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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要该项目的长期目标是开发一种治疗诊断（用于诊断和治疗）靶向药物神经降压素受体 1 (NTSR1) 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。大约 1 英寸 9 名男性一生中将被诊断出患有前列腺癌。尽管其诊断和治疗方面最近取得了进展尽管经过治疗，晚期前列腺癌的生存率仍然很低。事实上，晚期患者阶段前列腺癌最初对激素治疗的反应率可能超过 90%，但可能会复发进入激素抵抗状态，一般在3年内死亡。显然，这种未满足的迫切需求需要进一步探索用于患者筛查、转移性疾病检测的临床相关分子靶标，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）在前列腺癌进展中发挥关键作用。在我们最近的组织学分析中，所有检查的 PSMA 阴性前列腺癌组织均发现 NTSR1 表达阳性，表明 NTSR1 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NTSR1靶向治疗。在这个项目中，AccuNovo Biotech Inc.将与Profs合作。 Zibo Li 和 Rihe Liu 在 UNC Chapel Hill 进行开发基于配体发现的最新进展，针对 NTSR1 的新治疗诊断剂。最近，我们发现将交联多胺引入 SR142948A（导致新试剂 SR-CP-05）可能会增加与肽类药物相比，肿瘤摄取增加10倍。这一发现为我们提供了前所未有的开发 NTSR1 靶向治疗诊断剂的机会。我们将专注于显像剂的开发第一阶段。该提案的具体目标是：目标 1：开发 64Cu 标记的 NTSR1 靶向 PET 试剂，高且持续的肿瘤摄取；目标 2：对前列腺癌的主要药物进行并排比较小鼠模型并选择最佳药物进行 II 期疗效研究。该项目的成功不仅将引领一种基于成像的精确方法，可有效检测前列腺癌中的 NTSR1 表达（对于患者筛查和治疗监测），还可进一步开发为基于放射性核素的前列腺药剂癌症治疗。