Clinical Investigations and Precision Therapeutics

临床诊断和精确治疗 项目总结/摘要 临床研究和精确治疗（CIPT）计划的总体目标是将 优秀的科学进入早期阶段试验，以开发新的诊断，预防和治疗策略 用于人类癌症，并促进从实验室到床边和背部的双向翻译。CIPT提供了一个 基础科学和人口科学计划与临床之间的翻译桥梁，并进行 它自己的程序化的翻译研究。CIPT的独特之处在于它集中了 利用分子生物学、基因组学、成像分析等方面的专业知识开展早期临床试验， 系统生物学、统计学和生物标志物开发。CIPT成员翻译科学发现， 新的范例在板凳上，并在诊所，并定位在这个多学科的框架， 获得高影响力转化研究所需的专业知识。高影响力的翻译项目是 优先提供机构支持。CIPT有来自22个部门和7所学校的60名成员。CIPT 研究得到了560万美元的年度直接同行评审拨款支持，其中440万美元用于癌症研究， 重点项目（9个多PI），NCI提供230万美元（8个R 01等效项目/7个PI，1个UM 1）。在上一个供资期间， CIPT成员发表了929篇论文，其中42%是合作论文（29%是内部论文，25%是内部论文）。 51%与其他机构合作。这意味着， 与上一个项目期间相比，合作出版物。影响力科学包括发现 与癌细胞协同再活化p53的特定构象突变体的化合物 药理学计划（CP）; MAPK途径和细胞凋亡合理组合的开发 抑制，并通过抑制自噬与癌症的合作靶向癌症代谢 代谢和生长计划（CMG）;以及鉴定PARP抑制剂耐药机制， BRCA 1突变癌症与基因组不稳定性和癌症遗传学计划（GICG）合作。这些 这些方法正在临床和小鼠模型中进行评估。CIPT调查人员与CMG合作， GICG研究人员将确定对免疫检查点治疗反应的新标志物，包括存在 子宫内膜癌中的DNA聚合酶突变与生物医学工程师合作，以CP为主导 开发分类器，以帮助指导早期ER+乳腺癌的治疗，基于 数字组织学图像的计算分析。与癌症预防和控制的合作 CPC项目导致了评估精神疾病对老年人乳腺癌预后影响的研究。 最后，免疫检查点疗法在默克尔细胞癌中的临床研究导致FDA批准了 avelumab用于晚期疾病。CIPT科学是由研究项目中的发现翻译推动的， 以及临床发现的反向翻译，以鉴定应答和抗性的新分子机制。 CPC，第一部分：叙述，第1页，共1页;草案1/19/18上午11：56

CLINICAL INVESTIGATIONS AND PRECISION THERAPEUTICS PROJECT SUMMARY/ABSTRACT The overall goals of the Clinical Investigations and Precision Therapeutics (CIPT) Program are to translate outstanding science into early phase trials, to develop new diagnostic, prevention, and therapeutic strategies for human cancer, and to promote bidirectional translation from bench to bedside and back. CIPT provides a translational bridge between the basic science and population science programs and the clinic, and conducts its own programmatically aligned translational research. CIPT is unique in its centralization of experience in the development of early phase clinical trials with expertise in molecular biology, genomics, imaging analysis, systems biology, statistics, and biomarker development. CIPT members translate scientific findings to create new paradigms at the bench and in the clinic, and are positioned within this multidisciplinary framework to access the expertise necessary for high impact translational research. High impact translational projects are prioritized for institutional support. CIPT has 60 members from 22 Departments and 7 Schools. CIPT research is well funded with $5.6M annual direct peer-reviewed grant support, $4.4M of which is cancer- focused (9 multi-PI), with $2.3M from the NCI (8 R01-equivalent/7 PIs, one UM1). In the last funding period CIPT members published 929 papers, 42% of which were collaborative (29% intra- and 25% inter- collaborations) with 51% collaborative with other institutions. This represents an increase in both total and collaborative publications compared with last project period. Impactful science includes discovery of compounds that reactivate specific conformational mutants of p53 in collaboration with the Cancer Pharmacology Program (CP); development of rational combinations of MAPK pathway and apoptosis inhibition, and targeting cancer metabolism by inhibiting autophagy in collaboration with the Cancer Metabolism and Growth Program, (CMG); and identification of mechanisms of resistance to PARP inhibitors in BRCA1 mutant cancers in collaboration with Genome Instability and Cancer Genetics Program (GICG). These approaches are being assessed in the clinic and in mouse models. CIPT investigators worked with CMG and GICG investigators to identify novel markers of response to immune checkpoint therapy, including presence of DNA polymerase-epsilon mutations in endometrial cancer. Collaboration with biomedical engineers in CP led to development of a classifier to help guide treatment of early stage ER+ breast cancer based on computational analysis of digital histology images. Collaboration with the Cancer Prevention and Control Program (CPC) led to studies evaluating the impact of mental illness on breast cancer outcome in the elderly. Finally, clinical investigation of immune checkpoint therapy in Merkel cell carcinoma led to FDA approval of avelumab for advanced disease. CIPT science is fueled by translation of findings in the Research Programs, and reverse translation of clinical findings to identify novel molecular mechanisms of response and resistance. CPC, Part I: Narrative, Page 1 of 1; DRAFT 1/19/18 11:56 AM