Current cancer treatment options may include surgery, medicines and/or radiotherapy. New cancer treatment modalities focus on immunotherapy, hadron therapy or targeted radionuclide therapy and hold promise to be more effective and to reduce the detrimental effects on the healthy tissues. Radiopharmaceuticals for targeted radionuclide therapy consist of a cancer-seeking molecule, such as antibodies or antibody fragments, peptides or low molecular weight ligands, labeled with an appropriate radionuclide to deliver therapeutic doses of ionizing radiation directly to the cancer sites, both in the primary tumor as well as in metastatic lesions. When injected into the patient’s bloodstream, the radiopharmaceuticals diffuse in the whole body, concentrate in the disease, and progressively destroy the disease.
Beginning 2018, Lutathera® (Lu177-DOTATATE) was approved for the treatment of gastroenteropancreatic neuroendocrine pancreatic tumors. In addition, several radiopharmaceuticals for targeted radionuclide therapy are currently being studied in clinical trials and many more are investigated in discovery projects. Also alpha-emitters are in this context increasingly studied, with promising results.
However, the precision and personalisation of targeted radionuclide therapy, i.e. tailoring of the treatment to the individual patient, is currently not fully reached. This is in great contrast to radiotherapy with external beams that is based on a detailed individual treatment planning balancing the radiation dose to the tumour tissue and the out-of-field dose received by surrounding healthy tissues. The radiobiology of tumour response and the safety margins of ionising radiation beam exposure is leading in designing optimal treatments. However, much of the radiobiology is not fully investigated for radionuclide therapy and hence it is considered more convenient to submit patients to fixed activity doses. As a consequence many patients may be undertreated while others may encounter unnecessary high absorbed doses in normal tissue, which could lead to undesirable high adverse effects and second cancers.
Therefore, within this PhD project, we aim to obtain a better understanding of the cellular and molecular mechanisms underlying the therapeutic and cytotoxic responses of targeted radionuclide therapy. As such, we aim to contribute to the development of biomarkers useful for patient-specific treatment planning in the clinic leading to a more effective treatment and an increase of quality of life post treatment. In this study we will focus on radionuclides Lu177 and Ac255, and the respective radiopharmaceuticals Lu177-DOTATATE and Ac225-DOTATATE, envisaged for the treatment of neuroendocrine tumours.
Task 1: Radiobiological effects on tumour and normal cells in vitro
Task 2: Radiobiological effects on tumour and normal tissues in vivo
Techniques that will be applied are cell culture, ELISA, flow cytometry, live cell imaging, western blot, RT-qPCR, colorimetric assays and fluorescence microscopy, tissue dissection, sampling of mouse blood and urine, immunohistochemistry, multiplex technology, SPECT/CT imaging.