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Opening the Therapeutic Window for PSMA-Targeted Molecular Radiotherapy

打开 PSMA 靶向分子放射治疗的治疗窗口

基本信息

批准号：
10153738
负责人：
Daniel Lyndon Jaffe Thorek
金额：
$ 37.79万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10153738
关键词：
Ablation Address Affect Affinity Alpha Particle Emitter Alpha Particles Anatomy Animals Antibodies Autopsy Biodistribution Biological Biological Assay Caliber Cancer Etiology Cancer Patient Cell surface Cells Cessation of life Cleaved cell Clinic Clinical Clinical Chemistry Clinical Treatment Clinical Trials Complete Blood Count Coupled Data Detection Development Diagnostic Diagnostic Imaging Diagnostic radiologic examination Discipline of Nuclear Medicine Disease Disease model Dose Drug Kinetics Ensure Evaluation FOLH1 gene Genetic Engineering Goals Human Hybrids Image Ionizing radiation Isotopes Kidney Label Length Life Ligand Binding Ligands Linear Energy Transfer Location Long-Term Care Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Mediating Medical Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Methods Modeling Molecular Molecular Target Monitor Monitoring for Recurrence Normal tissue morphology Organ Outcome Output Pathologic Pathology Patient Care Patients Physics Positron-Emission Tomography Prodrugs Prostatic Neoplasms Radiation Dose Unit Radiation Tolerance Radiation therapy Radiochemistry Radioisotopes Radiolabeled Radiology Specialty Radiopharmaceuticals Renal function Reporting Research Personnel Role Salivary Salivary Glands Schedule Sea Site Specificity Survival Rate Targeted Radiotherapy Testing Therapeutic Time Tissues Toxic effect Toxicology Tracer Transgenic Organisms Translations Tumor Burden Variant Width Xenograft procedure Xerostomia cancer cell cancer radiation therapy comorbidity cytotoxicity drug development falls human disease imaging agent improved inhibitor/antagonist insight interest man men molecular imaging molecular oncology mouse model multidisciplinary novel novel strategies optimal treatments overexpression particle particle therapy patient population pinacolyl methylphosphonic acid preclinical imaging prevent prophylactic prostate cancer model quantitative imaging radioligand response serum PSA side effect single photon emission computed tomography small molecule subcutaneous success targeted agent targeted treatment therapeutic evaluation treatment response tumor uptake

项目摘要

PROJECT SUMMARY – This application addresses critical needs and deficiencies in prostate cancer (PCa) patient management. The five year survival rates for localized primary PCa are excellent, but sadly fall to below 1 in 3 for those with metastatic disease. The deluge of academic and clinical efforts to harness targeted agents for imaging of Prostate Specific Membrane Antigen (PSMA), widely overexpressed on prostate cancer tissues, for improved detection represents a sea change in how malignant disease will be monitored. Advancing close behind is a systematic evaluation of therapeutic variants of these agents that deliver an ionizing radiation dose to PSMA- expressing sites of disease. There is considerable interest in alpha particle (α-particle) emitting radionuclides for this targeted radiotherapy as the high linear energy transfer imparts 5-8 MeV in a dense track that is only several cell diameters in length. Unfortunately, widespread background-organ expression of PSMA results in untoward side-effects of absorbed dose to normal tissues. Off-target toxicity places limitations on the activity dose which may be administered; the patient population eligible for the treatment; the requirements for involved long term care of comorbidities; and ultimately the overall impact this treatment will have in the clinic. Here, we propose a strategy that enables organ specific reduction in absorbed dose without affecting tumor targeted uptake. We focus on the salivary glands and kidneys; radiosensitive organs that demonstrate intense PSMA-ligand targeting in pre- and clinical imaging and treatment studies. We have developed and acquired significant insight into a novel prodrug, Tris-POC-2-PMPA that is preferentially deliverd to the kidneys and salivary, and selectively cleaved in these organs, to release the high affinity PSMA inhibitor, 2-PMPA. Our Preliminary Data demonstrate the potential to ensure that tumor specific ablation without toxicity can be achieved while sparing kidney and salivary tissue. Taking advantage of a hybrid imaging and therapy approach, we will define the optimal treatment course required for tumor control, without normal organ toxicity, in multiple small animal xenograft and in an advanced genetically engineered model that most closely recapitulates human disease. This application is being undertaken by a multidisciplinary team composed of experts in radiochemistry, medical physics, pathology, drug development and clinical molecular imaging. This group of investigators and the strength of our data addressing key issues in alpha particle emitting radiopharmaceutical development demonstrate that this application has the potential to realize the transformative capabilities of molecularly targeted radiotherapy for cancer patients.

项目概要 – 该应用程序解决了前列腺癌 (PCa) 患者管理中的关键需求和缺陷。局部原发性 PCa 的五年生存率非常高，但遗憾的是，对于那些患有局部原发性 PCa 的患者来说，五年生存率降至三分之一以下。转移性疾病。利用靶向药物进行成像的大量学术和临床努力前列腺特异性膜抗原 (PSMA) 在前列腺癌组织中广泛过度表达，可改善检测代表了恶性疾病监测方式的巨大变化。紧随其后前进的是对这些向 PSMA 传递电离辐射剂量的药物的治疗变体进行系统评估表达疾病部位。人们对发射放射性核素的α粒子（α粒子）有相当大的兴趣，用于这一目标放射治疗，因为高线性能量转移在只有几个细胞直径的密集轨道中传递 5-8 MeV 长度。不幸的是，PSMA 的广泛背景器官表达会导致不良副作用正常组织吸收的剂量。脱靶毒性对活性剂量造成限制，这可能是管理；符合治疗条件的患者群体；涉及长期护理的要求合并症；最终这种治疗对临床产生的总体影响。在这里，我们提出了一种策略，可以在不影响器官特异性的情况下减少吸收剂量肿瘤靶向摄取。我们重点关注唾液腺和肾脏；放射敏感器官表现出在预前和临床成像和治疗研究中进行强烈的 PSMA 配体靶向。我们已经开发并对优先输送至肾脏的新型前药 Tris-POC-2-PMPA 有了重要的了解和唾液，并在这些器官中选择性裂解，释放高亲和力 PSMA 抑制剂 2-PMPA。我们的初步数据表明有潜力确保实现无毒性的肿瘤特异性消融同时保留肾脏和唾液组织。利用混合成像和治疗方法，我们将确定肿瘤控制所需的最佳治疗疗程，不产生正常器官毒性，在多个小动物异种移植和最接近人类的先进基因工程模型疾病。该应用程序由放射化学专家组成的多学科团队进行，医学物理学、病理学、药物开发和临床分子成像。这组调查人员和我们的数据实力解决了α粒子发射放射性药物开发中的关键问题证明该应用有潜力实现分子靶向的变革能力癌症患者的放射治疗。