Abstract
Background. Gastrointestinal stromal tumors (GISTs) can be effectively treated with tyrosine kinase inhibitors (TKIs). However, some patients with GIST develop drug resistance, and alternative treatment strategies are therefore needed. The aim of this study was to analyze the expression of somatostatin receptors (SSTR) in GIST as a target for peptide receptor-mediated radiotherapy (PRRT). Material and methods. Expression profiling of SSTR1–5 was performed on biopsies from 34 GISTs (16 gastric tumors, 15 small intestinal tumors, and three rectal tumors). SSTR scintigraphy (111In-octreotide) and measurement of 111In activity in tumor specimens was performed in seven patients. Uptake and internalization of 177Lu- octreotate was studied in primary cell cultures from two patients. Results. Quantitative PCR analysis showed expression of SSTR1 and SSTR2 in the majority of tumors, while SSTR3–5 were expressed at low levels. Immunohistochemical analysis confirmed the presence of SSTR1 and SSTR2 proteins in all GISTs, and SSTR3–5 in a subset of tumors. Diagnostic imaging by SSTR scintigraphy, using 111In-octreotide, demonstrated tumor uptake of 111In in three of six GIST patients. Measurement of 111In activity in excised tumor specimens from five patients gave tumor-to-blood (T/B) activity ratios of between eight and 96. Tumor cells in primary culture (gastric and small intestinal GIST) specifically bound and internalized 177Lu when incubated with the therapeutic compound 177Lu-octreotate for 4–48 hours (p < 0.05). Conclusion. Peptide receptor-mediated radiotherapy via SSTR may provide a novel treatment strategy in carefully selected GIST patients with TKI-resistant tumors.
Acknowledgements
The expert technical assistance of Gülay Altiparmak, Malin Berntsson, Pauline Brattberg, Ann-Christine Illerskog, Linda Inge, Lilian Karlsson, Ann Wikström, and Milan Lomsky is greatly appreciated. This study was supported by the Swedish Cancer Society, the Swedish Research Council, Sahlgrenska Academy (the government ALF agreement), the Johan Jansson Foundation for Cancer Research, the Assar Gabrielsson Research Foundation, the Sahlgrenska University Hospital Research Foundation, and the Royal Society of Arts and Sciences in Gothenburg.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.