Abstract / Summary
Integrin α V β 3 , a transmembrane receptor involved in tumor growth and metastasis, specifically recognizes and binds proteins with the Arg-Gly-Asp (RGD) peptide sequence. Using mRNA and/or protein expression data from 496 thyroid cancer (TC) samples in The Cancer Genome Atlas, 14 TC cell lines, and 70 TC and 10 normal thyroid tissues, we found that papillary TC exhibits the highest α V β 3 integrin expression. We then evaluated the therapeutic efficacy of a radiolabeled RGD analog, 177 Lu-DOTA-EB-cRGDfK, in TC. Genetic knockout and overexpression of α V β 3 in TC cell lines confirmed the target specificity of 177 Lu-DOTA-EB-cRGDfK. In mouse xenograft models established from human TC cell lines with high α V β 3 expression, 177 Lu-DOTA-EB-cRGDfK demonstrated superior antitumor efficacy compared with standard-of-care lenvatinib and placebo. However, no synergistic benefit was observed with combination therapy. Biodistribution studies identified the kidneys as the dose-limiting organ. RNA-seq analysis of resected tumors demonstrated that 177 Lu-DOTA-EB-cRGDfK induced a type I IFN response, characterized by upregulation of IFI6 , IFIT1-2 , and MX1 , compared with both lenvatinib-treated tumors and placebo. These findings identify α V β 3 integrin as a promising therapeutic target in a subset of TCs and demonstrate that 177 Lu-DOTA-EB-cRGDfK exhibits superior efficacy to lenvatinib, supporting its potential clinical translation for progressive TC refractory to standard therapies.