Small Molecule PSMA-Targeted Alpha Therapy

描述（由申请人提供）：尽管治疗去势抵抗性前列腺癌（CRPC）的新靶向药物越来越多，但这种疾病仍然无法治愈，近一半患有这种前列腺癌（PCa）的男性在两年内发生骨转移。转移性骨病的一年生存率约为40%。新的靶向治疗在机制上差异很大，从抑制雄激素产生的，如CYP酶抑制剂醋酸阿比特龙，到专注于转移性骨沉积的，如？粒子发射器，223RaCl2。最近的一项III期安慰剂对照ALSYMPCA试验研究了223RaCl2在CRPC和症状性骨转移患者中的应用，该试验显示出明显的生存获益，因此该试验提前终止。然而，223RaCl2仅将中位总生存期从11.2个月增加到14个月。在此，我们打算在初步临床成功的基础上，用？-发射器疗法通过产生发射？-针对骨定位和软组织定位肿瘤的特异性颗粒。粒子是氦核，具有短而致命的范围，并且被证明比？-粒子发射器在分子靶向癌症放射治疗中的应用。发展的目标？-发射器是为了尽量减少对周围组织的损害，这是目前标准的外部光束治疗无法达到的。它们以前曾在临床上用于治疗前列腺癌，但作为抗体偶联物，往往对实体肿瘤有限制。在这里，我们将把针对前列腺特异性膜抗原（PSMA）的低分子量前列腺癌放射药物的开发项目扩展到分子放射治疗药物，特别是针对前列腺特异性膜抗原的化合物的合成和优化。发射器疗法。我们已经在临床研究中表明，我们的药物能够同时针对骨骼和软组织。由于PSMA是在配体结合的基础上内化的，我们的化合物的荧光版本定位于核周区域，靠近放射治疗的主要目标-细胞DNA。初步剂量学研究表明，在正常组织（包括肾脏）沉积可接受的放射性水平下，可以实现有效的治疗。我们认为转移性CRPC的治疗是一个未被满足的医学需求。-排放者-是理想的选择。我们将采取分级方法，跨越三个目标，可以总结为：(1)合成含有？发射器,211;(2)符合亲和力和稳定性标准的化合物的生物学特性；(3)在相关PCa小鼠模型中使用合适的导联，并比较顶级导联及其131i标记类似物与临床新兴的psma靶向放疗药物人源化抗psma抗体177Lu-J591的相对生物学有效性。目标是在这个资助期结束时，有一个先导化合物准备好通过必要的步骤，转化为CRPC和仅生化复发的患者。

DESCRIPTION (provided by applicant): Despite the expanding arsenal of new targeted agents to treat castrate-resistant prostate cancer (CRPC), the disease remains incurable, with nearly half of men with this form of prostate cancer (PCa) developing bone metastases at two years. Metastatic bone disease carries a one year survival rate on the order of 40%. New targeted therapies vary widely in mechanism, from those that inhibit androgen production, such as the CYP enzyme inhibitor abiraterone acetate, to those that focus on metastatic bone deposits, such as the ?-particle emitter, 223RaCl2. The recent Phase III, placebo-controlled ALSYMPCA trial, which studied 223RaCl2 in men with CRPC and symptomatic bone metastases, demonstrated such a clear survival benefit that the trial was discontinued early. Nevertheless, 223RaCl2 only increased median overall survival from 11.2 to 14 months. Here, we intend to build on this initial clinical success with ?-emitter therapy by generating targeted compounds that emit ?-particles specific for both bone-localized and soft tissue-localized tumors. Alpha particles are helium nuclei that have a short but highly lethal range and have proved much more effective than ?-particle emitters in the context of molecularly targeted radiotherapy for cancer. A goal of developing ? - emitters is to minimize damage to adjacent, surrounding tissue, which is currently unattainable by standard external beam therapy. They have been employed clinically for treatment of PCa previously, but as antibody conjugates, which tend to have limited access to solid tumors. Here we will extend our program in the development of low molecular weight radiopharmaceuticals for PCa that target the prostate-specific membrane antigen (PSMA) to molecular radiotherapeutics - specifically for the synthesis and optimization of compounds for ?-emitter therapy. We have shown in clinical studies that our agents are capable of targeting both bone and soft tissue. Because PSMA is internalized upon ligand binding, fluorescent versions of our compounds localize to the perinuclear area, near the primary target for radiation therapy - cellular DNA. Preliminary dosimetry studies suggest effective treatment can be achieved with acceptable levels of radioactivity deposited to normal tissues, including kidney. We believe that treatment of metastatic CRPC is an unmet medical need for which molecular radiotherapy - particularly with targeted ?-emitters - is ideally suited. We will take a graded approach across three aims that can be summarized as: (1) synthesis of PSMA binding agents that incorporate the ?-emitter, 211At; (2) biological characterization of compounds meeting affinity and stability criteria; and, (3) radiotherapy of suitable leads in relevant mouse models of PCa and comparison of relative biological effectiveness of the top lead, and its 131I-labeled analog, to the emerging clinical PSMA-targeted radiotherapeutic, the humanized anti-PSMA antibody, 177Lu-J591. The goal is to have a lead compound at the end of this funding period ready to progress through the necessary steps for translation to patients with CRPC and biochemical-only recurrence.