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Targeting CXCR4/CXCL12 axis via [177Lu]Lu-DOTAGA.(SA.FAPi)2 with CXCR4 antagonist in triple-negative breast cancer

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Title: Targeting CXCR4/CXCL12 axis via [177Lu]Lu-DOTAGA.(SA.FAPi)2 with CXCR4 antagonist in triple-negative breast cancer
Authors: Guangfa Bao, Ziqiang Wang, Luoxia Liu, Buchuan Zhang, Shuang Song, Dongdong Wang, Siyuan Cheng, Eu-Song Moon, Frank Roesch, Jun Zhao, Bo Yu, Xiaohua Zhu
Source: Eur J Nucl Med Mol Imaging
Publisher Information: Springer Science and Business Media LLC, 2024.
Publication Year: 2024
Subject Terms: 0301 basic medicine, Receptors, CXCR4, Benzylamines, 0303 health sciences, Triple Negative Breast Neoplasms/drug therapy [MeSH], Cell Line, Tumor [MeSH], Receptors, CXCR4/antagonists, Triple-negative breast cancer (TNBC), Triple Negative Breast Neoplasms/radiotherapy [MeSH], Serine Endopeptidases/metabolism [MeSH], Radiopharmaceuticals/pharmacology [MeSH], Cyclams/pharmacology [MeSH], Original Article, Heterocyclic Compounds/pharmacology [MeSH], Membrane Proteins/metabolism [MeSH], CXCR4 antagonist, Cyclams/therapeutic use [MeSH], CXCR4/CXCL12, [, Chemokine CXCL12/metabolism [MeSH], Receptors, CXCR4/metabolism [MeSH], Lutetium [MeSH], Female [MeSH], Gelatinases/metabolism [MeSH], Humans [MeSH], Animals [MeSH], Triple Negative Breast Neoplasms/diagnostic imaging [MeSH], Heterocyclic Compounds/chemistry [MeSH], Endopeptidases [MeSH], Benzylamines/pharmacology [MeSH], Mice [MeSH], Cell Proliferation/drug effects [MeSH], Radiopharmaceuticals/therapeutic use [MeSH], Serine Endopeptidases, Membrane Proteins, Triple Negative Breast Neoplasms, Lutetium, Cyclams, Chemokine CXCL12, Mice, 03 medical and health sciences, Heterocyclic Compounds, Gelatinases, Cell Line, Tumor, Endopeptidases, Animals, Humans, Female, Radiopharmaceuticals, Cell Proliferation
Description: Purpose Radiopharmaceutical therapies targeting fibroblast activation protein (FAP) have shown promising efficacy against many tumor types. But radiopharmaceuticals alone in most cases are insufficient to completely eradicate tumor cells, which can partially be attributed to the protective interplay between tumor cells and cancer-associated fibroblasts (CAFs). The C-X-C chemokine receptor type 4/C-X-C motif chemokine 12 (CXCR4/CXCL12) interaction plays an important role in orchestrating tumor cells and CAFs. We hereby investigated the feasibility and efficacy of [177Lu]Lu-DOTAGA.(SA.FAPi)2, a FAP-targeting radiopharmaceutical, in combination with AMD3100, a CXCR4 antagonist, in a preclinical murine model of triple-negative breast cancer (TNBC). Methods Public database was first interrogated to reveal the correlation between CAFs’ scores and the prognosis of TNBC patients, as well as the expression levels of FAP and CXCR4 in normal tissues and tumors. In vitro therapeutic efficacy regarding cell proliferation, migration, and colony formation was assessed in BALB/3T3 fibroblasts and 4T1 murine breast cancer cells. In vivo therapeutic efficacy was longitudinally monitored using serial 18F-FDG, [18F]AlF-NOTA-FAPI-04, and [68Ga]Ga-DOTA-Pentixafor PET/CT scans and validated using tumor sections through immunohistochemical staining of Ki-67, α-SMA, CXCR4, and CXCL12. Intratumoral abundance of myeloid-derived suppressive cells (MDSCs) was analyzed using flow cytometry in accordance with the PET/CT schedules. Treatment toxicity was evaluated by examining major organs including heart, lung, liver, kidney, and spleen. Results CAFs’ scores negatively correlated with the survival of TNBC patients (p 177Lu]Lu-DOTAGA.(SA.FAPi)2 and AMD3100 significantly suppressed cell proliferation, migration, and colony formation in cell culture, and exhibited synergistic effects in 4T1 tumor models along with a decreased number of MDSCs. PET/CT imaging revealed lowest tumor accumulation of 18F-FDG and [18F]AlF-NOTA-FAPI-04 on day 13 and day 14 after treatment started, both of which gradually increased at later time points. A similar trend was observed in the IHC staining of Ki-67, α-SMA, and CXCL12. Conclusion The combination of [177Lu]Lu-DOTAGA.(SA.FAPi)2 and AMD3100 is a feasible treatment against TNBC with minimal toxicity in main organs.
