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

摘要 在这一应用中，我提出了一种新的精准医学方法，旨在提高对 胃肠胰腺神经内分泌癌的多肽受体放射性核素治疗 该奖项将提供受保护的研究时间和培训，为独立的R01基金做准备。 在过去的十年中，GEP-Net的管理模式发生了根本性的转变，通过 使用生长抑素受体2型(SSTR2)靶向PRRT。FDA最近批准了临床使用 177Lu-DOTATE(Lutathera)，一种含有治疗性放射性核素177Lu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 PRRT，使他们的治疗选择有限。SSTR2的低表达主要通过 表观遗传基因沉默。在这里，我们建议通过短期脉冲刺激上调SSTR2的表达 表观基因组调节化疗使Net对PRRT重新增敏并提高其治疗指数 减少PRRT的非靶向副作用。在初步实验中，我们已经显示出剂量依赖性的健壮性。 靶向一系列聚梳蛋白(PcG)上调SSTR2的体内外表达 在基因沉默方面。我们建议在一系列模型中评估这种方法，目标是优化剂量 以及去抑制化疗的时机。如果成功，这项研究将为临床试验和 使用临床批准的成像和PRRT试剂进行近期翻译可显著提高疗效 通过增加相对于非靶器官向肿瘤提供的辐射剂量来提高治疗的效率。 这项提议将使我能够成为平移精密成像领域的独立研究员。我的 最终目标是领导一个独立资助的翻译小说治疗学的研究计划 改善癌症护理。为了促进我走向独立，我和我的导师们一起设计了一份职业生涯 发展计划，包括量身定做的教学课程、研讨会、研讨会和实践培训，将 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 剂量学。这个项目的主要导师是著名的翻译精确度专家奥马尔·马哈茂德博士 成像。Adam Bass博士和Ciprian Catana博士将担任二级导师，提供他们在癌症方面的专业知识 遗传学和表观遗传学，以及辐射剂量学模型。此外，我将与一个团队合作 来自MGH的顾问/顾问，包括David Ryan、Daniel Chung、Ryan Corcoran和Peter Caravan博士 世卫组织将作为我的科学咨询委员会的一部分提供额外的专业知识和指导。 这项研究将在马蒂诺斯中心进行，该中心是世界领先的翻译成像机构 研究。该项目将极大地受益于MGH癌症中心Martinos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与MGH和Dana建立关系- 法伯癌症中心和领先的网络专家，提高了我的研究的影响力和可见度。

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.