Enhancing the therapeutic effect of receptor radionuclide therapy in neuroendocrine tumors by somatostatin receptor upregulation

通过上调生长抑素受体增强神经内分泌肿瘤受体放射性核素治疗的疗效

• 批准号: 10436208
• 负责人: Pedram Heidari
• 金额: $ 26.97万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10436208
• 关键词: Advisory Committees; Apoptosis; Award; Bass; Beta Particle; Biodistribution; Biological Availability; Cancer Center; Cell surface; Chemotherapy-Oncologic Procedure; Chromatin Structure; Chronic; Clinical; Clinical Trials; Combined Modality Therapy; Computational Biology; Core Facility; Data; Development; Development Plans; Dose; Drug Combinations; Education; Educational workshop; Effectiveness; Epigenetic Process; FDA approved; Fostering; Foundations; Funding; Gene Silencing; Generations; Genes; Genetic Transcription; Goals; Image; In Vitro; Institution; Lead; Left; Lesion; Ligands; Malignant Neoplasms; Mediating; Mentors; Modeling; Molecular Target; Neuroendocrine Tumors; Normal tissue morphology; Organ; Patients; Peptide Receptor; Phase; Physiologic pulse; Polycomb; Preparation; Prior Chemotherapy; Promoter Regions; Proteins; Radiation Dose Unit; Radiation therapy; Radiochemistry; Radiolabeled; Radiometry; Radionuclide therapy; Regimen; Regulation; Repression; Research; Research Personnel; Resources; SSTR2 gene; Series; Somatostatin Receptor; Targeted Radiotherapy; Testing; Therapeutic Effect; Therapeutic Index; Time; Training; Translating; Translations; Treatment outcome; Up-Regulation; Work; cancer care; cancer cell; cancer genetics; career development; chemotherapy; chromatin remodeling; cytotoxic; daughter cell; derepression; design; dosimetry; epigenetic drug; epigenetic marker; epigenetic silencing; epigenome; experimental study; gastroenteropancreatic neuroendocrine tumor; human subject; improved; improved outcome; in vivo; inhibitor; insight; mouse model; neoplastic cell; novel; patient population; pre-clinical; precision medicine; programs; receptor; receptor upregulation; response; side effect; somatostatin analog; somatostatin receptor 2; success; systemic toxicity; theranostics; treatment response; tumor; tumor growth; uptake

Abstract In this application, I propose a novel precision medicine approach aimed at enhancing the therapeutic effect of peptide receptor radionuclide therapy (PRRT) in gastroenteropancreatic neuroendocrine carcinomas (GEP- NET)s. This award will provide protected research time and training in preparation for independent R01 funding. Over the past decade, there has been a fundamental paradigm shift in the management of GEP-NETs through use of somatostatin receptor type 2 (SSTR2) targeted PRRT. The FDA has recently approved clinical use of 177Lu-DOTATATE (Lutathera), a somatostatin analog loaded with the therapeutic radionuclide 177Lutetium, for PRRT of SSTR2-expressing GEP-NETs. Patients with low SSTR2 expressing tumors are often unresponsive to PRRT, leaving them with limited treatment options. Low SSTR2 expression is mainly mediated through epigenetic gene silencing. Here we propose to upregulate SSTR2 expression by using short-term pulsed epigenome-modulating chemotherapy to re-sensitize NETs to PRRT and improve its therapeutic index while reducing the non-target side effects of PRRT. In preliminary experiments we have shown dose-dependent robust upregulation of SSTR2 both in vitro and in vivo by targeting a series of ploycomb group proteins (PcG) involved in gene silencing. We propose to assess this approach in a range of models with the goal of optimizing the dosing and timing of the de-repression chemotherapy. If successful, this study will pave the way for clinical trials and near-term translation using clinically approved imaging and PRRT agents to markedly improve the effectiveness of therapy by increasing the radiation dose delivered to tumors relative to non-target organs. This proposal will enable me to become an independent investigator in translational precision imaging. My ultimate goal is to lead an independently-funded research program in the translation of novel theranostics for improving cancer care. To facilitate my progression to independence, I have designed with my mentors a career development plan involving tailored didactic coursework, workshops, seminars, and hands-on training that will provide me with formal education in epigenetics, computational biology, radiochemistry and radiotherapy dosimetry. The primary mentor for this project is Dr. Umar Mahmood, a renowned expert in translational precision imaging. Drs. Adam Bass and Ciprian Catana will serve as secondary mentors, lending their expertise in cancer genetics and epigenetics, and radiation dosimetry modeling, respectively. In addition, I will work with a team of advisors/consultants from MGH, including Drs. David Ryan, Daniel Chung, Ryan Corcoran, and Peter Caravan who will provide additional expertise and guidance as part of my scientific advisory committee. This research will be performed at the Martinos Center, a world-leading institution for translational imaging research. The project will greatly benefit from the unique resources of the Martinos Center, MGH Cancer Center and other MGH core facilities. This collaborative framework will help me foster relationships with MGH and Dana- Farber Cancer Centers and leading experts in NETs to increase the impact and visibility of my research.

