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，遗传性癌症易感突变是10万多名成年人癌症的潜在原因。 美国每年的癌症对于许多遗传性癌症综合征， 接近百分之百。尽管“组学”技术取得了革命性的进展，但我们对分子生物学的理解仍然是一个问题。 支持建立癌前病变和促进早期肿瘤发展所需的改变 这方面的工作仍然非常有限，从而阻碍了有效干预措施的发展。的多学科团队 福克斯大通癌症中心（FCCC）的研究人员，在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经组装，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，用于精确的癌症预防和早期拦截， 癌症高危人群。所有研究都由FCCC风险的独特资源提供便利。 评估计划，其中包括超过12，000个癌症高危家庭和2000个确认的生殖细胞 变异携带者用于开发癌症预防和拦截剂的全面管道 提出了一个由三个发展成熟的研究领域：目标验证（目标1），主体识别 和筛选（目标2），以及初步体内疗效研究（目标3）。每个领域将由一名气候变化框架公约调查员领导， 他是该领域的国家领导人。提出了两个高度创新的项目，说明了 CAP-IT框架的稳健性。项目1（进入目标验证）重点是开发 一种新发现的能重折叠突变型p53的药物。其靶向与Li-相关的TP 53突变的能力， Fraumeni综合征和抑制癌前病变的突变p53的设置将进行评估。计划2 （在药物鉴定和筛选时进入）唯一靶向启动的胰腺基质，作为 在胰腺癌形成的早期拦截。抗基质蛋白Netrin的中和抗体 已经发现G1可以使成纤维细胞恢复成肿瘤抑制表型。具有改善的 将在体内鉴定和测试其阻断胰腺上皮内癌进展的能力 肿瘤形成所有CAP-IT研究和培训将得到领导团队的大力支持， 行政核心的活动，由克拉珀博士领导。生物统计学、生物信息学和数据方面的专业知识 管理将由Ross博士领导的信息学核心向CAP-IT研究人员提供。合作 在NCI，FCCC和其他CAP-IT中心之间，以及通过数据共享数据和资源， 和资源协调中心，将促进整个CAP-IT网络的生产力和整合（目标4）。 FCCC在临床风险评估和临床前预防剂开发方面的长期遗产， 结合药物设计和癌症生物学方面的广泛专业知识，使该中心成为独一无二的 有助于发现分子靶向药物以预防或阻断早期肿瘤发生。