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Poster

AACR 2026 Poster #5812

Preclinical evaluation of [177Lu] Lu-PSMA-617 and [225Ac] Ac-PSMA-617 in mice bearing castration-resistant prostate adenocarcinoma patient-derived xenografts

Summary

Background Patient-derived xenograft (PDX) models are essential for radiopharmaceutical evaluation because they preserve the genetic and microenvironmental complexity of human tumors, offering a more clinically relevant platform than traditional cell lines. This enables more accurate prediction of drug distribution, target engagement, and therapeutic efficacy, reducing translational gaps in radiopharmaceutical development. This study presents a comprehensive preclinical evaluation of two PSMA-targeted radiopharmaceuticals, [177Lu]Lu-PSMA-617 and [225Ac]Ac-PSMA-617, in murine models bearing PDXs of metastatic, castration-resistant prostate adenocarcinoma. These models are deeply characterized across multiple layers, including in-depth molecular data such as phosphoproteomics. Methods PSMA-617 was successfully radiolabeled with lutetium-177 and actinium-225 using optimized protocols that ensured high radiochemical purity. Preclinical evaluation of [177Lu]Lu-PSMA-617 and [225Ac]Ac-PSMA-617 was conducted in mice bearing CTG-2428 (PSMA+) PDX tumors derived from a 67-year-old Caucasian male with metastatic, castration-resistant prostate adenocarcinoma, and CTG-3537 (PSMA-) PDX tumors derived from a 63-year-old African American male with metastatic, castration-resistant prostate adenocarcinoma. Biodistribution studies of [177Lu]Lu-PSMA-617 were performed in mice bearing PSMA+ and PSMA- PDX tumors. Mice received 0.3 mCi (11 MBq) [177Lu]Lu-PSMA-617, and tumors and major organs were collected, weighed, and measured for radioactivity 24 hours post-injection.

Therapeutic efficacy of [177Lu]Lu-PSMA-617 and [225Ac]Ac-PSMA-617 was assessed in mice bearing CTG-2428 (PSMA+) PDX tumors. Mice received 1 mCi (37 MBq) of [177Lu]Lu-PSMA-617 or 1 μCi (37 kBq) of [225Ac]Ac-PSMA-617, and tumor size and body weight were measured twice weekly throughout the study. Results [177Lu]Lu-PSMA-617 and [225Ac]Ac-PSMA-617 were obtained with radiochemical purity greater than 98%, as determined by radio-TLC and radio-HPLC. The radiotracers demonstrated selective uptake in PSMA-positive tumors, with minimal accumulation in PSMA-negative PDX, confirming target specificity. Importantly, the radiotracers showed excellent tumor-to-tissues ratios. Both agents significantly inhibited tumor growth compared to controls in mice bearing PSMA-positive PDX tumors. Treatment was well tolerated, with no significant weight loss or acute toxicity observed.

Conclusions Further studies are warranted to optimize dosing strategies and evaluate long-term safety. Importantly, this work underscores the critical role of PDX models in capturing real receptor expression and tumor heterogeneity, thereby enhancing the translational relevance of radiopharmaceuticals in preclinical development.

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