Helping Neuro-oncologists Navigate Expanded Access

帮助神经肿瘤学家扩大访问范围

• 批准号: 9928657
• 负责人: MELISSA L. BONDY
• 金额: $ 15.55万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9928657
• 关键词: Affect; Area; Belief; Bioethics; Biology; Cancer Patient; Candidate Disease Gene; Case-Control Studies; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Data; Data Sources; Development; Disease; Empirical Research; Ethical Theory; Ethics; Etiology; Exercise; Family; Family Physicians; Family history of; Future; Genes; Genetic; Genetic Predisposition to Disease; Genetic screening method; Genome; Glioma; Gliomagenesis; Individual; Informed Consent; Inherited; International; Interview; Life; Literature; Medicine; Mutation; Oncologist; Patients; Pharmaceutical Preparations; Physicians; Play; Recommendation; Recording of previous events; Reporting; Research Ethics; Research Personnel; Risk; Role; Sampling; Structure; Susceptibility Gene; Technology; Terminally Ill; Untranslated RNA; Variant; base; clinically relevant; cohort; disorder risk; experience; federal policy; high risk; insertion/deletion mutation; insight; interest; knowledge base; mouse model; novel; parent grant; programs; recruit; success; telomere; tool; tumor

ABSTRACT Parent grant: Genetic susceptibility plays a significant role in glioma development. An individual with two or more first- and/or second-degree affected relatives has a two-fold increased risk of the disease. We were the first to suggest mutations in POT1 (Protection of Telomeres 1) as causative in familial glioma (FG). We have now established the presence of POT1 mutations in 5 different families, providing the strongest evidence of its role in glioma. However, we do not yet have direct functional evidence that loss of POT1 is causal in glioma leaving few options for carrier surveillance or potential treatment targets. We are currently able to explain the genetic basis of glioma in up to 12% of our families, using highly stringent criteria for calling a mutation deleterious and causal. In contrast, the majority of our families remain unexplained though several candidate genes have emerged as ‘suspects of interest (SOIs)’. We propose a data-driven, knowledge-based, computational approach to guide candidate gene selection for functional characterization. In order to further our efforts to explain the genetic basis of FG we propose two specific aims to: Identify new gene candidates that may cause FG through WGS (Aim 1). We will identify SNVs, small indels, and structural variants in both coding and noncoding regions of the genome, intensively annotate those variants using more than 50 data sources, and we will rank these variants using multiple criteria based on their likelihood to cause disease. In addition to the 270 FG cases (from 203 FG families) with sequence data already available, we will also sequence an additional 100 cases (from 100 families) already collected in our Glioma International Case-Control Study with a reported family history using Gliogene criteria, and 200 newly recruited cases (from 100 families) with a strong family history of glioma to enhance our discovery, and 150 familial glioma tumor samples. The second aim is to functionally validate SOIs to include: A) POT1 mutations and B) newly discovered FG susceptibility genes (SOIs) from Aim 1 using a novel experimental mouse model of gliomagenesis. To determine the functional contributions of POT1 and novel mutations identified in our WGS studies, we will evaluate these genes in glioma mouse models using CRISPR gene editing technology. This study has the potential for future genetic testing in high-risk families, success will offer much needed insight on the underlying biology and etiology of glioma in both familial and sporadic cases. Supplement: The FDA’s expanded access program (EAP)—sometimes called “compassionate use” for individual requests—is a potential option for patients with immediate, life-threatening conditions when no comparable or satisfactory options are available to gain access to experimental medicines outside of clinical trials. Yet we know little about how oncologists and patients navigate EAP requests, their understanding of federal policy, or how they manage informed consent after a request has been approved. There is no empirically-derived ethical guidance for oncologists considering experimental drugs as treatment options for their patients. We propose to develop and offer guidance to neuro-oncologists through a stepwise approach of empirical research and normative ethics. First, we will conduct individual, in-depth interviews through family-physician dyads, and ask about their experiences in discussing options of providing an experimental drug through compassionate use or expanded access. Family cohorts will include at least two living glioma cases, and will be identified through recruitment in the Discovery, Biology and Risk of Inherited Variants in Glioma (GLIOGENE) parent grant. Then, we will combine ethical principles and paradigmatic cases from the literature with the themes and cases derived from interviews to identify salient ethical areas of concern. Once identified, we will synthesize case scenarios and questions for normative discussion with investigators on the parent grant and three practicing neuro-oncologists. This exercise will be used to generate a set of clinically-relevant recommendations and decision tools for practitioners.

