177Lu-Pentixather

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.

68Ga-Pentixafor, as a radiolabeled tracer, shows high specificity and affinity for CXCR4 in tumors. Thus, CXCR4-directed imaging with 68Ga-Pentixafor has been investigated to evaluate CXCR4 expression in patients non-invasively. In recent years, many small cohorts, including those of individuals with hematologic malignancies, solid tumors, and cardiovascular and infectious diseases, have been reported. So far, 68Ga-Pentixafor has been used successfully in individuals with hematologic malignancies. In addition, Lutetium-177 (177Lu) or Yttrium-90 (90Y)-labeled Pentixather (an analog of Pentixafor) suggested high potential applicability in tumor endoradiotherapy (ERT) with CXCR4 overexpression. Patients with advanced-stage multiple myeloma, refractory acute leukemia, and diffuse large B-cell lymphoma received a certain amount of 177Lu-Pentixather or 90Y-Pentixather. This review aimed to overview the current CXCR4-directed positron emission computed tomography (PET) molecular imaging based on Pentixafor in several diseases and ERT.