Project 1: Theranostics in Neuroendocrine Tumors

项目 1：神经内分泌肿瘤的治疗诊断学

基本信息

批准号：
10264528
负责人：
Yusuf Menda
金额：
$ 5.86万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10264528
关键词：
90Y Adult Affinity Animals Binding Biodistribution Biological Specimen Banks Biopsy Specimen Chemicals Child Clinical Trials Collaborations Combined Modality Therapy Cyclization Data Development Diagnosis Diagnostic Disease Disease Progression Drug Kinetics External Beam Radiation Therapy G-Protein-Coupled Receptors Gastric Inhibitory Polypeptide Goals Health Human In Vitro Incidence Islet Cell Tumor Isotopes Lead Ligands Lysine Malignant Neoplasms Melanocortin 1 Receptor Modeling Modification Molecular Target Neuroendocrine Tumors Octreotide Operative Surgical Procedures Orphan Oxytocin Oxytocin Receptor Pancreas Patients Pattern Peptide Library Peptide Receptor Peptides Pharmaceutical Preparations Positron-Emission Tomography Pre-Clinical Model Preclinical Testing Prevalence Process Publications Radiation therapy Radiolabeled Radionuclide therapy Radiopharmaceuticals Reproducibility Research Residual state Resistance SDZ RAD SSTR2 gene Safety Serum Small Intestines Specialized Program of Research Excellence Specificity Techniques Testing Therapeutic Time Tissue Banks Tissue Microarray Tracer United States Vasoactive Intestinal Peptide alpha-Melanocyte stimulating hormone analog candidate marker chemotherapy curative treatments cytotoxicity design effective therapy first-in-human high throughput screening human imaging improved in vivo in vivo evaluation innovation interest lead candidate molecular targeted therapies mouse model novel diagnostics novel therapeutics patient registry pre-clinical preclinical toxicity receptor receptor expression somatostatin receptor 2 targeted agent targeted treatment theranostics therapeutic target three-dimensional modeling tumor tumor xenograft unnatural amino acids vasoactive intestinal peptide receptor 1

项目摘要

Neuroendocrine tumors (NETs) constitute an unrecognized health threat to children and adults. The incidence and prevalence of NETs is rising in the United States; yet, there is very little research on NETs, and no effective treatment for patients with metastatic disease, over half of whom die within five years of diagnosis according to latest SEER data. These tumors do not respond to conventional chemotherapy or external beam radiation, making development of new diagnostic and therapeutic options imperative. We hypothesize that theranostics, use of a single compound as both a therapeutic and a diagnostic agent, will meet this critical need for children and adults with NETs. The translational component of this proposal will identify new theranostic targets, design and synthesize new targeting agents, and test their efficacy in vivo. Lead compounds that meet strict criteria as high affinity PET tracers and molecularly targeted therapeutic agents in pre-clinical models of bronchial, small bowel, or pancreatic neuroendocrine tumors will be brought forward to first in human PET imaging trials through an Exploratory IND mechanisms. Specific aims are: 1. Design and synthesize unique, high-affinity, stable ligands for use in GPCR targeted theranostics. Expression data from Project 3 has identified three GPCR (OXTR, VPAC1, MC1R) as new targets in NETs. Theranostic radiopharmaceuticals will be designed and synthesized using NMR and 3-D modeling to guide chemical modifications that enhance affinity, specificity and stability of candidate ligands. Peptide libraries incorporating D- and unnatural amino acids, cyclization strategies, and lysine substitutions for DOTA conjugation will be synthesized; binding affinity, specificity and stability will be determined in vitro. 2. Characterize in vivo specificity, stability, pharmacokinetics, and cytotoxicity of new GPCR targeted theranostic compounds in mouse models of neuroendocrine tumors. We will conduct theranostic pre- clinical in vitro and in vivo testing of lead GPCR targeted ligands in mouse models of NETs with the goal of having at least two analogs ready to test as PET tracers in humans by year 5. 3. Examine safety and efficacy of new GPCR targeted PET tracers in humans using exploratory IND. Agents that pass rigorous pre-clinical testing will then be synthesized under GMP conditions. An exploratory IND will be obtained to examine the ability of lead candidates to localize to neuroendocrine tumors in first in human trials. Successful tracers that meet the strict theranostic criteria and demonstrate safety, specificity, and reproducibility as a PET tracer in patients with NETs, will be further developed through a full IND. Successful completion of these pre-clinical theranostic trials and first in human molecularly targeted PET imaging trials will pave the way for development of new radiotherapeutics with the ultimate goal of providing dual-target, dual-radionuclide therapy for patients with neuroendocrine tumors.

神经内分泌肿瘤（NET）对儿童和成人构成了未被认识到的健康威胁。发病率在美国，NET 的流行率正在上升；然而，关于 NET 的研究却很少，也没有对转移性疾病患者的有效治疗，其中一半以上在诊断后五年内死亡根据最新的 SEER 数据。这些肿瘤对传统化疗或外照射没有反应辐射，使得开发新的诊断和治疗方案势在必行。我们假设治疗诊断学，使用单一化合物作为治疗剂和诊断剂，将满足这一关键要求需要拥有 NET 的儿童和成人。该提案的翻译部分将确定新的治疗诊断目标，设计和合成新的靶向剂，并测试其体内功效。带领符合高亲和力 PET 示踪剂和分子靶向治疗剂严格标准的化合物支气管、小肠或胰腺神经内分泌肿瘤的临床前模型将被提出首先通过探索性 IND 机制进行人体 PET 成像试验。具体目标是： 1. 设计和合成独特、高亲和力、稳定的配体，用于 GPCR 靶向治疗诊断。项目 3 的表达数据已将 3 个 GPCR（OXTR、VPAC1、MC1R）确定为 NET 中的新靶标。将使用 NMR 和 3-D 建模来设计和合成治疗诊断放射性药物增强候选配体的亲和力、特异性和稳定性的化学修饰。肽库纳入 D- 和非天然氨基酸、环化策略以及 DOTA 的赖氨酸取代将合成缀合；结合亲和力、特异性和稳定性将在体外测定。 2.表征新GPCR靶向的体内特异性、稳定性、药代动力学和细胞毒性神经内分泌肿瘤小鼠模型中的治疗诊断化合物。我们将进行治疗诊断前在 NET 小鼠模型中对先导 GPCR 靶向配体进行临床体外和体内测试，目的是到第 5 年，至少有两种类似物可以作为 PET 示踪剂在人体中进行测试。 3. 使用探索性 IND 检查新型 GPCR 靶向 PET 示踪剂在人体中的安全性和有效性。通过严格的临床前测试的药物将在 GMP 条件下合成。一个探索性的将获得 IND 以检查先导候选药物定位神经内分泌肿瘤的能力人体试验。成功的示踪剂符合严格的治疗诊断标准并表现出安全性、特异性、以及作为 NET 患者 PET 示踪剂的可重复性，将通过完整的 IND 进一步开发。成功完成这些临床前治疗诊断试验，并且是人类分子靶向 PET 中的首次试验成像试验将为开发新的放射治疗方法铺平道路，最终目标是提供对神经内分泌肿瘤患者进行双靶点、双放射性核素治疗。