LAUSR

Background: Integrins are cell adhesion receptors consisting of 18α and 8β subunits. A subset of integrins (αvβ3) recognizes Arg-Gly-Asp (RGD) peptide motifs which are involved in the neovascularization and progression of various cancers. The aim of the study was to investigate if αvβ3 can serve as a molecular target for the treatment of thyroid cancer (TC) with a novel radiolabeled RGD analog 177Lu-EB-RGD. Methods: Integrin αvβ3 mRNA and/or protein expression was evaluated in 496 TC included in The Cancer Genome Atlas, tissue microarray including 70 TC and 10 normal thyroid samples, and 14 TC cell lines. BRAF-like or RAS-like expression profile was determined through standard BRS scores ranging from -1 to 0 for BRAF-like and 0 to 1 for RAS-like TC. The association between BRS and the αvβ3 expression was tested by the Spearman correlation (r). Nude mice xenografts developing αvβ3 expressing TC after subcutaneous injection of 5*10^6 TC cells were subjected to monotherapy with 0.5 mCi 177Lu-EB-RGD (177Lu) or in combination with Lenvatinib (177Lu+L). The therapeutic efficacy of 177Lu-EB-RGD was compared with standard-of-care Lenvatinib alone (L) and placebo (P). The continuous data were presented as medians with [25-75% interquartile ranges] and compared using Kruskal-Wallis test. The mixed-effects models were used for longitudinal data analysis with adjusted p≤ 0.05 considered statistically significant. Results: We found a moderate negative correlation between BRS and αv (r=-0.5, p<0.001), and β3 (r=-0.27, p<0.001), revealing that BRAF-like tumors have a higher mRNA expression of αvβ3 integrins. Consistently, the highest αvβ3 mRNA and/or protein expression was found in the BRAF-like TC cell lines OCUT2 (BRS=-0.56), TPC1 (BRS=-0.4), K1 (BRS=-0.29), and Hurthle TC cell line XTC1 (BRS=-0.46). The immunostaining revealed a higher αvβ3 expression in papillary TC compared with follicular TC (p=0.002), and in normal thyroid (p<0.001). Poorly differentiated TC had a similar αvβ3 expression to papillary TC (p=0.14). In the thyroid cancer xenograft mouse model, all treatment modalities were more effective than the placebo in decreasing tumor size as early as 5 days after therapy initiation. A significant difference in growth curve and tumor volume was maintained at the study endpoint (L 0.584 cm3 [0.196-0.984] vs P 0.911 cm3 [0.183-1.68], p=0.001; 177Lu 0.259 cm3 [0.103-0.376] vs P, p<0.001; and 177Lu+L 0.274 cm3 [0.108-0.406] vs P, p<0.001). The combination therapy (177Lu+L) resulted in decreased tumor volume as compared with monotherapy with Lenvatinib (p=0.05) but had a similar effect as compared with 177Lu-EB-RGD monotherapy (p=0.99). Conclusions: The radiolabeled αvβ3 analog 177Lu-EB-RGD has potent growth inhibitory effects in TC characterized by a high integrins expression. The αvβ3 integrin could potentially serve as a molecular target for therapy with radiolabeled RGD analogs in TC. Citation Format: Sonam Kumari, Zhantong Wang, Shilpa Thakur, Laura Abaandou, Oksana Gavrilova, Huiyan Lu, Lixin Lang, Dale Kiesewetter, Vasyl Vasko, Joanna Klubo-Gwiezdzinska. Radiolabeled αvβ3 analog 177Lu-EB-RGD is an effective therapeutic agent in thyroid cancer xenograft mouse model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3946.