Abstract 5034: Targeting CXCR4 and thioredoxin reductase in high grade neuroendocrine tumors and neuroendocrine carcinomas

Introduction/Background: Atypical lung carcinoids and lung neuroendocrine carcinomas (NECs) are currently incurable. Most of these cancers express the C-X-C chemokine receptor 4 (CXCR4), making CXCR4 an attractive target for cancer diagnosis and treatment using radioligand therapy (RLT) with nuclides such as alpha emitter Pb212 conjugated to Pentixather (Pent). Alpha particles produce dense ionization tracks and damage cytosolic structures such as mitochondria, leading to the generation of reactive oxygen species such as superoxide (O2 ●−) and hydroperoxides (H2O2 and ROOH) in targeted cancer cells. The FDA approved thioredoxin reductase inhibitor, auranofin (Aur), inhibits peroxiredoxin-mediated hydroperoxide metabolism increasing cell killing in targeted cancer cells. Hypothesis: Inhibition of hydroperoxide metabolism using Aur can enhance therapeutic efficacy of alpha particle emitting 212Pb-Pent in preclinical models of lung carcinoids and NECs. Results: Clinically, IHC revealed greater than 75% of atypical carcinoids and NECs tested had moderate to high CXCR4. qRT-PCR, flow cytometry and immunohistochemistry performed on different lung carcinoid and NEC lung cell lines, determined that the majority moderately or highly express CXCR4. The minimal non-toxic dose of Aur that inhibits 50-70% of thioredoxin reductase activity was 4 mg/kg (intraperitoneal once a day) in DMS273 (small cell lung cancer) xenografts 212Pb-Pent given IV (1 and 3 µCu/g) was effective at increasing the survival of mice with DMS273 xenografts. Mice were then treated with 1.5, 3 or 6 µCu/g 212Pb-Pent w/wo Aur 4 mg/kg/day. A trend test showed that both increasing dose of 212Pb-Pent and the addition of Aur, caused a significant (p