177Lu-labeled DOTA-EB-RGD as a candidate for thyroid cancer therapy
4 affiliations
- 1Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases
- 2Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, and
- 3Molecular Tracer and Imaging Core Facility, National Institute of Biomedical Imaging and Bioengineering, NIH, Bethesda, Maryland, USA.
- 4Department of Pediatric Endocrinology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
Abstract
Integrin αVβ3, 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 αVβ3 integrin expression. We then evaluated the therapeutic efficacy of a radiolabeled RGD analog, 177Lu-DOTA-EB-cRGDfK, in TC. Genetic knockout and overexpression of αVβ3 in TC cell lines confirmed the target specificity of 177Lu-DOTA-EB-cRGDfK. In mouse xenograft models established from human TC cell lines with high αVβ3 expression, 177Lu-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 177Lu-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 αVβ3 integrin as a promising therapeutic target in a subset of TCs and demonstrate that 177Lu-DOTA-EB-cRGDfK exhibits superior efficacy to lenvatinib, supporting its potential clinical translation for progressive TC refractory to standard therapies.
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BibTeX
@article{kumari2026177lulabeled,
title = {{177Lu-labeled DOTA-EB-RGD as a candidate for thyroid cancer therapy}},
author = {Sonam Kumari and Rhitajit Sarkar and Zhantong Wang and Shilpa Thakur and Laura Abaandou and Oksana Gavrilova and Huiyan Lu and Noha Behairy and Lixin Lang and Dale Kiesewetter and Vasyl Vasko and Joanna Klubo-Gwiezdzinska},
journal = {JCI Insight},
year = {2026},
month = oct,
doi = {10.1172/jci.insight.200594},
url = {https://doi.org/10.1172/jci.insight.200594},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - 177Lu-labeled DOTA-EB-RGD as a candidate for thyroid cancer therapy
AU - Sonam Kumari
AU - Rhitajit Sarkar
AU - Zhantong Wang
AU - Shilpa Thakur
AU - Laura Abaandou
AU - Oksana Gavrilova
AU - Huiyan Lu
AU - Noha Behairy
AU - Lixin Lang
AU - Dale Kiesewetter
AU - Vasyl Vasko
AU - Joanna Klubo-Gwiezdzinska
PY - 2026
DA - 2026/10/08
JO - JCI Insight
DO - 10.1172/jci.insight.200594
UR - https://doi.org/10.1172/jci.insight.200594
AB - Integrin αVβ3, 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 αVβ3 integrin expression. We then evaluated the therapeutic efficacy of a radiolabeled RGD analog, 177Lu-DOTA-EB-cRGDfK, in TC. Genetic knockout and overexpression of αVβ3 in TC cell lines confirmed the target specificity of 177Lu-DOTA-EB-cRGDfK. In mouse xenograft models established from human TC cell lines with high αVβ3 expression, 177Lu-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 177Lu-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 αVβ3 integrin as a promising therapeutic target in a subset of TCs and demonstrate that 177Lu-DOTA-EB-cRGDfK exhibits superior efficacy to lenvatinib, supporting its potential clinical translation for progressive TC refractory to standard therapies.
SN - 2379-3708
ER -