Tracer development for pancreatic β-cell imaging

The β-cells, which can be found in small structures within the pancreas called the islets of Langerhans, are necessary in normal metabolic function of the body, but are also of importance in a variety of diseases, such as diabetes mellitus, insulinomas, and congenital and adult hyperinsulinemic hypoglycemia (CHI and AHH, respectively). The glucagon-like peptide-1 receptor (GLP-1R) is highly abundant on the β-cells, thus making it a good target for radiopharmacy. In our approach, we target the GLP-1R with tracers based on the peptide exendin-4, which can be radiolabeled for diagnostic imaging or for therapy. It is very similar in structure to the endogenous ligand of GLP-1R, GLP-1, but is much more stable in the body. Exendin-4 tracers are already in clinical use for the detection of insulinomas, however, further improvement is needed to address some of their shortcomings, such as the characteristically high accumulation in the kidneys, which on one hand could distort the image obtained during a diagnostic scan (depicted in Figure Insulinoma), and on the other hand may have a negative impact on the patient’s health.
Insulinoma in close proximity to the kindeys, imaged with 68Ga-DOTA-Exendin-4 (Antwi et al. Journal of Nuclear Medicine (2015). 56: p1075-1078)
We have made a number of these improvements, such as further stabilization of the structure for better clinical use, and addressing the kidney uptake through changing the pharmacokinetic properties of the peptide. Currently, we are investigating the interaction between GLP-1R and its different ligands. This research is performed under the collaborative project BetaCure funded by the European Commission under the 7th framework program. The following members of the Radiopharmacology group are involved in this project: Simon Käppeli, Alain Blanc.
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HE staining of pancreatic tissue, indicating the islets and pancreatic ducts.

Targeting structure proteins in extracellular matrix (ECM)

The extracellular matrix is the structure in the tissue which keeps the cells in the tissue together. It consists of around 300 proteins like collagen, fibronectin or elastin. It became evident over the last year that the role of ECM in diseases was underestimated. It plays an important if not major role in different diseases like invasive cancers, muscle dystrophy, fibrotic diseases etc DOI: nrm3904. The ECM interacts in different ways with the cells. In diseases it changes it stiffness (concentration of ECM proteins), the steric structure as well as the chemical structure of the proteins. The aim is to target these changes with peptides to develop new possibilities for diagnostic and therapeutic intervention in early stage of the disease. Therefore we developed in cooperation with the group of Prof. Viola Vogel a radiolabeled peptide which binds specifically to relaxed fibronectin. Fibronectin is stretched in healthy tissue but if the concentration becomes higher during the development of diseases the fibronectin structure is more and more relaxed and can be targeted with peptides derived from bacterial adhesins. We radiolabeled the peptide FnBPA5 and could show that we find a specific binding in to ECM in a prostate cancer in s.c. mouse model DOI: s41467-017-01846-0. We received a 4 year SNF grant including 2 PhD students for the further evaluation of this approach.
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Binding of the FnBPA5 derived from bacterial adhesion proteins to relaxed fibronectin.

Therapy of gastrin derivatives

The CCK-2 receptor is overexpressed in medullary thyroid cancer and small cell lung cancers. There is no good therapy option for both cancer types if they are metastasized. Therefore new therapeutic strategies are necessary. One option is to use the CCK-2 receptor as a target. Different receptor binding peptide were evaluated and minigastrin derivatives were figured out as the lead substance with the highest tumour uptake. The disadvantage of these compounds was the high kidney uptake which leads to kidney damage in the therapeutic approach. The reason for the high kidney uptake was the chain of six Glutamic acids in the peptide.

Different research efforts were made to overcome the kidney uptake problem. These research efforts are summarized in a review from the Radiopharmacy group in Njimegen. The research were the focused and combined in a european COST action in which 12 compounds were compared. The best compounds will be more deeply evaluated and will be applied as a therapeutic radiopharmaceutical first in preclinicals and later on if good results can be shown in clinical settings.

Radiolabeled antibodies for therapy and imaging

One of our current research goals is the development of novel concepts and tools for preclinical radioimmunotherapy of disseminated ovarian cancer by targeting the L1 cell adhesion molecule (L1CAM) with the antibody chCE7. We attempt to further improve the potency of radioimmunotherapy by using novel therapeutic radionuclides, including Terbium-161 (e.g. Grünberg et al. 2014: DOI: s00259-014-2798-3. We will evaluate strategies for combination of radioimmunotherapy with existing therapy modalities for disseminated ovarian cancer (e.g. Lindenblatt et al., 2014, DOI: s13550-014-0054-2. Further we are analysing the role of L1CAM expression in ovarian cancer stem cells (CSCs), a rare cancer cell population with stem cell-like properties. These cells have the ability for self-renewal and differentiation. These properties are likely the reason for treatment failures, disease recurrence and metastases. CSCs are highly tumorigenic and therapy resistant. We will test if it is possible to overcome the radioresistance of cancer stem cells and therefore to eradicate these cells with a suitable radioisotope for therapy. For this project we set up a close collaboration with Prof. Dr. Anna Dubrovska from the National Center for Radiation Research in Oncology (OncoRay) in Dresden and Prof. Dr. med. Viola Heinzelmann, chair of the Women’s Hospital Basel and of the Department of Gynaecology, University Hospital Basel. This work is supported by the Swiss Cancer Research Foundation (Project No. KFS 3585-02-2015) to Jürgen Grünberg.

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