Identifying Actionable Signatures of Duodenopancreatic Neuroendocrine Tumor Progression in MEN1

项目摘要 多发性内分泌瘤1型（MEN 1）患者几乎总是发生多发性内分泌瘤。 胰腺神经内分泌肿瘤（dpNET），但只有一个子集进展到转移。目前我们 缺乏识别那些具有发展侵袭性和转移性疾病高风险的患者的能力。手术 当dpNET局限于局部时，切除术是唯一的治疗选择，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，存在关键的未满足的需求。 dpNET提供风险分层的标志物，或代表治疗靶点。我们的长期目标是 开发一种液体活检方法，以识别具有MEN 1相关dpNET的高风险患者， 发展远处转移和发展新的靶向治疗以防止转移。整体 本研究的目的是通过进行综合的多项研究， 从小鼠模型纵向收集的血浆、血浆衍生的外来体和组织的组学分析 MEN 1-pNET和MEN 1相关dpNET患者的回顾性血液样本。为了解决这个 我们提出两个具体目标。在特定目标1中，我们将收集纵向等离子体，等离子体衍生的 外泌体和来自MEN 1-pNET的Men 1fl/flPdx 1-CreTg小鼠模型的组织样品，并且使用这些 生物样本，进行基于质谱的代谢组学、蛋白质组学和免疫复合物分析， 识别与疾病发展和进展相关的特征。在《特殊目标2》中，我们将识别血液- 基于MEN 1相关dpNET人类样本中与转移性疾病相关的特征。这将是 在回顾性研究中，通过血液的非靶向代谢组学、蛋白质组学和免疫复合物分析来完成 伴有远处转移的dpNET的MEN 1患者队列（病例; n=15）; dpNET的MEN 1患者 无远处转移（n=30）和无dpNET的MEN 1患者（n=15）。盲态验证已确定 将在第二个同等大小的独立患者组中进行生物标志物的测定。 这种独特的合作利用了最先进的质谱技术， MEN 1相关pNET的相关遗传小鼠模型以及来自三个充分表征的 来自美国和欧洲专家中心的MEN 1队列，其唯一目标是识别可操作特征 这可能为风险分层提供实用性或提供治疗靶点。这个项目意义重大，因为它旨在 通过鉴定与疾病进展相关的血液生物标志物来解决未满足的临床需求 MEN 1相关dpNETs患者的肿瘤转移以及鉴定一组与MEN 1相关dpNETs相关的肿瘤抗原 这些dpNET可用于随后开发用于有风险的受试者的疫苗和/或 免疫学应用的目标。这种方法为风险分层开辟了新的视野， 探索MEN 1相关dpNETs的新治疗靶点。由于超过40%的散发性pNET携带体细胞 MEN 1突变，这些发现也可能与更广泛的患者人群相关。

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.