摘要 父母资助：遗传易感性在胶质瘤的发展中起着重要作用。一个人有两个或两个 更多的一级和/或二级亲属患上这种疾病的风险增加了一倍。我们是 首次提出POT1(端粒保护1)突变是家族性胶质瘤(FG)的原因。我们有 现在证实在5个不同的家系中存在POT1突变，这为其 在神经胶质瘤中的作用。然而，我们还没有直接的功能证据表明POT1的缺失是神经胶质瘤的原因。 对携带者的监视或潜在的治疗目标几乎没有选择。我们目前能够解释 高达12%的家庭中神经胶质瘤的遗传基础，使用非常严格的标准来称为突变 有害的和因果的。相比之下，我们大多数家庭仍然没有得到解释，尽管有几个候选人 基因已经成为“感兴趣的嫌疑人(SOI)”。 我们提出了一种数据驱动的、基于知识的计算方法来指导候选基因选择 功能特性。为了进一步解释FG的遗传基础，我们提出了两个 具体目标是：通过WGS确定可能导致FG的新候选基因(目标1)。我们将确定 SNV、小Indels和基因组编码区和非编码区的结构变体 使用50多个数据源注释这些变体，我们将使用多个标准对这些变体进行排名 基于它们引发疾病的可能性。除270个FG病例(来自203个FG家庭)外， 测序数据已经可用，我们还将对另外100个病例(来自100个家庭)进行测序 收集在我们的国际胶质瘤病例对照研究中，并报告了使用Gliogene标准的家族史， 和200例新招募的病例(来自100个家庭)，有很强的胶质瘤家族史，以加强我们的 发现了150例家族性脑胶质瘤标本。第二个目标是从功能上验证SOI，以包括： A)POT1突变和B)从AIM 1新发现的FG易感基因(SOI)使用一种新的 实验性脑胶质瘤小鼠模型的建立。确定POT1和NOVICE的功能贡献 在我们的WGS研究中发现的突变，我们将使用CRISPR在胶质瘤小鼠模型中评估这些基因 基因编辑技术。 这项研究有可能在未来的高危家庭中进行基因测试，成功将提供亟需的 深入了解家族性和散发性脑胶质瘤的潜在生物学和病因学。 补充：FDA的扩大准入计划(EAP)--有时被称为对 个人要求-对于有直接、危及生命的情况的患者来说，当没有 有类似的或令人满意的选择，以获得临床以外的实验药物 审判。然而，我们对肿瘤学家和患者如何处理EAP请求、他们对 联邦政策，或他们如何在请求获得批准后管理知情同意。没有 为考虑将实验药物作为治疗方案的肿瘤学家提供的经验性伦理指导 他们的病人。 我们建议通过循序渐进的经验方法发展和指导神经肿瘤学家。 研究和规范伦理。首先，我们将通过家庭医生进行个人深入采访 二人，询问他们在讨论通过以下方式提供实验药物的选择时的经验 富有同情心地使用或扩大访问。家庭队列将包括至少两例活着的胶质瘤病例，并将 在胶质瘤遗传变异的发现、生物学和风险中通过招募来确定 (GLIOGENE)家长资助。然后，我们将结合伦理原则和文献中的范例案例。 通过访谈得出的主题和案例，找出值得关注的突出道德领域。一旦被确认， 我们将综合案例情景和问题，与调查人员就家长问题进行规范讨论 格兰特和三位实习神经肿瘤学家。这项练习将被用来产生一套与临床相关的 为从业者提供建议和决策工具。