Clinical cancer research : an official journal of the American Association for Cancer Research · 2022
Targeting Refractory Mantle Cell Lymphoma for Imaging and Therapy Using C-X-C Chemokine Receptor Type 4 Radioligands.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Kwon Daniel, Takata Katsuyoshi, Zhang Zhengxing, Chong Lauren, Fraser Bryan, Zeisler Jutta, Miyata-Takata Tomoko, Merkens Helen, Rousseau Julie, Aoki Tomohiro, Kuo Hsiou-Ting, Tan Ruiyan, Zhang Chengcheng, Lau Joseph, Villa Diego, Uribe Carlos F, Lin Kuo-Shyan, Steidl Christian, Benard Francois
Аннотация
PURPOSE: Mantle cell lymphoma (MCL) is associated with poor survival. The purpose of this study was to assess whether the C-X-C chemokine receptor type 4 (CXCR4) is a useful target for imaging and radioligand therapy of MCL, using a novel pair of radioligands, [68Ga]Ga and [177Lu]Lu-BL02.
EXPERIMENTAL DESIGN: We performed a retrospective analysis of 146 patients with MCL to evaluate CXCR4 expression and its correlation with outcomes. Guided by in silico methods, we designed BL02, a new radioligand labelled with 68Ga or 177Lu for PET imaging and therapy, respectively. We performed imaging and biodistribution studies in xenograft models with varying CXCR4 expression. We evaluated [177Lu]Lu-BL02 in MCL models, and evaluated its potential for therapy in Z138 MCL xenografts.
RESULTS: Phosphorylated and nonphosphorylated CXCR4 expression were correlated with poor survival in patients with MCL and characterized by unique underlying molecular signatures. [68Ga]Ga-BL02 uptake correlated with CXCR4 expression, and localized lesions in a metastatic xenograft model. [177Lu]Lu-BL02 showed high uptake in MCL xenografts. Therapy studies with a single dose in the Z138 model showed tumor regression and improved survival compared with a control group. Upon regrowth, the treated mice experienced concurrent metastasis alongside localized xenograft regrowth, and recurrent lesions showed enhanced CXCR4 signaling.
CONCLUSIONS: CXCR4 is an independent factor of poor prognosis for MCL and a promising target for imaging and radioligand therapy. [68Ga]Ga-BL02 showed high contrast to visualize CXCR4-expressing xenografts for PET imaging and [177Lu]Lu-BL02 induced rapid tumor regression in a preclinical model of MCL.
EXPERIMENTAL DESIGN: We performed a retrospective analysis of 146 patients with MCL to evaluate CXCR4 expression and its correlation with outcomes. Guided by in silico methods, we designed BL02, a new radioligand labelled with 68Ga or 177Lu for PET imaging and therapy, respectively. We performed imaging and biodistribution studies in xenograft models with varying CXCR4 expression. We evaluated [177Lu]Lu-BL02 in MCL models, and evaluated its potential for therapy in Z138 MCL xenografts.
RESULTS: Phosphorylated and nonphosphorylated CXCR4 expression were correlated with poor survival in patients with MCL and characterized by unique underlying molecular signatures. [68Ga]Ga-BL02 uptake correlated with CXCR4 expression, and localized lesions in a metastatic xenograft model. [177Lu]Lu-BL02 showed high uptake in MCL xenografts. Therapy studies with a single dose in the Z138 model showed tumor regression and improved survival compared with a control group. Upon regrowth, the treated mice experienced concurrent metastasis alongside localized xenograft regrowth, and recurrent lesions showed enhanced CXCR4 signaling.
CONCLUSIONS: CXCR4 is an independent factor of poor prognosis for MCL and a promising target for imaging and radioligand therapy. [68Ga]Ga-BL02 showed high contrast to visualize CXCR4-expressing xenografts for PET imaging and [177Lu]Lu-BL02 induced rapid tumor regression in a preclinical model of MCL.