Abstract
Preclinical evaluation of CXCR4 as novel radio-theranostic target for high grade neuroendocrine and neuroblastoma tumors
The Journal of nuclear medicine (1978), Vol.59, p.1313
05/01/2018
Abstract
Objectives: Somatostatin receptor subtype 2 (SSTR2) targeting is a mainstay of diagnosis and therapy for low grade neuroendocrine tumors (NETs), and SSTR2 directed peptide-receptor therapy (PRRT) is effective in patients with G1 and G2 NETs. However, the approach is relatively ineffective for neuroendocrine carcinomas (NECs) and G3 NETs because SSTR2 expression is low in these tumor types. Advanced neuroblastoma, as the most common extracranial solid tumor of childhood, remains a clinical challenge with poor survival. Thus, there is a critical need for new theranostic targets that are expressed in NECs and neuroblastoma. Chemokine receptor 4 (CXCR4) has been proven to stimulate cell proliferation, angiogenesis, migration, and metastasis of cancer cells via the PI3K/Akt/mTOR pathway and CXCR4 expression levels inversely correlate with prognosis. In this study we evaluated the expression of CXCR4 in high grade NETs and neuroblastoma cancer cell lines in vitro and in vivo and evaluated the microPET/CT imaging profile of 68Ga-Pentixafor (a CXCR4 antagonist), in mice bearing high-grade NETs and neuroblastoma xenografts. Methods: CXCR4 mRNA and protein expression was quantified by qGPCR array assay and flow cytometry in high-grade tumor cell lines. Tumor xenografts from mice were collected for immunohistochemistry staining evaluation. Pentixafor was labeled with 68GaCl3 for microPET/CT imaging in tumor-bearing mice, followed by euthanasia and assessment of the biodistribution. Results: IMR32 neuroblastoma cells expressed high levels of SSTR2 and CXCR4 while H727 lung neuroendocrine cells expressed a moderate level of CXCR4 and minimal SSTR2, as evidenced by both in vitro and in vivo tests. MicroPET/CT imaging of 68Ga-Pentixafor demonstrated high retention in IMR32 and H727 tumor xenografts (5.8% and 1.1% ID/g, respectively) 1 hr post-injection with primarily renal clearance and partial distribution to digestive tract. 68Ga-Pentixafor tumor uptake was specifically blocked by co-injection of excess mass of unlabeled Pentixafor analog, Plerixafer. Conclusion: CXCR4 is expressed at variable levels in G3 NETs and neuroblastoma cell lines. 68Ga-Pentixafor is a potential radiopharmaceutical for microPET/CT imaging of CXCR4 expression in mice bearing high-grade NETs and neuroblastoma. 68Ga/177Lu-, 68Ga/90Y-Pentixafor are promising radio-theranostic pairs for targeting CXCR4 in patients with G3 NETs or NECs and neuroblastoma.
Details
- Title: Subtitle
- Preclinical evaluation of CXCR4 as novel radio-theranostic target for high grade neuroendocrine and neuroblastoma tumors
- Creators
- Dijie LiuMengshi LiAndrew BellizziYusuf MendaDongyoul LeeKimia NourmahnadSilvia GhobrialMichael SchultzM ODorisio
- Resource Type
- Abstract
- Publication Details
- The Journal of nuclear medicine (1978), Vol.59, p.1313
- Publisher
- Society of Nuclear Medicine
- ISSN
- 0161-5505
- eISSN
- 1535-5667
- Language
- English
- Date published
- 05/01/2018
- Academic Unit
- Pathology; Radiology; Stead Family Department of Pediatrics; Radiation Oncology
- Record Identifier
- 9984314284302771
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