抽象的 在本申请中，我提出了一种新颖的精准医学方法，旨在增强治疗效果 肽受体放射性核素治疗（PRRT）治疗胃肠胰神经内分泌癌（GEP- NET）。该奖项将提供受保护的研究时间和培训，为独立 R01 资助做好准备。 在过去的十年中，GEP-NET 的管理发生了根本性的范式转变： 使用 2 型生长抑素受体 (SSTR2) 靶向 PRRT。近日，FDA批准临床使用 177Lu-DOTATATE (Lutathera)，一种装载有治疗性放射性核素 177Lutetium 的生长抑素类似物，用于 表达 SSTR2 的 GEP-NET 的 PRRT。 SSTR2 低表达肿瘤的患者通常对治疗无反应 PRRT，使他们的治疗选择有限。 SSTR2低表达主要是通过 表观遗传基因沉默。在这里，我们建议通过使用短期脉冲来上调 SSTR2 表达 表观基因组调节化疗使 NET 对 PRRT 重新敏感并提高其治疗指数，同时 减少 PRRT 的非目标副作用。在初步实验中，我们已经证明了剂量依赖性的稳健 通过靶向一系列涉及的多梳组蛋白 (PcG)，在体外和体内上调 SSTR2 在基因沉默中。我们建议在一系列模型中评估这种方法，以优化剂量 以及去抑制化疗的时机。如果成功，这项研究将为临床试验铺平道路 使用临床批准的成像和 PRRT 药物进行近期翻译，以显着提高有效性 通过增加相对于非靶器官的肿瘤的辐射剂量来进行治疗。 这个提案将使我成为平移精密成像领域的独立研究者。我的 最终目标是领导一个独立资助的研究项目，将新颖的治疗诊断学转化为 改善癌症护理。为了促进我走向独立，我与我的导师一起设计了职业生涯 发展计划，包括量身定制的教学课程、讲习班、研讨会和实践培训， 为我提供表观遗传学、计算生物学、放射化学和放射治疗方面的正规教育 剂量测定。该项目的主要导师是著名翻译精度专家 Umar Mahmood 博士 成像。博士。 Adam Bass 和 Ciprian Catana 将担任二级导师，传授他们在癌症方面的专业知识 分别是遗传学和表观遗传学以及辐射剂量测定模型。此外，我将与一个团队合作 MGH 的顾问/顾问，包括博士。大卫·瑞安、丹尼尔·钟、瑞安·科科伦和彼得·卡万 作为我的科学咨询委员会的一部分，谁将提供额外的专业知识和指导。 这项研究将在世界领先的转化成像机构马蒂诺斯中心进行 研究。该项目将极大受益于Martinos中心、MGH癌症中心的独特资源 和其他 MGH 核心设施。这个协作框架将帮助我培养与 MGH 和 Dana 的关系 法伯癌症中心和 NET 领域的领先专家提高了我的研究的影响力和知名度。