Advancing RAS and RASopathy Therapies

在2019财年，CCR和DCEG的一组调查人员成功地为Rasopathies的新NCI计划竞争资金。有了这笔资金，我们在2019年2月的一个项目启动会上召集了一个由国际RA专家组成的多学科小组。作为这次会议的结果，我们为非NF1风湿病患者进行了一项纵向队列研究，这项研究将通过DCEG进行。该议定书最近得到了CIRB的批准，目前正在登记。这项试验的目标是前瞻性地研究这些患者的癌症发生情况，并确定可用于监测介入试验成功或失败的特定可测量终点。已经确定了可能的第一个介入试验，并进行了适当的行业接触，包括与库拉肿瘤科就替普法尼在Costello综合征中的使用进行了CRADA。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模型中研究替法尼布，并在MEKY30C模型中研究米达美替尼。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工作中，我们的目标是识别新的Rasathy变种和基因。该项目已经开始，新确定的变种将在Yohe实验室进行功能验证。

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.