Project title: Developing a functional in vitro model to investigate renal toxicity of radionuclide therapy agents

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Project Description:

Dr. Kossatz and her team aims to establish a new cell-based technology that could accelerate discovery and optimization of radiopharmaceuticals for NET treatment. High kidney uptake and retention of therapeutic radiopeptides is currently a major factor that limits clinical translation and application of peptide receptor radionuclide therapy (PRRT). Their goal is to establish an in vitro assay system using functional proximal tubule epithelial cells that can predict in vivo kidney uptake and retention of radiopharmaceuticals.

What critical NET problem will you try to solve through your research?

High kidney uptake and retention of therapeutic radiopeptides is currently a major factor that limits clinical translation and application of peptide receptor radionuclide therapy (PRRT). An important bottleneck in the development of new radiopharmaceuticals is not their synthesis, but the biological evaluation of each new compound. While many characteristics can be efficiently screened in vitro to assess their potential for in vivo studies and translation, kidney uptake and retention are crucial aspects of radiopharmaceuticals that cannot yet be evaluated in vitro.

Why is this important?

Currently, renal uptake and retention of new radiopharmaceuticals is only evaluated once a ligand reaches the in vivo level, which does not allow for high-throughput screening to identify novel ligands with a suitable renal uptake profile for PRRT. This results in a limited number of radiopharmaceuticals that can be screened in vivo, which in turn contributes to the lack of a clear understanding of kidney uptake and retention of radiopharmaceuticals and how they can be controlled. Furthermore, it limits the ability for broad testing of available and novel approaches for renal protection.

What will you do as part of this research project?

Dr. Kossatz’s goal is to establish a cell-based in vitro assay system that can predict the uptake and retention of novel radiopharmaceuticals via proximal epithelial tubule cells and therefore enhance the identification of novel ligands with potential for clinical translation. They will also explore if the model is suitable to investigate the mechanisms of renal uptake and retention of radiopharmaceuticals as well as renal injury at the cellular level.

How might your research improve the diagnosis and/or treatment of NETs? 

Having an improved preclinical pipeline for radioligand development and renal protection will likely result in the discovery of enhanced PRRT ligands for existing and novel NET biomarkers and enable their clinical translation. Overall, NET patients would benefit from having access to additional radiopharmaceuticals for efficient treatment at early and late disease stages and for different NET types.

Outcomes:

Peptide-receptor radionuclide terapy (PRRT) in neuroendocrine tumors (NETs) is a powerful treatment option for NET patients, even if they suffer from advanced, metastatic disease. The approval of Lutathera was a milestone for radioligand therapy in NETs. However, important clinical needs remain to be addressed, e.g. to increase response rates in sstr2-expressing tumors and to develop PRRT agents for other biomarkers to enable treatment of sstr2-non-expressing tumors. The often-high kidney uptake and retention of NET PRRT agents leads to radiation exposure of the kidney, which can lead to renal injury and nephrotoxicity. This is a major roadblock in the development of therapeutic molecules, since their kidney uptake either limits the number of PRRT cycles a patient can receive (e.g. moderate kidney uptake of sstr2-PRRT) or it impedes the application of PRRT altogether, as it is currently the case for peptides targeting the biomarker GLP-1R, which show very high kidney uptake. If kidney uptake and retention could be evaluated via in vitro screenings instead of at the in vivo stage, as it is currently the case, radiopharmaceutical development for NETs and other tumor types could be drastically accelerated and improved. In vivo testing is a bottleneck in the evaluation of kidney uptake and retention of radiopharmaceuticals since it is time and resource intensive and does not allow for broad systematic studies to keep the number of research animals as low as possible. If an in vitro method could provide predictive information for kidney uptake and retention of radiopharmaceuticals, larger compound libraries could be screened, the mechanisms for kidney uptake and retention could be studied in-depths and methods for kidney protection could be systematically investigated and improved.

Our proposal was set up to establish a new cell-based technology that could accelerate discovery and optimization of radiopharmaceuticals for NET treatment. With this new technology, we aimed to increase the predictability of kidney uptake of tumor-targeting radio-peptidic tracers in correlation to their target uptake. High kidney uptake and retention of therapeutic radiopeptides is currently a major factor that limits clinical translation and application of peptide receptor radionuclide therapy (PRRT). Here, we propose to implement the conditionally immortalized proximal tubule epithelial cell line (ciPTEC) as physiologically relevant predictive in vitro tool to evaluate radioligand uptake in proximal tubule cells. This human cell model was established in 2016 (PMID: 26821801) to evaluate drug-induced nephrotoxicity, but has not yet been studied in the context of kidney uptake and retention of radiopharmaceuticals.
Specific Aim 1: We proposed to establish the ciPTEC model in our lab and evaluate its ability to predict in vivo kidney uptake of NET-PRRT agents and the efficacy of kidney protection strategies, using existing clinical and preclinical in vivo data for validation.

Specific Aim 2: We wanted to explore if the model is suitable to investigate the mechanisms of renal uptake and retention of radiopharmaceuticals as well as renal injury at the cellular level.
Within this pilot project, we have successfully set up the proposed in vitro kidney model in our lab. We have established protocols and have gathered substantial data that show that this model is suitable to assess the binding and retention of theranostic radioligands and multimodal ligands that are relevant in NET treatment, to kidney cells in vitro. We also have established proof-of-concept data that kidney protection strategies can be investigated using this in vitro model. However, we will continue this project beyond the timeline of the pilot grant to further optimize experimental protocols and substantiate our data. We have focused on ligands targeting the Somatostatin-2-receptor (SSTR2), a well-established biomarker in neuroendocrine tumors, and avb6-Integrin and PSMA-targeting ligands, to validate our results.

While we did not achieve the full and final establishment of ciPTEC cells as a validated in vitro model for kidney uptake and retention yet, we continue to consider this a highly promising approach with enormous impact. Our results lay the foundation for the continued investigation of ciPTEC cells as in vitro model for in vivo kidney uptake retention, which will be further pursued by our group. We also believe that other groups will follow this example after our first publication on the topic is published, which we plan to do in 2026.

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