Therapy of neuroendocrine tumors with 177Lu-octreotate - Human tumor cell types and models and optimization of treatment

Abstract: Neuroendocrine (NE) tumors (NET) have often metastasized at the time of diagnose, which makes it hard to cure patients with NET. Radiolabeled hormone analogues (especially somatostatin analogues, SS) can be used for diagnostics (e.g. 111In-octreotide) and therapy (e.g. 177Lu-octreotate). For development of the treatment methods, realistic tumor cell lines and models are valuable. Human NET cell lines and models are few, and there is a need to find suitable models for different types of NET, with e.g. relevant expression of hormone receptors, e.g. somatostatin receptors (SSTR), cholecystokinin-2/gastrin receptors, and catecholamine transporters. In this work, several types of human NET models (paraganglioma, gastrointestinal stromal tumor (GIST), human medullary thyroid cancer (GOT2), and midgut carcinoid (GOT1)) were studied, with the aim to evaluate the binding and/or uptake of radiolabeled hormone analogues (177Lu-octreotate, 111In-octreotide, 111In-MG0, and 131I-MIBG). Activity concentration in tumor and non-tumor tissues was measured in vitro or in vivo in different NETs. The activity concentration after 111In-octreotide injection indicated a large variation in somatostatin receptor expression in different NETs. A specific uptake and internalization of radiolabeled 111In-octreotide or 177Lu-octreotate was found in vitro in paraganglioma and in GIST, respectively, as well as a specific uptake of 131I-MIBG in paraganglioma. The tumor uptake of 111In-octreotide and 131I-MIBG in the patient with paraganglioma, and of 111In-octreotide in several individuals with GIST showed that some of these patients might benefit from radionuclide therapy. All studied human NETs in this work will serve as good models in the development of increased therapeutic effect of different NETs. 177Lu-octreotate is today routinely used for treatment of carcinoids and endocrine pancreatic tumors, but needs to be optimized. A novel treatment schedule was tested, giving a priming administration of 177Lu-octreotate before administering the therapeutic amount. This procedure resulted in higher mean absorbed dose to tumor tissue and increased therapeutic effect compared with those for a single administration. To improve the individual following-up after fractionated treatment with 177Lu-octreotate, the possibility to use urinary retinol binding protein (RBP) and valine hydantoin (VH) in blood as biomarkers for radiation induced nephrotoxicity was studied. RBP4 was shown to be a potential biomarker for nephrotoxicity, before kidney injury was demonstrated by morphology.