Targeting CXCR4 and Thioredoxin Reductase in Theranostics of Atypical Carcinoid and Neuroendocrine Carcinoma

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Introduction: Atypical carcinoid and small cell lung cancer (SCLC) are currently incurable. There is thus a critical need for new diagnostic and therapeutic strategies for lung neuroendocrine neoplasms (LNEN). Chemokine receptor 4 (CXCR4), a G protein coupled receptor and theranostic target, plays a crucial role in metastases of LNEN. We hypothesize combination of thioredoxin reductase (TR) inhibitor represents a metabolic strategy to enhance cytotoxicity in peptide-receptor radionuclide therapy (PRRT) of LNEN.

Aim(s): 1) evaluate CXCR4 expression in cell lines and patient specimens; 2) determine the preclinical efficacy and toxicity of 177Lu-Pentixather (CXCR4 antagonist) in combination with auranofin (TR inhibitor).

Materials and methods: CXCR4 expression was determined by qPCR and flow cytometry in typical, atypical carcinoid and SCLC cell lines; human LNEN specimens were examined using CXCR4 immunohistochemistry. 68Ga-Pentixafor PET imaging was performed in tumor-bearing mice. 177Lu-pentixather +/- auranofin were tested for in vitro cytotoxicity, normal organ toxicity in CD1 mice and therapeutics in tumor-bearing NSG mice.

Conference: 17th Annual ENETSConcerence (2020)

Presenting Author: Liu D

Authors: Liu D, Fath M, Robles Planells C, Balk E, Bellizzi A,

Keywords: CXCR4, thioredoxin reductase inhibitor, theranostics, atypical carcinoid, small cell lung cancer,