Cancer Prevention-Interception Targeted Agent Discovery Program at Fox Chase Cancer Center

福克斯蔡斯癌症中心的癌症预防-拦截靶向药物发现计划

• 批准号: 10505611
• 负责人: MARGIE L. CLAPPER
• 金额: $ 123.16万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10505611
• 关键词: Address; Adult; African ancestry; Antibodies; Area; Atlases; Award; Barrett Esophagus; Bioinformatics; Biological Assay; Biometry; Cancer Biology; Cancer Burden; Cell Line; Chronic; Collaborations; Colonic Polyps; Computational Biology; Contractor; Custom; Data; Development; Disease; Division of Cancer Prevention; Dose; Drug Design; Early Detection Research Network; Early treatment; Engineering; Epithelial Cells; Event; Family; Fibroblasts; Fostering; Fox Chase Cancer Center; Future; Genetic Risk; Germ-Line Mutation; Goals; Growth; Hereditary Malignant Neoplasm; Hereditary Neoplastic Syndromes; Heritability; High-Risk Cancer; In Vitro; Individual; Informatics; Inherited; Intercept; Intervention; Knowledge; Laboratory Research; Lead; Leadership; Lesion; Li-Fraumeni Syndrome; Malignant Neoplasms; Malignant neoplasm of pancreas; Medical Genetics; Molecular; Molecular Abnormality; Molecular Profiling; Molecular Target; Mutation; Operative Surgical Procedures; Oral Leukoplakia; Organ; Pancreas; Pancreatic Intraepithelial Neoplasia; Pathway interactions; Phenotype; Plant Roots; Population; Predisposition; Prevention strategy; Preventive; Productivity; Proteins; Regimen; Research; Research Personnel; Research Training; Resource Sharing; Resources; Risk; Risk Assessment; TP53 gene; Technology; Testing; Toxic effect; Validation; Variant; base; biological specimen archives; cancer diagnosis; cancer prevention; cancer risk; cell stroma; clinical risk; clinically relevant; cohort; data management; data resource; data sharing; disorder risk; drug development; drug discovery; efficacious intervention; efficacy study; experience; genetic variant; high risk; improved; in vivo; individualized prevention; innovation; insight; lifetime risk; member; molecular modeling; mouse model; multidisciplinary; mutant; mutation carrier; netrin-G1; neutralizing antibody; novel; overexpression; pre-clinical; precision cancer prevention; premalignant; prevent; preventive intervention; programs; prophylactic; public database; rational design; screening; targeted agent; therapy development; time use; tumor; tumor initiation; tumor microenvironment; tumorigenesis

PROJECT SUMMARY - OVERALL Hereditable cancer-predisposing mutations are estimated to be an underlying cause of more than 100,000 adult cancers in the US each year. For many hereditary cancer syndromes, the life-time risk of developing cancer approaches 100%. Despite revolutionary advances in “omics” technologies, our understanding of the molecular alterations required to support the establishment of precancerous lesions and promote early tumor development remains very limited, thus hindering the development of efficacious interventions. A multidisciplinary team of accomplished investigators at Fox Chase Cancer Center (FCCC), with combined expertise in cancer prevention, heritable cancer risk, cancer biology, molecular modeling, and drug discovery has been assembled to address this unmet in an unprecedented way. The goal of the FCCC CAP-IT Center is to effectively coordinate the development of efficacious molecularly-targeted agents for precision cancer prevention and early interception in populations at high risk for cancer. All studies are facilitated by the unique resources of the FCCC Risk Assessment Program, which includes over 12,000 families at high risk for cancer and 2000 confirmed germline mutation carriers. A comprehensive pipeline for the development of agents for cancer prevention and interception is proposed that consists of three well-developed research domains: target validation (Aim 1), agent identification and screening (Aim 2), and pilot in vivo efficacy studies (Aim 3). Each domain will be led by a FCCC investigator, who is a national leader in the respective field. Two highly innovative projects are proposed that illustrate the robustness of the CAP-IT framework. Project 1 (entering at Target Validation) focuses on the development of a newly-identified agent that refolds mutant p53. Its ability to target the TP53 mutations associated with Li- Fraumeni Syndrome and inhibit precancerous lesions in a setting of mutant p53 will be evaluated. Project 2 (entering at Agent Identification and Screening) uniquely targets the initiated pancreatic stroma as a strategy for early interception in the formation of pancreatic cancer. A neutralizing antibody against the stromal protein Netrin G1, that can revert fibroblasts to a tumor-suppressive phenotype, has been discovered. Antibodies with improved potency will be identified and tested in vivo for their ability to intercept the progression of pancreatic intraepithelial neoplasia. All CAP-IT research and training will be strongly supported by the Leadership Team and coordinating activities of the Administrative Core, led by Dr. Clapper. Expertise in biostatistics, bioinformatics, and data management will be provided to CAP-IT investigators by an Informatics Core, led by Dr. Ross. Collaborations among the NCI, FCCC and other CAP-IT Centers, as well as the sharing of data and resources through the Data and Resource Coordination Center, will foster productivity and integration across the CAP-IT Network (Aim 4). The long legacy of FCCC in clinical risk assessment and preclinical preventive agent development, when combined with extensive expertise in drug design and cancer biology, makes this Center uniquely poised to be instrumental in the discovery of molecularly-targeted agents to prevent or intercept early oncogenesis.

