Project 1: Theranostics in Neuroendocrine Tumors

神经内分泌肿瘤(NETs)对儿童和成人的健康构成了未被认识到的威胁。发病率 而在美国，Net的流行率正在上升；然而，关于Nets的研究很少，而且没有 对转移性疾病患者的有效治疗，其中超过一半的患者在确诊后五年内死亡 根据最新的SEER数据。这些肿瘤对常规化疗或外照射无效。 辐射，使得开发新的诊断和治疗方案势在必行。我们假设 使用单一化合物作为治疗剂和诊断剂的体视学将满足这一关键要求。 需要儿童和成人使用Net。该提案的翻译部分将确定新的 治疗靶点，设计和合成新的靶向剂，并在体内测试其疗效。铅 符合严格标准的化合物，如高亲和力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前到 首次在人体PET成像试验中通过探索性的IND机制。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。 来自项目3的表达数据已经确定了三个GPCR(OXTR、VPAC1、MC1R)作为NETS中的新靶点。 医用放射性药物的设计和合成将使用核磁共振和三维建模来指导 增强候选配体的亲和力、特异性和稳定性的化学修饰。多肽文库 结合D-氨基酸和非天然氨基酸、环化策略和DOTA的赖氨酸取代 将合成偶联；结合亲和力、特异性和稳定性将在体外测定。 2.体内特异性、稳定性、药代动力学和细胞毒性研究 神经内分泌肿瘤小鼠模型中的鼻咽癌化合物。我们将进行射频消融前的 铅GPCR靶向配体在小鼠模型中的临床、体外和体内测试 至少有两个类似物准备好在5年前作为PET示踪剂在人体上进行测试。 3.使用探索性IND检查新的GPCR靶向PET示踪剂在人类中的安全性和有效性。 通过严格临床前测试的药物将在GMP条件下合成。探索性的 将获得IND以检查先导候选者在第一个月中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标准，并显示出安全性、特异性、 作为蚊帐患者的PET示踪剂，其重复性将通过全面的IND得到进一步发展。 成功完成这些临床前治疗试验，并首次在人类分子靶向PET中 成像试验将为开发新的放射疗法铺平道路，最终目标是提供 神经内分泌肿瘤的双靶点、双核素治疗。

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.