Data from Effective Treatment of Disseminated Prostate Cancer Using CD46-Targeted 225Ac Therapy
Year: 2025
Type: other
Abstract: Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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
Authors: Anil P. Bidkar, Robin Peter, Anju Wadhwa, Kondapa Naidu Bobba, Scott Bidlingmaier, Niranjan Meher, Jonathan Chou, Nancy Greenland, Chandrashekhar Dasari, Shubhankar Naik, Athira Raveendran, Megha Basak, Juan Antonio Camara Serrano, Veronica Steri, Scott Kogan, Adam Oskowitz, Jiang He, David M. Wilson, Rahul Aggarwal, Renuka Sriram, Henry F. VanBrocklin, Youngho Seo, Bin Liu, Robert R. Flavell
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4412417537