Advancing RAS and RASopathy Therapies

推进 RAS 和 RAS 病治疗

• 批准号: 10487025
• 负责人: Marielle Yohe
• 金额: $ 14.82万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10487025
• 关键词: Animal Model; CCR; Childhood; Clinical; Clinical Protocols; Clinical Trials; Collaborations; Cooperative Research and Development Agreement; Costello syndrome; Development; Diagnosis; Disease; Division of Cancer Epidemiology and Genetics; Enrollment; Failure; Failure to Thrive; Funding; General Population; Genes; Genetic Diseases; Genomic approach; Genomics; Germ-Line Mutation; Goals; Grant; Incidence Study; Industry; International; Intervention Trial; Life; Longitudinal cohort study; MEKs; Malignant Childhood Neoplasm; Malignant Neoplasms; Measurable; Modeling; Monitor; Mutation; Neurofibromatosis 1; Noonan Syndrome; Oncology; Pathogenicity; Pathway interactions; Patients; Pediatric Oncology; Peripheral Nerve Sheath Neoplasm; Plexiform Neurofibroma; Population; Prevention strategy; Prospective Studies; Protocols documentation; Research Personnel; Risk; Therapeutic; Tipifarnib; Variant; Work; cardiofaciocutaneous syndrome; congenital heart disorder; early phase clinical trial; effective therapy; efficacy evaluation; inhibitor/antagonist; meetings; multidisciplinary; preclinical study; success; targeted agent; targeted treatment; tumor

In FY 2019, a group of investigators from CCR and DCEG successfully competed for funding for a new NCI initiative for the RASopathies. With this funding, we assembled a multi-disciplinary group of international RASopathy experts at a project kick-off meeting in February 2019. As a result of this meeting, we have produced a longitudinal cohort study for patients with non-NF1 RASopathies that will be conducted through DCEG. This protocol was recently approved by the CIRB and is currently enrolling. The goals of this trial are to prospectively study the incidence of cancer development in these patients but also to identify specific measurable endpoints that can be used for monitoring the success or failure of interventional trials. Potential first interventional trials were identified, and appropriate industry contacts have been made, including a CRADA with Kura Oncology for the use of tipifarnib in Costello syndrome. In addition to the clinical protocol, we also have initiated several preclinical studies to evaluate the efficacy of RAS-targeting agents in RASopathies. We plan a study of tipifarnib in an HRASG12S model of Costello syndrome and a study of mirdametinib in a MEKY30C model of CFC. These studies will be conducted in collaboration with CAPR and Dr. Lino Tessarollo. Finally, in a population genomics effort headed by Dr. Douglas Stewart, we aim to identify new RASopathy variants and genes. This project has begun, and newly identified variants will be functionally validated in the Yohe lab.

在2019财年，来自CCR和DCEG的一组调查人员成功地为RASopathies的新NCI计划争取到了资金。有了这笔资金，我们在2019年2月的项目启动会议上组建了一个由国际RASopathy专家组成的多学科小组。作为这次会议的结果，我们已经为非NF1 RASopathies患者进行了一项纵向队列研究，将通过DCEG进行。该方案最近获得了CIRB的批准，目前正在招募。本试验的目标是前瞻性研究这些患者癌症发展的发生率，同时确定可用于监测干预试验成功或失败的特定可测量终点。确定了潜在的第一个干预性试验，并建立了适当的行业联系，包括与Kura Oncology合作的CRADA，用于Costello综合征中的替吡法尼。除了临床方案，我们还启动了几项临床前研究，以评估RAS靶向药物在RASopathies中的疗效。我们计划在Costello综合征的HRASG12S模型中进行替吡法尼的研究，并在CFC的MEKY30C模型中进行Mirdametinib的研究。这些研究将与CAPR和Lino Tessarollo博士合作进行。最后，在道格拉斯斯图尔特博士领导的人口基因组学研究中，我们的目标是确定新的RAS病变体和基因。该项目已经开始，新发现的变体将在Yohe实验室进行功能验证。