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

项目总结--总体 据估计，可遗传的癌症易感突变是10万多名成年人的潜在原因 美国每年都有癌症病例。对于许多遗传性癌症综合征来说，患癌症的终生风险 接近100%。尽管“组学”技术取得了革命性的进步，但我们对分子生物学的理解 支持癌前病变的建立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。一支多学科的团队 福克斯·蔡斯癌症中心(Fcc)经验丰富的研究人员，拥有癌症预防方面的综合专业知识， 可遗传的癌症风险、癌症生物学、分子建模和药物发现已经汇集在一起，以解决 这是一种前所未有的未得到满足的方式。Fccccp-it中心的目标是有效地协调 用于癌症精确预防和早期阻断的高效分子靶向药物的研究进展 癌症高危人群。所有的研究都是由fccc风险的独特资源推动的。 评估计划，其中包括12,000多个癌症高危家庭和2000个确认的生殖系 突变携带者。开发癌症预防和截止剂的全面流水线 提出了由三个成熟的研究领域组成：目标确认(Aim 1)、代理识别 和筛选(目标2)，以及体内疗效试验(目标3)。每个领域将由一名fccc调查员领导， 世卫组织在各自领域处于国家领先地位。提出了两个极具创新性的项目，以说明 CAP-IT框架的健壮性。项目1(在目标验证时进入)侧重于开发一个 新发现的折叠突变型P53的试剂。其靶向与LI-1相关的TP53突变的能力 将对Fraumeni综合征和抑制癌前病变的突变型P53进行评估。项目2 (进入试剂鉴定和筛选)独特地针对启动的胰腺间质作为一种策略 胰腺癌形成中的早期截留。一种抗基质蛋白Netrin的中和抗体 已经发现了G1，它可以将成纤维细胞恢复为肿瘤抑制表型。经过改进的抗体 将在体内鉴定和测试它们拦截胰腺上皮内进展的能力 肿瘤。所有CAP-IT研究和培训都将得到领导班子和协调的大力支持 克拉珀博士领导的行政核心的活动。在生物统计学、生物信息学和数据方面的专业知识 管理将由罗斯博士领导的信息学核心部门提供给CAP-IT调查人员。协作 在国家协调中心、联合国气候变化框架公约和其他履约协助方案信息技术中心之间，以及通过数据共享数据和资源 和资源协调中心，将促进整个履约协助方案--信息技术网络的生产力和一体化(目标4)。 Fccc在临床风险评估和临床前预防药物开发方面的长期遗产 与药物设计和癌症生物学方面的广泛专业知识相结合，使该中心成为 有助于发现分子靶向的药物以预防或阻断早期肿瘤的发生。

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.