A novel radiolabelled biomarker for medullary thyrois cancer (GRA-T-MTC)

Medullary thyroid carcinoma (MTC) is still one of the most challenging cancers for both physicians and patients. Epidemiological studies have shown that during the past 30 years neither a change in stage at diagnosis nor improvement in survival has occurred for MTC patients. Therefore, it is necessary to develop alternative therapeutic strategies to control tumour growth, possibly through the use of new biomarkers. The cholecystokinin-2 (CCK-2) receptor is overexpressed in MTC with very high density and incidence (over 90%), as revealed by autoradiographic studies. Within a trans-European collaborative project, COST BM0607, several gastrin and cholecystokinin analogues were studied in vitro and in preclinical animal models. In this study DOTA-DGlu-DGlu-DGlu-DGlu-DGlu-DGlu-Ala-Tyr-Glu-Trp-Met-Asp-Phe-NH 2 (CP04) showed most promising characteristics in terms of high stability and receptor affinity, high and persistent tumour uptake and low kidney retention and therefore was selected for further clinical evaluation. Within this phase I clinical trial a multinational cooperation will be established with the aim to evaluate the potential of CP4 as imaging biomarker and for targeted radionuclide therapy. The project coordinates the work of partners from Austria, Greece, Poland, Italy, Slovenia and Germany. The Department of Nuclear Medicine of Innsbruck Medical University (MUI) will be involved in both proposed working packages (WP). In the preclinical WP 1 (Pharmaceutics) MUI will focus on pharmaceutical parameters of the radiolabelled peptide, such as radiolabelling studies, analytical validations as well as binding experiments for the radiolabelled peptide in the cross validation with partners in Poland and Greece. In particular optimization of analytical procedures required in the establishment of the clinical formulation including radio-HPLC, mass spectrometry and rapid purity testing methods (TLC, SPE) will be performed. The clinical formulation will be evaluated in receptor binding assays on CCK2 receptor positive cells as well using stability assays. Within WP2 after positive evaluation by the ethical committee and the national competent authority MUI will perform a clinical study with 3-5 patients with histologically proven MTC and confirmed metastasis. The primary objective is to establish the safety of the intravenous administration 111 In-CP04. Patients will be closely monitored regarding side effects and all adverse events will be documented and reported. The second objective is to determine the pharmacokinetics and the absorbed doses to normal organs and to tumours of 111 In-CP04 at an injected radioactivity of 222 MBq using hybrid SPECT/CT up to 48 h post injection to determine critical organs and the ability to detect cancer lesions. Additionally, using two randomized groups, the ability of a nephroprotective amino acid infusion in decreasing the kidney will be investigated. A biostatistician from MUI will be responsible to analyse biostatistics for all involved centres. Within this project the co-operation of multinational partners will be strengthened, which contributes to the progress in European science and clinical practice in the field of molecular imgaging and targeted radionuclide therapy. The ultimative aim of the project is to introduce CP04 into clinical practice as a more selective and efficient tool for the diagnosis, early detection and finally therapy of recurrent and metastatic MTC. CCK-2/gastrin receptors may become viable targets for radionuclide scintigraphy and radionuclide therapy, similarly to somatostatin receptors, which have been instrumental to establish nuclear medicine efficacy in clinical practice. Patients with recurrent of metastatic MTC for whom currently no effective diagnostic and therapeutic options are available will clearly benefit by this novel approach.

Medullary thyroid carcinoma (MTC) continues to be a challenge not only for the patients concerned but also for the treating physicians. In the past 30 years there has been no significant improvement in the stage of the disease at the time of first diagnosis and in the survival rate of MTC. Therefore, the development of new treatment strategies is urgently needed. Within a previous trans-European collaboration, several new biomarkers were tested and the peptide "CP04" was selected as the most promising candidate for further investigations. In this project cooperations of the University Clinic for Nuclear Medicine of the Medical University of Innsbruck (MUI) with partners from different European countries (Italy, Poland, Slovenia, Greece, Germany), all dealing with molecular imaging and radionuclide therapy, were established with the aim of creating a new biomarker for more efficient diagnostics and therapy of the MTC. In the first part of the project (WP1), MUI - together with partners in Poland and Greece - was instrumental in the pharmaceutical development of the new radioactive drug CP04. Highest quality standards were applied to ensure the safety of the application to patients in the study. In the second part of the project (WP2), Indium-111- labeled CP04 was evaluated in a multi-center Phase I clinical trial. Following the positive ethics committee vote and the approval by the competent authority (BASG), out of 6 eligible patients, 2 patients could ultimately be examined in Innsbruck. The patients underwent strict surveillance and every unexpected effect was documented. The collected study results were evaluated by the responsible biostatistician of the MUI. There were no unexpected side effects, which clearly confirmed the safety of the CP04. These results were confirmed by the other clinical partners. The project has strengthened multinational partners` collaboration, contributing to the advancement of European science and clinical practice in the field of molecular imaging and targeted radionuclide therapy. The ultimate goal of the project, namely the introduction of CP04 into clinical practice as a more selective and efficient tool for the diagnosis, early detection and eventual therapy of recurrent and metastatic MTC, has thus come a big step closer.