Bidkar Anil P, Peter Robin, Wadhwa Anju, Bobba Kondapa Naidu, Bidlingmaier Scott, Meher Niranjan, Chou Jonathan, Greenland Nancy, Dasari Chandrashekhar, Naik Shubhankar, Raveendran Athira, Basak Megha, Camara Serrano Juan Antonio, Steri Veronica, Kogan Scott, Oskowitz Adam, He Jiang, Wilson David M, Aggarwal Rahul, Sriram Renuka, VanBrocklin Henry F, Seo Youngho, Liu Bin, Flavell Robert R
Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California.
Department of Nuclear Engineering, University of California, Berkeley, California.
Clin Cancer Res. 2025 Jul 15;31(14):2963-2977. doi: 10.1158/1078-0432.CCR-24-2850.
Metastatic castration-resistant prostate cancer has limited treatment options and a poor prognosis. Recently, prostate-specific membrane antigen (PSMA)-targeted alpha-particle therapy agents using actinium-225 (225Ac) have shown promising results in prostate cancer treatment, but a significant fraction of patients with advanced mCRPC demonstrate loss of PSMA expression. We have previously reported that PSMA-null and PSMA-positive tumors can be detected and treated effectively with CD46-targeted radiopharmaceuticals. This study evaluates the CD46-targeting PET imaging agent [89Zr]DFO-YS5, and the radioimmunotherapy agent [225Ac]Macropa-PEG4-YS5, in disseminated prostate cancer tumors.
Microtumor lesions, primarily observed in the liver, kidneys, and lungs, were successfully detected with [89Zr]DFO-YS5 PET imaging. We used disseminated 22Rv1 tumors for biodistribution studies, dosimetry assessments, and therapeutic efficacy evaluations of [225Ac]Macropa-PEG4-YS5.
Quantitative digital alpha-particle autoradiography revealed high radiation dose deposition from [225Ac]Macropa-PEG4-YS5 in microtumors compared with surrounding liver tissues, although in larger lesions (>1 mm diameter), the dose distribution was heterogeneous. Early treatment of smaller disseminated tumors with a uniform radiation dose was more effective in ablating tumors and promoting survival. In late-stage lesions of large size, heterogeneous dose deposition limited therapeutic efficacy, requiring higher administered activity to achieve a complete response.
Our findings highlight that [225Ac]Macropa-PEG4-YS5 holds the potential for clinical translation for metastatic prostate cancer and reinforces the value of microdosimetry in understanding the efficacy of and resistance to targeted alpha therapy. See related commentary by Patel et al., p. 2847.
转移性去势抵抗性前列腺癌的治疗选择有限，预后较差。最近，使用锕 - 225（225Ac）的前列腺特异性膜抗原（PSMA）靶向α粒子治疗药物在前列腺癌治疗中显示出有前景的结果，但相当一部分晚期转移性去势抵抗性前列腺癌（mCRPC）患者表现出PSMA表达缺失。我们之前报道过，PSMA阴性和PSMA阳性肿瘤可以用靶向CD46的放射性药物有效检测和治疗。本研究评估了靶向CD46的正电子发射断层显像（PET）显像剂[89Zr]DFO - YS5以及放射免疫治疗药物[225Ac]Macropa - PEG4 - YS5在播散性前列腺癌肿瘤中的作用。
主要在肝脏、肾脏和肺中观察到的微肿瘤病灶通过[89Zr]DFO - YS5 PET显像成功检测到。我们使用播散性22Rv1肿瘤进行生物分布研究、剂量测定评估以及[225Ac]Macropa - PEG4 - YS5的治疗效果评估。
定量数字α粒子放射自显影显示，与周围肝组织相比，[225Ac]Macropa - PEG4 - YS5在微肿瘤中的辐射剂量沉积较高，尽管在较大病灶（直径>1 mm）中，剂量分布不均匀。用均匀辐射剂量对较小的播散性肿瘤进行早期治疗在消融肿瘤和提高生存率方面更有效。在大尺寸的晚期病灶中，不均匀的剂量沉积限制了治疗效果，需要更高的给药活度才能实现完全缓解。
我们的研究结果表明，[225Ac]Macropa - PEG4 - YS5具有用于转移性前列腺癌临床转化的潜力，并强化了微剂量测定在理解靶向α治疗的疗效和耐药性方面的价值。见Patel等人的相关评论，第2847页。
