Colorectal cancer is one of the most frequently diagnosed cancers in the western world and third most common cause of cancer deaths. Patients with colon cancers that have not spread to distant sites usually have surgery as the main treatment, possibly followed by adjuvant chemotherapy. If the cancer has spread to distant organs, therapy consists out of a combination of surgery (resection of metastasis), chemotherapy, external X-ray beam therapy or selective targeted therapy with monoclonal antibodies (mAbs) or small molecules. To treat cancer efficiently, there is an urgent need for the development of new therapeutic molecules to enlarge and improve the treatment options offered to the patients nowadays.
Apart from external high energy X-ray beam therapy, Targeted RadioNuclide Therapy (TRNT) is another approach to deliver radiation to cancer cells. TRNT is distributed within the body by the vascular system and allows targeted irradiation of a primary tumor and all its metastases, resulting in substantially less collateral damage to normal tissues as compared to external radiotherapy. It is a systemic cancer therapy, tackling systemic spread of the disease, which is the cause of death in the vast majority of cancer patients. TRNT with radionuclides with short-range emission (alpha, beta, Auger) is particularly of interest to target microscopic metastases in the adjuvant or pseudo-adjuvant setting.
The overall aim of this project is to develop and to pre-clinically evaluate 161Tb-based radiopharmaceuticals for the treatment of colorectal cancer. Up to now, only few studies have used 161Tb for the evaluation of its therapeutic potential which makes it an innovative radionuclide. Nanobodies (Nbs), which are antigen-binding fragments derived from heavy-chain-only antibodies occurring naturally in Camelid species, will be used as vector molecules. Nbs bind their antigens very fast and specifically with high affinity in vivo, whereas unbound Nbs are rapidly cleared from the blood by the kidneys. Physiological uptake of Nbs in liver and in abdomen is limited. Therefore, Nbs can be considered as ideal vectors for in vivo imaging and radionuclide therapy.
To achieve the overall objective of the project, optimization of the conjunction and radiolabeling methods has to be established. Thereafter, the stability, specificity, affinity, degree of internalization and cytotoxicity of the 161Tb-based radiopharmaceuticals will be investigated in vitro using appropriate cell models. Additionally, biodistribution and stability of the 161Tb-based radiopharmaceuticals will be evaluated in vivo. Finally, the therapeutic potential of the 161Tb-based radiopharmaceuticals will be evaluated in tumour bearing mouse models.