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Advancing RAS and RASopathy Therapies

推进 RAS 和 RAS 病治疗

基本信息

批准号：
10926368
负责人：
Marielle Yohe
金额：
$ 25.5万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
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/10926368
关键词：
Animal Model Biochemical Breeding CCR Cell Proliferation Cells Childhood Clinical Clinical Protocols Clinical Trials Collaborations Cooperative Research and Development Agreement Costello syndrome Development Diagnosis Disease Division of Cancer Epidemiology and Genetics Embryo Enrollment Failure Failure to Thrive Family Funding General Population Genes Genetic Diseases Genomic approach Genomics Germ-Line Mutation Goals Grant Guanosine Triphosphate Incidence Study Industry International Intervention Trial Life Longitudinal cohort study MEKs Malignant Childhood Neoplasm Malignant Neoplasms Measurable Modeling Monitor Morphology Mus Mutation Neurofibromatosis 1 Noonan Syndrome Oncology Participant Pathway interactions Patients Pediatric Oncology Peripheral Nerve Sheath Neoplasm Plexiform Neurofibroma Population Prevention strategy Process Prospective Studies Protocols documentation RAS genes Research Personnel Risk Therapeutic Tipifarnib Transgenes Validation Variant Visit Work Zebrafish behavioral health beta Actin cardiofaciocutaneous syndrome clinical center cohort congenital heart disorder early phase clinical trial effective therapy efficacy evaluation inhibitor meetings melanoma mouse model multidisciplinary novel preclinical study protein purification success symposium targeted agent targeted treatment tumor virulence gene

项目摘要

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. Over 60 participants have enrolled in the field cohort and 6 patients have visited the clinical center to date. 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. This includes the use of PROs, being spearheaded by the behavioral health core in the POB. 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 MEKY130C model of CFC. These studies will be conducted in collaboration with CAPR (Zoe Weaver-Ohler)and Dr. Lino Tessarollo. The HRASG12S model project will be presented in abstract form at the RASopathiesNET symposium. We have begun the process of creating new mouse models of Noonan syndrome in collaboration with Raj Chiari and Roackie Awasthi. Founder mice with incorportation of the transgene into the germline have been identified, and these mice will now be bred with b-actin Cre mice to express the transgene. 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 RAS variants will be functionally validated in the Yohe lab. This validation includes biochemical assessment with purified protein (collaboration with the Rossman lab), assessment of RAS-GTP and pERK and pAKT levels in cells (Yohe lab), assessment of cellular localization (Turbyville lab), assessment of interactions with downstream effectors (Turbyville lab), impact on myogenic differentiation (Yohe lab), impact on cell proliferation (Yohe lab), and impact on zebrafish embryo morphology (Christine Kettenhofen in the LCDS aquatics core). Results from the characterization of HRAS variants will be presented at the RASopathiesNet symposium, Novel RAF variants will be functionally characterized in the Morrison lab. Novel LZTR1 variants identified through the RASopathy population genomics effort and through collaborations with Dr. Michael Sargen (melanoma prone families) will also be assessed 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NF 1 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。迄今为止，已有60多名参与者入组现场队列，6名患者访问了临床中心。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。这包括使用PRO，由POB中的行为健康核心带头。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HRASG 12 S模型中进行替吡法尼的研究，并在CFC的MEKY 130 C模型中进行Mirdametinib的研究。这些研究将与CAPR（Zoe Weaver-Ohler）和Lino Tessarollo博士合作进行。HRASG 12 S模型项目将在RASphathiesNET研讨会上以抽象形式展示。我们已经开始与Raj基亚里和Roackie Awasthi合作创建努南综合征新小鼠模型的过程。已经鉴定了将转基因并入生殖系的创始小鼠，并且这些小鼠现在将与b-肌动蛋白Cre小鼠一起繁殖以表达转基因。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RAS变体将在Yohe实验室进行功能验证。该验证包括纯化蛋白的生化评估（与Rossman实验室合作），评估细胞中RAS-GTP和pERK和pAKT水平（Yohe实验室），细胞定位评估（Turbyville实验室），评估与下游效应物的相互作用（Turbyville实验室），对肌源性分化的影响（Yohe实验室），对细胞增殖的影响（Yohe实验室），以及对斑马鱼胚胎形态的影响（LCDS aquatics核心中的克莉丝汀凯顿霍芬）。HRAS变体的表征结果将在RAPathiesNet研讨会上展示，新型RAF变体将在莫里森实验室进行功能表征。通过RASopathy人群基因组学研究以及与Michael Sargen博士（黑色素瘤易感家族）合作发现的新型LZTR 1变体也将在Yohe实验室进行评估。