Opening the Therapeutic Window for PSMA-Targeted Molecular Radiotherapy

项目总结- 这一应用解决了前列腺癌(PCA)患者管理中的关键需求和不足。 局部性原发PCa的五年存活率很高，但不幸的是，对于那些患有 转移性疾病。学术和临床努力的洪流，以利用靶向药物进行成像 前列腺癌组织中广泛过度表达的前列腺特异性膜抗原(PSMA) 检测代表着恶性疾病监测方式的巨大变化。紧随其后是一种 对向PSMA提供电离辐射剂量的这些药物的治疗变体进行系统评估- 表达疾病的部位。 为了这个目标，人们对发射放射性核素的阿尔法粒子(α粒子)有相当大的兴趣 放射治疗作为高线性能量传递，在只有几个细胞直径的致密轨道上提供5-8 MeV 在篇幅上。不幸的是，PSMA广泛的背景器官表达导致了 对正常组织的吸收剂量。靶外毒性对活动性剂量造成限制，可能是 给予；有资格接受治疗的患者人数；涉及长期护理的要求 合并症；以及最终这种治疗将在临床上产生的总体影响。 在这里，我们提出了一种策略，使器官特异性吸收剂量减少而不影响 肿瘤靶向摄取。我们关注的是唾液腺和肾脏；对辐射敏感的器官 在前期和临床成像和治疗研究中强烈的PSMA配体靶向。我们已经开发出了 对一种新的前药Tris-POC-2-PMPA有了重大的洞察力，它优先被输送到肾脏 和唾液，并选择性地在这些器官中裂解，释放高亲和力的PSMA抑制剂2-PMPA。我们的 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疗程，无正常器官毒性，在多个小的 异种动物移植和最接近人类的先进基因工程模型 疾病。 这项应用是由一个由放射化学专家组成的多学科团队承担的， 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 我们解决阿尔法粒子发射放射性药物开发中关键问题的数据的强度 证明这一应用具有实现分子靶向的转化能力的潜力 癌症患者的放射治疗。

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.