Opening the Therapeutic Window for PSMA-Targeted Molecular Radiotherapy

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。 局限性原发性PCa的5年生存率非常好，但对于那些患有原发性PCa的患者， 转移性疾病大量学术和临床努力利用靶向药物进行成像 前列腺特异性膜抗原（PSMA），在前列腺癌组织中广泛过表达，用于改善 检测代表着恶性疾病监测方式的巨大变化。紧随其后的是 对这些药物的治疗变体进行系统评价，这些药物将电离辐射剂量递送至PSMA， 表达疾病的部位。 对于这种靶向的α粒子（α粒子）发射放射性核素存在相当大的兴趣。 放射治疗作为高线性能量转移在仅几个细胞直径的密集轨道中给予5-8 MeV 长的不幸的是，PSMA的广泛背景器官表达导致PSMA的不良副作用。 正常组织吸收剂量。脱靶毒性对活性剂量造成限制， 管理;适合治疗的患者人群;参与长期护理的要求 合并症;以及最终这种治疗在临床上的总体影响。 在这里，我们提出了一种策略，使器官特异性减少吸收剂量，而不影响 肿瘤靶向摄取。我们专注于唾液腺和肾脏;放射敏感器官， 在临床前和临床成像和治疗研究中的强烈PSMA配体靶向。我们已经开发并 获得了一个新的前体药物，Tris-POC-2-PMPA，优先输送到肾脏的重要见解 和唾液，并在这些器官中选择性地裂解，以释放高亲和力PSMA抑制剂2-PMPA。我们 初步数据表明，有可能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过程，无正常器官毒性，在多个小 动物异种移植和先进的基因工程模型，最接近地概括人类 疾病 由放射化学专家组成的多学科小组正在进行这项申请， 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 我们的数据解决了α粒子发射放射性药物开发中的关键问题 证明这种应用有可能实现分子靶向的转化能力， 癌症患者的放疗。

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.