项目概要 - 总体 据估计，可遗传的癌症诱发突变是超过 100,000 名成年人罹患癌症的根本原因 美国每年都有癌症。对于许多遗传性癌症综合征来说，终生患癌症的风险 接近100%。尽管“组学”技术取得了革命性的进步，但我们对分子的理解 支持癌前病变的形成和促进早期肿瘤发展所需的改变 仍然非常有限，从而阻碍了有效干预措施的发展。多学科团队 福克斯蔡斯癌症中心 (FCCC) 的资深研究人员拥有癌症预防方面的综合专业知识， 遗传性癌症风险、癌症生物学、分子建模和药物发现已被整合起来以解决 这是前所未有的。 FCCC CAP-IT 中心的目标是有效协调 开发有效的分子靶向药物，用于精准癌症预防和早期拦截 癌症高危人群。 FCCC 风险的独特资源促进了所有研究 评估计划，包括 12,000 多个癌症高危家庭和 2000 个已确认的种系 突变携带者。开发癌症预防和拦截药物的综合管道 提议由三个成熟的研究领域组成：目标验证（目标 1）、代理识别 和筛选（目标 2），以及体内功效研究（目标 3）。每个域将由一名 FCCC 调查员领导， 谁是各自领域的国家领导者。提出了两个高度创新的项目来说明 CAP-IT 框架的稳健性。项目 1（进入目标验证）侧重于开发 新发现的能够重折叠突变体 p53 的试剂。它能够靶向与 Li-相关的 TP53 突变 将评估突变 p53 设置中的 Fraumeni 综合征和抑制癌前病变。项目2 （进入药剂识别和筛选）独特地针对启动的胰腺基质作为策略 早期拦截胰腺癌的形成。针对基质蛋白 Netrin 的中和抗体 G1 被发现可以使成纤维细胞恢复到肿瘤抑制表型。改进的抗体 将在体内鉴定和测试其拦截胰腺上皮内病变进展的能力 瘤形成。所有 CAP-IT 研究和培训都将得到领导团队和协调人员的大力支持 由 Clapper 博士领导的行政核心的活动。生物统计学、生物信息学和数据方面的专业知识 由 Ross 博士领导的信息学核心将向 CAP-IT 研究人员提供管理。合作 NCI、FCCC 和其他 CAP-IT 中心之间的协作，以及通过 Data Center 共享数据和资源 和资源协调中心，将促进整个 CAP-IT 网络的生产力和集成（目标 4）。 FCCC 在临床风险评估和临床前预防药物开发方面的悠久遗产，当 结合药物设计和癌症生物学方面的广泛专业知识，使该中心具有独特的优势 有助于发现分子靶向药物以预防或阻止早期肿瘤发生。