Project title: Targeted alpha therapy of NETs using somatostatin-based radiopharmaceuticals with improved tumor-to-kidney ratio, the theranostic approach.

Description

Cleeren will explore developing new radiopharmaceuticals for radionuclide therapy of neuroendocrine tumors that would increase the therapeutic effect while decreasing kidney toxicity.

What problem will your research try to answer?

The limitation of existing radionuclide therapies is that some patients only achieve stabilization of disease and a significant number of patients do not respond to this particular type of radiation therapy. Another issue with existing radionuclide therapy for NETs is potential kidney toxicity. A significant fraction of the administered radionuclides is retained in the kidneys, which can lead to radiation induced chronic kidney failure. We will work to develop and evaluate new radiopharmaceuticals for radionuclide therapy with increased therapeutic effect and decreased kidney toxicity.

Why is this important?

If patients do not respond to the standard type of radiation therapy (e.g. 177Lu-DOTATATE, Lutathera®) or only achieve stabilization, the treatment alternatives available are either limited or non-existent. Further, high accumulation of therapeutic radionuclides in the kidneys can cause kidney toxicity. Concomitant substances can be given to decrease retention of the radioactive drug in the kidney and potential kidney toxicity, but this causes side effects for patients such as nausea and vomiting.

What will you do as part of this research project?

Our team will attempt to develop new probes for radionuclide therapy that will increase the therapeutic effect by using more powerful radionuclides (in technical terms: alpha-emitter). These extremely powerful radionuclides release their energy at a much shorter distance so that cancer cells are killed more effectively and healthy tissues are better spared. Moreover, we aim to further decrease kidney toxicity effects by using innovative techniques so that radionuclides are excreted more efficiently towards the bladder instead of being retained in the kidneys. Further, the same radioprobes can be used for both diagnostic and therapeutic purposes, allowing more accurate and better personalized therapy of NET patients.

How might your research improve the treatment of NETs?

We aim to offer patients that have no treatment options left or do not respond to existing radionuclide therapy, an effective and safe treatment alternative using targeted alpha therapy.

What is your next step?

These new radionuclide therapy probes will be first evaluated on cells and in mouse NET models in a theranostic setting (first diagnostic imaging, followed by targeted alpha therapy). The best radioprobes will be prepared for clinical translation.

Outcomes:

Therapy with radioactive drugs is an established, evidence-based treatment modality in the case of inoperable/well-differentiated neuroendocrine tumors (NETs). The limitation of existing radionuclide therapies is that some patients only achieve stabilization of disease and a significant number of patients do not respond to this particular type of radiation therapy. These patients have limited or non-existing treatment alternatives. One promising option is the use of different radioisotopes which are much more powerful, but release their energy at much shorter distance so that cancer cells are killed more effectively and healthy tissues are better spared. Another issue with existing radionuclide therapy for NETs is potential kidney toxicity. A significant fraction of the administered radionuclides are retained in the kidneys, which can lead to radiation induced chronic kidney failure. Concomitant substances can be given to decrease retention of the radioactive drug in the kidney and potential kidney toxicity, but this causes side effects for patients such as nausea and vomiting.

To solve these two problems, we developed new probes for radionuclide therapy with increased therapeutic effect by using more powerful radionuclides called alpha-emitters and decreased toxicity effects by using innovative techniques so that radionuclides are excreted more efficiently towards the bladder instead of being retained in the kidneys. Further, the same radioprobes can be used for both diagnostic and therapeutic purposes, allowing more accurate and better personalized therapy. These new radionuclide therapy probes were first evaluated on cells and in mouse NET models. Important steps have been taken during this project to translate alpha-therapy for neuroendocrine tumors in an efficient way in the near future.

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