.