Document Type: Article
Other literature type
Language: English
ISSN: 1619-7089
1619-7070
DOI: 10.1007/s00259-024-06704-y
Access URL: https://pubmed.ncbi.nlm.nih.gov/38587644
https://repository.publisso.de/resource/frl:6521149
Rights: CC BY
Accession Number: edsair.doi.dedup.....6f70f75240a5e359c84f862b15d8ec50
Database: OpenAIRE
Description
Abstract:Purpose Radiopharmaceutical therapies targeting fibroblast activation protein (FAP) have shown promising efficacy against many tumor types. But radiopharmaceuticals alone in most cases are insufficient to completely eradicate tumor cells, which can partially be attributed to the protective interplay between tumor cells and cancer-associated fibroblasts (CAFs). The C-X-C chemokine receptor type 4/C-X-C motif chemokine 12 (CXCR4/CXCL12) interaction plays an important role in orchestrating tumor cells and CAFs. We hereby investigated the feasibility and efficacy of [177Lu]Lu-DOTAGA.(SA.FAPi)2, a FAP-targeting radiopharmaceutical, in combination with AMD3100, a CXCR4 antagonist, in a preclinical murine model of triple-negative breast cancer (TNBC). Methods Public database was first interrogated to reveal the correlation between CAFs’ scores and the prognosis of TNBC patients, as well as the expression levels of FAP and CXCR4 in normal tissues and tumors. In vitro therapeutic efficacy regarding cell proliferation, migration, and colony formation was assessed in BALB/3T3 fibroblasts and 4T1 murine breast cancer cells. In vivo therapeutic efficacy was longitudinally monitored using serial 18F-FDG, [18F]AlF-NOTA-FAPI-04, and [68Ga]Ga-DOTA-Pentixafor PET/CT scans and validated using tumor sections through immunohistochemical staining of Ki-67, α-SMA, CXCR4, and CXCL12. Intratumoral abundance of myeloid-derived suppressive cells (MDSCs) was analyzed using flow cytometry in accordance with the PET/CT schedules. Treatment toxicity was evaluated by examining major organs including heart, lung, liver, kidney, and spleen. Results CAFs’ scores negatively correlated with the survival of TNBC patients (p 177Lu]Lu-DOTAGA.(SA.FAPi)2 and AMD3100 significantly suppressed cell proliferation, migration, and colony formation in cell culture, and exhibited synergistic effects in 4T1 tumor models along with a decreased number of MDSCs. PET/CT imaging revealed lowest tumor accumulation of 18F-FDG and [18F]AlF-NOTA-FAPI-04 on day 13 and day 14 after treatment started, both of which gradually increased at later time points. A similar trend was observed in the IHC staining of Ki-67, α-SMA, and CXCL12. Conclusion The combination of [177Lu]Lu-DOTAGA.(SA.FAPi)2 and AMD3100 is a feasible treatment against TNBC with minimal toxicity in main organs.
ISSN:16197089
16197070
DOI:10.1007/s00259-024-06704-y