Improving Clinical Translation of Radiopharmaceuticals Using PDX Models

Denis Beckford Vera, head of Radiopharmacology, Champion Oncology, discusses the critical role of patient-derived xenograft (PDX) models in advancing radiopharmaceutical development. PDX models are created by implanting fragments of a patient's actual tumor into immunocompromised mice, a process that preserves the tumor’s original architecture, molecular characteristics, and inherent heterogeneity.

Vera emphasizes that traditional, simplified cell lines often fail to capture the complexity of human cancer, which can lead to biased data and an overestimation of drug uptake. To ensure accurate clinical translation, researchers must utilize models that mimic real-world conditions rather than relying on oversimplified systems.

Vera further explores the importance of biodistribution studies, which are fundamental to developing radiopharmaceuticals. By utilizing a larger cohort of PDX models, researchers can account for heterogeneity between different patients. This approach provides a much clearer picture of how a lead compound will behave in a human clinical setting.

As Vera explains, "The more that you involve this patient-derived xenograft, the biggest the cohort or the biggest the number of patient-derived xenograft that you use, even within one disease, is going to give you way better and more information on how your compound will really behave in a real scenario or in the clinic." Ultimately, the interview underscores that the power of PDX models lies in their ability to provide the biologically relevant data necessary for successful clinical translation.

Transcript:

Editor's note: This transcript is a lightly edited rendering of the original audio/video content. It may contain errors, informal language, or omissions as spoken in the original recording.

I'm Denis Beckford Vera I am the head of radiopharmacology at Champion Oncology. Patient-derived xenograft model are created by implanting, fragments of real patient's tumor into immunocompromised mice. What is very relevant of this model is that this approach research preserves much of the tumor's original architecture, heterogeneity, and molecular characteristics, which it is very important when you are translating targeted drugs, and in this case, targeted radiopharmaceuticals. Because, as we know, cancer and these diseases are very heterogeneous. And, most of the time, we really use very simplified, tumor models or cell lines that really don't express the real architecture of patient samples. Therefore, using patient-derived xenograft can really mimic what may later, later happen in the clinic, if you are assessing your radiopharmaceutical of your, lead compounds, in patient-derived xenograft. Let's say, rather than mentioning specific examples, I'm going to say in general, when patient-derived xenograft can really, change the development plan or the clinical translation, and again is similar. So if you have, cell lines that have very homogeneous receptor expression, for instance. So you may overestimate your drug uptake or your drug behavior in preclinical models. While if you have patient-derived xenograft, and I like to repeat that because it's very important that it keeps the architecture, the receptor heterogeneity expression, and as well a molecular characteristic of patient samples. Between patients and within a patient, if these samples are taken from the same patient or from different patients, you are really, getting the behavior of the drug that you really need in the, in the clinic. Basically, if you are oversimplifying your model, your animal model, you are basically lying to yourself. So you don't have the opportunity to really see which, the real behavior you sample. More importantly, the patient history. The patient history in those tumors. If you are already targeting a specific disease, you are going to be able to see if a standard of care of other drugs have not been working for that particular tumor or for that particular set of patient populations. So this is gonna be very powerful in translating your radiopharmaceutical, for example. So biodistribution studies are key to developing radiopharmaceuticals. And this is because with radiopharmaceuticals, you have the ability to see. You can treat what you see, and you can see what you treat. So biodistribution studies are probably one of the main components of, developing radiopharmaceuticals. And then we go back to the model. If you are developing, your radiopharmaceutical doing biodistribution, which biodistribution is tied to biology. So if you are oversimplifying your biology, again, you're lying to yourself. You are not really getting the real outcome. You are biasing the outcome. Whether if you use preclinical model with real clinical samples or clinically relevant, animal models, you are really getting the data that you need. The more that you involve this patient-derived xenograft, the biggest the cohort or the biggest the number of patient-derived xenograft that you use, even within one disease, is going to give you way better and more information on how your compound will really behave in a real scenario or in the clinic. You can not only evaluate the heterogeneity of this disease between patients, but also within the patient, if these samples have been taken from the same patient, but from different part of the disease or different part of the patient as well. So it's gonna be very powerful because it is all related to biology.