Identifying Actionable Signatures of Duodenopancreatic Neuroendocrine Tumor Progression in MEN1

识别 MEN1 十二指肠胰腺神经内分泌肿瘤进展的可操作特征

基本信息

批准号：
10041298
负责人：
SAMIR M HANASH
金额：
$ 41.65万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-10 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10041298
关键词：
Address Alleles Animals Antigen-Antibody Complex Area Under Curve Biological Biological Markers Biological Models Blinded Blood Blood specimen Cessation of life Clinical Clinical Management Collaborations Development Disease Disease Progression Distant Metastasis Duodenum Early Diagnosis Enterobacteria phage P1 Cre recombinase Europe Excision Exhibits Feasibility Studies Follow-Up Studies Future Genetic Genetically Engineered Mouse Goals Homeobox Human Immunotherapeutic agent Intervention Liquid substance Longitudinal Studies Mass Spectrum Analysis Metastatic Neoplasm to the Liver Mission Modeling Molecular Molecular Profiling Morbidity - disease rate Multiple Endocrine Neoplasia Type 1 Mus Mutation Neoplasm Metastasis Neuroendocrine Tumors Operative Surgical Procedures Pancreas Pancreatic Adenocarcinoma Patients Performance Persons Plasma Proteins Proteomics Public Health Receiver Operating Characteristics Reporting Research Retrospective cohort Risk Risk Marker Risk stratification Sampling Technology Tissue Sample Tissues Tumor Antigens Validation base blood-based biomarker cancer type case control cohort curative treatments exosome experience high risk human disease liquid biopsy lymph nodes metabolomics mouse model multiple omics neuroendocrine differentiation new therapeutic target patient population prevent progenitor promoter prospective test rare condition therapeutic target triple-negative invasive breast carcinoma tumor progression vaccine development

项目摘要

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.

项目概要 1 型多发性内分泌肿瘤 (MEN1) 患者几乎总是会出现多发性内分泌肿瘤十二指肠胰腺神经内分泌肿瘤（dpNET），但只有一部分进展为转移。目前，我们缺乏识别那些患有侵袭性和转移性疾病高风险的患者的能力。外科当 dpNETs 局部化时，切除是唯一的治疗选择，并且与显着的发病率相关。对于与转移性疾病的发展相关的分子、可操作的特征存在着关键的未满足的需求。 dpNET 提供风险分层标记或代表治疗靶点。我们的长期目标是开发一种液体活检方法来识别患有 MEN1 相关 dpNET 且具有高风险的患者发展远处转移并开发新的靶向疗法来预防转移。整体本研究的目的是通过执行综合多因素识别 pNET 进展的可操作特征从小鼠模型中纵向收集的血浆、血浆来源的外泌体和组织的组学分析 MEN1-pNET 和 MEN1 相关 dpNET 患者的回顾性血液样本。为了解决这个问题目标，我们提出两个具体目标。在具体目标 1 中，我们将收集纵向血浆、血浆衍生的血浆外泌体和来自 MEN1-pNET 的 Men1fl/flPdx1-CreTg 小鼠模型的组织样本，并使用这些生物样本，进行基于代谢组学、蛋白质组学和免疫复合物分析的质谱分析识别与疾病发生和进展相关的特征。在具体目标 2 中，我们将识别血液- 基于 MEN1 相关 dpNET 人类样本中与转移性疾病相关的特征。这将是通过回顾性对血液进行非靶向代谢组学、蛋白质组学和免疫复合物分析来完成具有远处转移的 dpNET 的 MEN1 患者队列（病例；n=15）；患有 dpNET 的 MEN1 患者无远处转移的患者 (n=30)，以及无 dpNET 的 MEN1 患者 (n=15)。盲法验证已确定的生物标志物将在第二个同等规模的独立患者队列中进行。这种独特的合作利用了最先进的质谱技术，一种疾病 MEN1 相关 pNET 的相关遗传小鼠模型以及来自三个充分表征的小鼠的血液样本来自美国和欧洲专家中心的 MEN1 队列的唯一目标是确定可操作的特征这可能为风险分层提供实用性或提供治疗目标。这个项目意义重大，因为它的目标通过识别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和 MEN1 相关 dpNET 患者的转移，以及鉴定一组相关的肿瘤抗原与 dpNET 一起，可用于后续为处于危险中的受试者和/或作为受试者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 dpNET 的新治疗靶点。由于超过 40% 的散发性 pNET 携带体细胞 MEN1 突变，这些发现也可能与更广泛的患者群体相关。