Recently, European Medicine Agency (EMA) recommended the marketing authorization of the radiopharmaceutical product Lutathera®. 177Lu-DOTATATE, also called 177Lu-DOTA-Tyr3-octreotate, 177Lu-octreotate or 177Lu-oxodotreotide the active substance of Lutathera®, is a radiolabelled peptide that targets subtype 2 somatostatin receptors. Since these receptors are often overexpressed in neuroendocrine tumors, Lutathera® will be used for the improvement of progression-free survival of patients with unresectable or metastatic, progressive, well-differentiated (grade 1 and grade 2), somatostatin receptor positive gastro-entero pancreatic neuroendocrine tumours (GEP-NETs). A recent trial has indeed showed promising results in patients treated with Lutathera®.
Currently, radionuclide based targeted therapy is mainly focused on the use of β- emitters such as 177Lu. Despite the limited availability of α-particle emitters that are relevant for clinical use, targeted α-radionuclide therapy (TAT) is gaining more and more attention in preclinical and clinical studies. Due to the short path length and high linear energy transfer of α-particles, the DNA damage caused by α-particles is much more difficult to repair than the DNA damage caused by β-particles. Furthermore, because of the limited range of the α-particle, toxicity to the healthy surrounding cells is expected to be quite low. An additional advantage of TAT is that the cytocidal efficacy is generally considered to be independent of dose fractionation, dose rate, or hypoxia and it can reverse resistance to chemotherapy or conventional external beam radiotherapy. Therefore, finding a somatostatine analogue which can be labelled with α-emitters such as 225Ac and 213Bi could provide a superior alternative for the treatment of neuroendocrine tumours.
Additionally, a common problem for Lutathera® and other radiolabelled peptides and proteins with a molecular weight less than 60 kDa is high uptake and retention in kidneys. These radiolabelled peptides can pass the glomerular membrane, after which a substantial part of these radiolabelled peptides or proteins may be reabsorbed in the proximal tubule of the kidneys after glomerular filtration. This causes a high radiation burden for the kidneys, hinders diagnostic accuracy and limits therapeutic applications. Therefore, the search for radiolabelled peptides with a higher tumour-to-kidney ratio continues. Derivatizing the octreotate backbone might lead to radiolabelled somatostatine receptor agonists with lower renal uptake.
This research project will focus on the development of somatostatin analogues which can be labelled with the α-emitters 225Ac and 213Bi to allow TAT for neuroendocrine tumours. To accomplish this, several derivatives of the octreotate backbone will be synthesized and their labelling capacity and renal absorption will be evaluated. Promising candidates will be radiolabelled with 225Ac and 213Bi and evaluated in vitro and in vivo to select the somatostatin analogues with the desired properties. Finally, the therapeutic efficacy of the best radiopharmaceuticals will be evaluated in tumour bearing mouse models.