Theranostic NTSR1-targeting Agents for Complementary Management of PSMA-negative Prostate Cancer

用于补充治疗 PSMA 阴性前列腺癌的治疗诊断 NTSR1 靶向药物

• 批准号: 10484532
• 负责人: Xiaomei Li
• 金额: $ 37.64万
• 依托单位: ACCUNOVO BIOTECHNOLOGIES INC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-05 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10484532
• 关键词: Antiandrogen Therapy; Antineoplastic Agents; Benign Prostatic Hypertrophy; Biotechnology; Cancer Etiology; Cancer Patient; Cessation of life; Chelating Agents; Clinical; Clinical Research; Collaborations; Colorectal Cancer; Complement; Data; Detection; Development; Diagnosis; Disease; Evaluation; FOLH1 gene; Fees; Future; Goals; Head Cancer; Histology; Hormones; Image; Immunotherapeutic agent; International; Label; Lead; Legal patent; Licensing; Ligands; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Methods; Molecular Target; Monitor; Neck Cancer; Neoplasm Metastasis; Neurotensin; Neurotensin Receptors; New Agents; Oncogenic; Organ; Patient Care; Patients; Peptides; Phase; Play; Polyamines; Positron-Emission Tomography; Prostate Cancer therapy; Proto-Oncogene Proteins c-akt; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Refractory; Relapse; Role; Sampling; Series; Side; Signal Pathway; Solid Neoplasm; Survival Rate; Technology; Therapeutic; Time; Tissues; Toxic effect; Tumor Antigens; United States; base; clinically relevant; commercial application; crosslink; dosimetry; efficacy study; hormone therapy; imaging agent; imaging modality; improved; innovation; malignant breast neoplasm; men; molecular marker; mouse model; neuroendocrine phenotype; novel; patient screening; personalized medicine; phase 2 study; prognostic method; prostate cancer model; prostate cancer progression; success; targeted agent; targeted imaging; targeted treatment; theranostics; therapeutically effective; treatment strategy; tumor; uptake

Project Summary The long-term goal of this project is to develop a theranostic (for both diagnosis and therapy) agent targeting neurotensin receptor 1 (NTSR1) for prostate cancer management. Prostate cancer is the second-leading cause of cancer deaths for men in the United States. Approximately 1 in 9 men will be diagnosed with prostate cancer in their lifetime. Despite recent developments in its diagnosis and treatments, the advanced stages of prostate cancer still have poor survival rates. In fact, patients with advanced stage prostate cancer may initially respond to hormone therapy with more than 90% rate, but they could relapse into the hormone-refractory state and generally die within 3 years. Clearly, this urgent unmet need warrants further exploration of clinically relevant molecular targets for patient screening, detection of metastatic disease, and corresponding treatment strategies. Accumulating evidence suggests that neurotensin (NTS) and neurotensin receptors (NTSRs) play key roles in prostate cancer progression. In our recent histology analysis, all examined PSMA-negative prostate cancer tissues were found to have positive NTSR1 expression, suggesting the potential complementary role of NTSR1 targeted imaging/therapy towards PSMA based imaging/therapy. In another word, NTSR1 targeted therapy could be used when PSMA targeted therapy fails. In this project, AccuNovo Biotech Inc. will partner with Profs. Zibo Li and Rihe Liu at UNC Chapel Hill to develop new theranostic agents targeting NTSR1 based on the recent progress on ligand discovery. Recently, we found that the introduction of crosslinked polyamines into SR142948A (leading to new agent SR-CP-05) could increase the tumor uptake by 10 times compared with peptide-based agent. This discovery offered us an unprecedented opportunity to develop NTSR1 targeted theranostic agents. We will focus on imaging agent development in Phase I. The specific aims of this proposal are: Aim 1: Develop 64Cu labeled NTSR1-targeting PET agents with high and persistent tumor uptake; Aim 2: Perform side-by-side comparison of lead agents in prostate cancer mouse models and select the best agent for Phase II efficacy study. The success of this project will not only lead to an accurate imaging-based method to efficiently detect NTSR1 expression in prostate cancer (for patient screening and treatment monitoring), but also be further developed into a radionuclide-based agent for prostate cancer therapy.

项目摘要 该项目的长期目标是开发一种治疗诊断（诊断和治疗）剂， 神经降压素受体1（NTSR 1）用于前列腺癌治疗。 前列腺癌是美国男性癌症死亡的第二大原因。中约有1位 9名男性一生中将被诊断患有前列腺癌。尽管最近的发展，在其诊断和 前列腺癌的早期症状有哪些？事实上，晚期患者 早期前列腺癌可能对激素治疗有超过90%的反应，但它们可能复发 进入难治性疾病状态，通常在3年内死亡。显然，这一迫切的未满足需求需要 进一步探索用于患者筛选，转移性疾病检测， 以及相应的治疗策略。越来越多的证据表明，神经降压素（NTS）和 神经降压素受体（NTSR）在前列腺癌进展中起关键作用。在我们最近的组织学分析中， 发现所有检查的PSMA阴性前列腺癌组织均具有阳性NTSR 1表达，提示 NTSR 1靶向成像/治疗对基于PSMA的成像/治疗的潜在补充作用。在 也就是说，当PSMA靶向治疗失败时，可以使用NTSR 1靶向治疗。 在这个项目中，AccuNovo Biotech Inc.将与教授合作。李淄博和刘日和在查佩尔山发展 基于配体发现的最新进展，新的治疗诊断剂靶向NTSR 1。最近，我们发现 在SR 142948 A中引入交联多胺（产生新试剂SR-CP-05）可能会增加 肿瘤摄取比肽类药物高10倍。这一发现为我们提供了前所未有的 开发NTSR 1靶向治疗诊断剂的机会。我们将专注于显像剂的开发， 一阶段本提案的具体目标是：目标1：开发64 Cu标记的NTSR 1靶向PET试剂， 高和持久肿瘤摄取;目的2：进行前列腺癌中主要药物的并行比较 小鼠模型，并选择最佳药物进行II期疗效研究。这个项目的成功不仅会导致 涉及一种基于精确成像的方法，以有效地检测前列腺癌中的NTSR 1表达（对于患者 筛查和治疗监测），而且还可以进一步开发成基于放射性核素的前列腺制剂。 癌症治疗。