Identifying Actionable Signatures of Duodenopancreatic Neuroendocrine Tumor Progression in MEN1

项目总结 多发性内分泌肿瘤1型(MEN1)患者几乎总是发生多发性 十二指肠胰腺神经内分泌肿瘤(DpNETs)，但只有一小部分进展为转移。目前，我们 缺乏识别高危患者发生侵袭性和转移性疾病的能力。外科手术 当dpNETs被定位时，切除是唯一的治疗选择，并且与显著的发病率相关。 对于与转移性肿瘤的发展相关的分子的、可操作的特征，存在着严重的未得到满足的需求 提供风险分层标志或代表治疗靶点的dpNETs。我们的长期目标是 开发一种液体活检方法来识别患有MEN1相关dpNETs的患者，这些患者有很高的 发展远处转移，并开发新的靶向治疗以防止转移。整体而言 本研究的目的是通过进行综合多项研究，确定pNET进展的可操作特征。 纵向收集的血浆、血浆衍生的外切体和小鼠模型组织的基因组图谱 MEN1-pNET和来自MEN1相关dpNETs患者的回顾血液样本。要解决这个问题 目的，我们提出了两个具体目标。在特定目标1中，我们将收集纵向血浆，从血浆中提取 Exosome，以及来自MEN1-pNET的Men1fl/flPdx1-CreTg小鼠模型的组织样本，并使用这些 Biospecimen，执行基于代谢组、蛋白质组和免疫复合体的质谱分析以 确定与疾病发展和进展相关的特征。在特定的目标2中，我们将识别血液- 基于与MEN1相关的dpnet人类样本中与转移性疾病相关的特征。这将是 通过对血液的非靶向代谢组、蛋白质组和免疫复合体进行回顾性分析完成 患有dpNETs并有远处转移的MEN1患者队列(n=15)； 无远处转移(n=30)和无dpNETs的MEN1患者(n=15)。身份验证的盲目验证 生物标记物将在第二个同等大小的独立患者队列中进行。 这一独特的合作利用了最先进的质谱学技术，一种疾病 相关遗传小鼠模型的MEN1相关pNET以及来自三个特征良好的血液样本 来自美国和欧洲专家中心的MEN1队列，唯一的目标是确定可操作的特征 这可能为风险分层提供实用价值或提供治疗靶点。这个项目意义重大，因为它的目标是 通过识别与疾病进展相关的血液生物标记物来满足未得到满足的临床需求 与MEN1相关的dpNETs患者的转移以及识别一组相关的肿瘤抗原 DpNET可被用于随后为高危对象和/或AS开发疫苗 免疫治疗应用的靶点。这种方法为风险分层和 探索MEN1相关dpNETs的新治疗靶点。因为超过40%的零星PNETs携带躯体 MEN1突变，这些发现也可能与更广泛的患者群体相关。

Project summary Patients with Multiple Endocrine Neoplasia type 1 (MEN1) almost invariably develop multiple duodenopancreatic neuroendocrine tumors (dpNETs), but only a subset progress to metastasis. Currently, we lack the ability to identify those patients at high risk of developing aggressive and metastatic disease. Surgical resection is the only curative option when dpNETs are localized, and is associated with significant morbidity. There is a critical unmet need for molecular, actionable features associated with the development of metastatic dpNETs that provide for markers of risk stratification, or represent therapeutic targets. Our long-term goals are to develop a liquid biopsy approach to identify patients with MEN1-related dpNETs that are at high risk of developing distant metastasis and to develop novel targeted therapies to prevent metastasis. The overall objective of this study is to identify actionable signatures of pNET progression by performing integrated multi- omic profiling of longitudinally collected plasma-, plasma-derived exosomes and tissue from a mouse model of MEN1-pNET and of retrospective blood samples from patients with MEN1-related dpNETs. To address this objective, we propose two specific aims. In Specific Aim 1 we will collect longitudinal plasma, plasma-derived exosomes, and tissue samples from a Men1fl/flPdx1-CreTg mouse model of MEN1-pNET and, using these biospecimen, perform mass spectrometry based metabolomic, proteomic and immune complex profiling to identify signatures associated with disease development and progression. In Specific Aim 2 we will identify blood- based signatures associated with metastatic disease in human samples of MEN1-related dpNET. This will be accomplished by untargeted metabolomic, proteomic and immune complex profiling of blood in a retrospective cohort of MEN1 patients with dpNETs with distant metastases (cases; n=15); MEN1 patients with dpNETs without distant metastases (n=30), and MEN1 patients without dpNETs (n=15). Blinded validation of identified biomarkers will be performed in a second equally sized independent patient cohort. This unique collaboration takes advantage of state-of-the-art mass spectrometry technology, a disease relevant genetic mouse model of MEN1-related pNET as well as blood samples from three well-characterized MEN1 cohorts from expert centers in the US and Europe with the sole objective of identifying actionable features that may offer utility for risk stratification or provide therapeutic targets. This project is significant because it aims to address an unmet clinical need by identifying blood-based biomarkers associated with disease progression and metastasis in patients with MEN1-related dpNETs as well as identifying a set of tumor antigens associated with dpNETs that may be harnessed for the subsequent development of vaccines for subjects at risk and/or as targets for immunotherapeutic applications. This approach opens new horizons for risk-stratification and exploration of novel therapeutic targets in MEN1-related dpNETs. As over 40% of sporadic pNETs carry somatic MEN1-mutations, these findings can also be relevant to this broader patient population.