Clinical Investigations and Precision Therapeutics

临床研究与精确治疗 项目摘要/摘要 临床研究和精确治疗(CIPT)计划的总体目标是将 将杰出的科学成果转化为早期试验，以开发新的诊断、预防和治疗策略 治疗人类癌症，并促进从长凳到床边和背部的双向转换。CIPT提供了 基础科学和人口科学计划与临床之间的翻译桥梁，并进行 它自己的程序一致的翻译研究。CIPT的独特之处在于它将经验集中在 开发具有分子生物学、基因组学、成像分析、 系统生物学、统计学和生物标记物开发。CIPT成员将科学发现转化为 法官和诊所的新范例，并在这一多学科框架内定位于 获取高影响力翻译研究所需的专业知识。高影响力的翻译项目有 优先提供制度支持。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议拨款支持，其中440万美元用于癌症-- Focus(9个多PI)，其中230万美元来自NCI(8个R01等值/7个PI，1个UM1)。在上一个资助期内 CIPT成员发表了929篇论文，其中42%是合作的(29%是内部的，25%是内部的 协作)，51%与其他机构协作。这代表着总量和 合作出版物与上一个项目期的比较。有影响力的科学包括发现 与癌症协同作用重新激活特定的p53构象突变的化合物 药理学计划(CP)；开发MAPK途径与细胞凋亡的合理组合 通过与癌症协同抑制自噬来抑制和靶向癌症代谢 代谢和生长计划(CMG)；以及对PARP抑制剂耐药机制的鉴定 BRCA1突变癌症与基因组不稳定和癌症遗传学计划(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和 GICG调查人员将确定免疫检查点治疗反应的新标记物，包括是否存在 子宫内膜癌中DNA聚合酶-epsilon突变的研究与CP领域的生物医学工程师进行协作 开发一种分类器来帮助指导早期ER+乳腺癌的治疗 数字组织学图像的计算分析。与癌症预防和控制中心合作 项目(CPC)导致了评估精神疾病对老年人乳腺癌预后的影响的研究。 最后，免疫检查点治疗默克尔细胞癌的临床研究导致FDA批准了 阿维卢单抗治疗晚期疾病。CIPT科学是通过翻译研究计划中的发现来推动的， 和反向翻译临床结果，以确定新的反应和耐药的分子机制。 CPC，第一部分：叙事，第1页，共1页；草案1-19-18 11：56 AM

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