Somatostatin receptor-targeting peptides are widely used for imaging and therapy of neuroendocrine tumors. Peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumor patients with radiolabeled somatostatin analogs has resulted in symptomatic improvement, prolonged survival and enhanced quality of life. The side-effects of PRRT are few and mostly mild, certainly when using kidney protective agents. If more widespread use of PRRT is possible, such therapy might become the therapy of first choice in patients with metastasized or inoperable neuroendocrine GEP tumors. Yet, much profit can be gained from improving the receptor-targeting strategies available and developing new strategies. This review presents an overview of several options to optimize receptor-targeted imaging and radionuclide therapy. These include optimization of peptide analogs, increasing the number of receptors on the tumor site, and combining PRRT with other treatment strategies. The development of new peptide analogs with increased receptor binding affinity and improved stability might lead to higher accumulation of radioactivity inside tumor cells. Analogs of somatostatin have been widely studied. However, much profit can be gained in improving peptide analogs targeting other tumor related receptors, including gastrin-releasing peptide (GRP) receptors, neurotensin (NT) receptors, cholecystokinin (CCK) receptors, and glucagon-like peptide-1 (GLP-1) receptors. Several peptide analogs targeting these receptors are well on their way to clinical utilization. Literature shows that it is possible to increase the receptor density on tumor cells using different methods which results in higher binding and internalization rates and thus a higher contrast during peptide-receptor-scintigraphy (PRS). In PRRT treatment, this would enable the administration of higher therapeutic doses to tumors, which might lead to a higher cure rate in patients. Combinations of radionuclide therapy with other treatment modalities like chemotherapy or pre-treatment with radiosensitizers might increase the impact of the treatment. Furthermore, administration of higher dosages of radioactivity to the patient enabled by combinations of PRRT with strategies reducing the radiation dose to healthy organs will improve the outcome of tumor treatment. Also targeting one or several tumor-specific receptors by using combinations of therapeutic agents, as well as by reducing non-target uptake of radioactivity, will enlarge the therapeutic window of PRRT. Clinical studies will provide more insight in the effects of combining treatment strategies in cancer patients.

peptide analogs, receptor targeting
E.P. Krenning (Eric) , M. de Jong (Marion)
Erasmus MC: University Medical Center Rotterdam
Erasmus MC: University Medical Center Rotterdam

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