Disclosure: S. Kumari: None. R. Sarkar: None. Z. Wang: None. S. Thakur: None. L. Abaandou: None. O. Gavrilova: None. H. Lu: None. L. Lang: None. D. Kiesewetter: None. V. Vasko: None. J. Klubo-Gwiezdzinska: None. Background: Integrin αVβ3, a transmembrane glycoprotein receptor involved in cell adhesion and tumor growth, invasion, angiogenesis, and metastasis, is specifically recognized by cyclic pentapeptide c(RGDfK) containing a tripeptide sequence Arg-Gly-Asp (RGD). The study intends to evaluate if αVβ3 can be a therapeutic target with a new radiolabeled RGD analog, 177Lu-EB-RGD, for thyroid cancer (TC). Methods: mRNA and/or protein expressions of αVβ3 were assessed in The Cancer Genome Atlas (n=496 TC), 14 TC cell lines, and commercially available Human Thyroid Cancer Tissue Microarray with 70 TC and 10 normal thyroid tissue samples. Well-established, clinically relevant BRS score was used to determine if the TC was BRAF-like (BRS from -1 to 0) or RAS-like (BRS from 0 to 1). Western blotting and membranous staining with flow cytometry was conducted to measure the expression of αVβ3 in TC cell lines and to select the ones with variable αVβ3 expression. Saturation binding analysis was performed to determine radiopeptide binding to TC cells and a maximum binding affinity (Bmax) was quantified. Mouse xenograft models utilizing cell lines with a high and low αVβ3 cell surface expression were treated with either standard care therapy with Lenvatinib (L), 0.5 mCi of 177Lu-EB-RGD (177Lu), combination therapy with 177Lu+L or placebo, and microPET imaging was performed. A p≤0.05 was rendered statistically significant.Results: Analysis of mRNAseq of 496 TC tissues revealed that αVβ3 is expressed in TC. Immunostaining indicated a significantly higher αVβ3 expression in papillary TC as compared to follicular TC (p=0.03) and normal thyroid (p<0.001). However, poorly differentiated TC exhibited no difference in expression compared to papillary TC (p=0.52). Also, BRAF-like TC cell lines had increased protein expressions of αV (Spearman correlation: r=-0.78, αV vs BRS) and β3 (r=-0.7, β3 vs BRS) compared to the RAS-like cell lines. The cell surface expression of αVβ3 was significantly higher in OCUT2 as compared with FTC133 (p<0.0001), which was corroborated by the radioligand-to-receptor binding capacity showing Bmax values of 382.2 and 79.35 fmol for OCUT2 and FTC133, respectively. TC xenograft mouse models demonstrated that 177Lu-EB-RGD therapy decreased tumor growth in the model characterized by high αVβ3 cell surface expression (OCUT2), but not in a model with low αVβ3 level (FTC133). Moreover, 177Lu+L resulted in a larger reduction of tumor growth as compared to L monotherapy (p=0.05). There was no difference between 177Lu and 177Lu+L therapy outcomes (p=0.99). Conclusions: The αVβ3 integrin is highly expressed in a subset of TC and can be successfully targeted by 177Lu-EB-RGD. The higher growth inhibitory potency of 177Lu-EB-RGD compared with current standard care monotherapy with Lenvatinib provides a translational perspective for this radioligand to be utilized in patients with progressive TC. Presentation: Sunday, July 13, 2025
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