Metastatic castration-resistant prostate cancer, or mCRPC, remains a major clinical challenge. While prostate-specific membrane antigen, PSMA, has emerged as a highly promising therapeutic target, differences in tumor biology, target expression, and radiopharmaceutical behavior continue to influence clinical outcomes. For PSMA-targeted radioligand therapies to reach their full potential, developers need preclinical models that reliably capture both tumor complexity and biodistribution behavior in vivo.
At AACR 2026, we presented data showing how patientderived xenograft (PDX) models can be used to evaluate PSMA-targeted radiopharmaceuticals at multiple levels. This included radiochemistry quality, biodistribution, and tumor selectivity. The work focused on two clinically relevant agents, [177Lu]LuPSMA617 and [225Ac]AcPSMA617, tested across a panel of mCRPC PDX models with variable PSMA expression.
Radiopharmaceutical therapies rely on far more than target binding alone. Successful translation depends on tumor uptake, retention, clearance from healthy tissues, and therapeutic index. Traditional cell line models fail to capture the architectural and microenvironmental features that shape these processes in patients.
PDX models preserve the genetic heterogeneity and tissue organization of the original human tumor. This makes them particularly well suited for studying radioligand distribution and efficacy in vivo. In the context of PSMA-targeted therapies, PDX models allow us to directly evaluate how differences in PSMA expression and tumor biology influence radiotracer uptake in clinically relevant tumor models.
In this study, we evaluated PSMA617 labeled with either lutetium177 or actinium225 across multiple prostate cancer PDX models representing metastatic, castration-resistant disease. The models spanned a range of PSMA expression levels, enabling us to assess how target expression directly relates to biodistribution.
We first confirmed robust radiochemical performance. PSMA617 was efficiently labeled with both isotopes, achieving high radiochemical purity that met stringent quality standards. Establishing radiochemistry consistency is a critical first step before moving into in vivo evaluation, particularly for comparative studies involving different isotopes.
Following radiotracer administration, we conducted biodistribution analyses at defined time points to quantify uptake across tumors and major organs. Rather than relying on a single model, we assessed multiple PDXs to capture biologically driven variability.
Across the panel, tumor uptake correlated strongly with PSMA expression levels. Models with high PSMA expression showed selective and robust radiotracer accumulation, while low-PSMA models demonstrated minimal uptake. This clear relationship confirms biological predictability and reinforces the value of molecularly annotated PDX panels when evaluating PSMA-targeted therapies.
Importantly, although both [177Lu]LuPSMA617 and [225Ac]AcPSMA617 demonstrated tumor targeting, differences emerged in tumor-to-normal tissue ratios. These distinctions highlight why side-by-side preclinical evaluation is essential when selecting isotopes and dosing strategies for clinical development.
One of the most important questions in PSMA radiopharmaceutical development is how different isotopes behave in vivo. Lutetium177 and actinium225 differ in emission properties, tissue penetration, and potential toxicity profiles.
Our comparative biodistribution analyses showed that while both agents localize to PSMA-expressing tumors, [177Lu]LuPSMA617 demonstrated more favorable tumortotissue ratios across several organs. These findings provide early insight into how isotope choice may influence therapeutic window and tolerability.
While alpha-emitters remain highly compelling for their potent cytotoxicity, data like this emphasize the importance of rigorous preclinical evaluation in clinically relevant models before advancing treatment strategies.
Radiopharmaceutical development is inherently multidisciplinary, integrating chemistry, biology, imaging, and therapeutic evaluation. PDX models provide a unifying platform where all of these components can be assessed in context.
Using well-characterized mCRPC PDXs allows us to:
This kind of integrated preclinical strategy is especially valuable as PSMA-targeted therapies continue to expand into earlier disease settings and combination regimens.
This blog highlights key findings, but the full study includes detailed radiochemistry validation, biodistribution data, tumor-to-tissue ratios, and efficacy results across multiple PDX models.