Chemokine Receptor CXCR4 Radioligand Targeted Therapy Using 177Lutetium-pentixather for Pulmonary Neuroendocrine Cancers

Melissa A Fath; Dijie Liu; Jordan T Ewald; Claudia Robles-Planells; Ann M Tomanek-Chalkley; Stephen A Graves; James R Howe; Thomas M O'Dorisio; Prerna Rastogi; Andrew M Bellizzi; M Sue O'Dorisio; Yusuf Menda; Douglas R Spitz

doi:10.1667/RADE-23-00064.1

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Chemokine Receptor CXCR4 Radioligand Targeted Therapy Using 177Lutetium-pentixather for Pulmonary Neuroendocrine Cancers

Journal article

Peer reviewed

Chemokine Receptor CXCR4 Radioligand Targeted Therapy Using 177Lutetium-pentixather for Pulmonary Neuroendocrine Cancers

Melissa A Fath, Dijie Liu, Jordan T Ewald, Claudia Robles-Planells, Ann M Tomanek-Chalkley, Stephen A Graves, James R Howe, Thomas M O'Dorisio, Prerna Rastogi, Andrew M Bellizzi, …

Radiation research, Vol.201(1), pp.35-47

01/2024

DOI: 10.1667/RADE-23-00064.1

PMCID: PMC10896455

PMID: 37989124

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https://pmc.ncbi.nlm.nih.gov/articles/PMC10896455/pdf/nihms-1960532.pdfView

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Abstract

Intermediate to high-grade lung neuroendocrine tumors (NETs; i.e., atypical carcinoid tumors) and neuroendocrine carcinomas (NECs) are currently difficult to cure. These tumors were found to express the CXCR4 G-protein coupled receptor that can be targeted with radioligands. PCR and flow cytometric analysis of lung NET and NEC cell lines using an anti-CXCR4 antibody demonstrated that all cell lines tested expressed CXCR4. PET/CT imaging with 68Galium-pentixafor in mouse xenografts of NETs and NECs verified tumor targeting that was blocked by a CXCR4 agonist. Clonogenic survival analysis demonstrated a more than additive enhancement of killing when 1 μM auranofin (a thioredoxin reductase inhibitor) was used as a radiosensitizer in combination with 177Lu-pentixather (10 μCi). DMS273 small cell lung cancer xenografts in female nude mice treated with 25 μCi/g 177Lu-pentixather induced inhibition of tumor growth and resulted in an increase in overall survival without causing unacceptable normal tissue toxicities. Immunohistochemical staining of 95 retrospective human samples (containing 90 small cell lung carcinomas) demonstrated 84% CXCR4 positivity. In a multivariable analysis of this cohort that included age, gender, stage, primary site, SSTR2 status, and CXCR4 status, Cox regression models determined that only distant metastasis at presentation (P < 0.01) and a CXCR4 H-score >30 (P = 0.04) were significantly associated with reduced survival. Prospective clinical testing of patient tumors identified CXCR4-positivity in 76% of 21 NECs, 67% of 15 lung NETs (including 8 of 10 atypical carcinoids), and 0% of 25 non-lung NETs (including 5 NETS G3s). These data support the hypothesis that CXCR4-targeted theranostics can be utilized effectively for select NETs and NECs.

Details

Title: Subtitle: Chemokine Receptor CXCR4 Radioligand Targeted Therapy Using 177Lutetium-pentixather for Pulmonary Neuroendocrine Cancers
Creators: Melissa A Fath
Dijie Liu
Jordan T Ewald
Claudia Robles-Planells
Ann M Tomanek-Chalkley
Stephen A Graves
James R Howe
Thomas M O'Dorisio
Prerna Rastogi
Andrew M Bellizzi
M Sue O'Dorisio
Yusuf Menda
Douglas R Spitz
Resource Type: Journal article
Publication Details: Radiation research, Vol.201(1), pp.35-47
DOI: 10.1667/RADE-23-00064.1
PMID: 37989124
PMCID: PMC10896455
NLM abbreviation: Radiat Res
eISSN: 1938-5404
Language: English
Electronic publication date: 11/21/2023
Date published: 01/2024
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Radiology; Stead Family Department of Pediatrics; Pathology; Surgery; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984513360202771

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