Metastatic castration-resistant prostate cancer (mCRPC) has limited treatment options and a poor prognosis. Recently, PSMA-targeted alpha particle therapy agents using Actinium-225 (225Ac) have shown promising results for 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 to surrounding liver tissues, although in larger lesions (>1 mm diameter) the dose distribution was heterogeneous. Early treatment of smaller disseminated tumors with 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.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2025 Feb 13 [Epub ahead of print]
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
University of California, San Francisco, San Francisco, CA, United States., University of California, Berkeley, United States., UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, United States., National Institute of Pharmaceutical Education and Research, Lucknow, UP, India., University of California, San Francisco, United States., University of California, Berkeley, Berkeley, United States., University of Virginia, Charlottesville, VA, United States.
PubMed http://www.ncbi.nlm.nih.gov/pubmed/39945595