Project 1: Theranostics in Neuroendocrine Tumors

项目 1：神经内分泌肿瘤的治疗诊断学

• 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
• 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

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（NETs）对儿童和成人构成了未被认识的健康威胁。发生率 在美国，NET的流行率正在上升;然而，对NET的研究很少，没有 转移性疾病患者的有效治疗，超过一半的患者在诊断后五年内死亡 根据最新的SEER数据。这些肿瘤对常规化疗或外照射无反应 辐射，使新的诊断和治疗方案的发展势在必行。我们假设 使用单一化合物作为治疗剂和诊断剂的治疗诊断学将满足这一关键要求。 儿童和成年人需要NET。本提案的翻译部分将确定新的 治疗诊断靶点，设计和合成新的靶向剂，并在体内测试其功效。铅 作为高亲和力PET示踪剂和分子靶向治疗剂， 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， 首次通过探索性IND机制进行人体PET成像试验。具体目标是： 1.设计和合成独特的、高亲和力的、稳定的配体，用于GPCR靶向治疗诊断学。 来自项目3的表达数据已经确定了三种GPCR（OXTR，VPAC 1，MC 1 R）作为NET中的新靶标。 治疗诊断放射性药物将设计和合成使用核磁共振和三维建模，以指导 增强候选配体的亲和力、特异性和稳定性的化学修饰。肽文库 掺入D-和非天然氨基酸、环化策略和DOTA的赖氨酸取代 将合成缀合物;将在体外测定结合亲和力、特异性和稳定性。 2.表征新型靶向GPCR的体内特异性、稳定性、药代动力学和细胞毒性 在神经内分泌肿瘤的小鼠模型中的治疗诊断化合物。我们将进行治疗诊断预- 在NET的小鼠模型中对前导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示踪剂在人类中进行测试。 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。探索性 IND将首先获得，以检查主要候选药物定位于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，并证明安全性，特异性， 作为NET患者的PET示踪剂的可重复性和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，并首次用于人体分子靶向PET 成像试验将为开发新的放射治疗药物铺平道路，最终目标是提供 神经内分泌肿瘤患者的双靶点、双放射性核素治疗。