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：
9920131
负责人：
Daniel Lyndon Jaffe Thorek
金额：
$ 40.12万
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/9920131
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.

项目摘要 - 该应用程序解决了前列腺癌（PCA）患者管理的关键需求和缺陷。局部初级PCA的五年生存率非常好，但可悲的是，患有转移性疾病。利用学术和临床努力来利用针对代理的成像前列腺特异性膜抗原（PSMA），在前列腺癌组织上广泛表达，以改善检测代表了如何监测恶性疾病的海洋变化。近距离前进是一个对这些药物的治疗变体的系统评估，这些变体将电离辐射剂量剂量付给PSMA- 表达疾病部位。对于该目标放射疗法作为高线性能量转移在密集的轨道中赋予5-8 MEV，仅是几个细胞直径长度。不幸的是，PSMA的宽度宽度背景和器官表达会导致不良副作用吸收到正常组织的剂量。非目标毒性对活动剂量的限制可能是管理；符合治疗的患者人群；涉及长期护理的要求合并症；最终，这种治疗方法将在诊所产生总体影响。在这里，我们提出了一种策略，该策略可以使器官特定减少吸收剂量的降低而不会影响肿瘤针对摄取。我们专注于唾液烤架和肾脏；放射敏感器官证明在临床和临床成像和治疗研究中进行强烈的PSMA-----靶向。我们已经开发了获得了对新型前药Tris-POC-2-PMPA的重要见解，该前药优先交付给孩子们和唾液，并在这些器官中有选择地清除，以释放高亲和力PSMA抑制剂2-PMPA。我们的初步数据证明了确保可以实现肿瘤特异性消融的潜力同时保留肾脏和唾液组织。利用混合成像和治疗方法，我们将定义多个小的肿瘤控制所需的最佳治疗方法，没有正常器官毒性动物异种移植物以及最紧密地概括人类的先进遗传学工程模型疾病。该应用程序由由放射化学专家组成的多学科团队进行，医学物理，病理，药物发育和临床分子成像。这组调查员和我们的数据的强度解决了α粒子发射放射性制剂中关键问题的强度证明该应用有可能实现分子靶向的变革能力癌症患者的放疗。