Evans Joanne S, Beaumont Jamie, Braga Marta, Masrour Nahal, Mauri Francesco, Beckley Alice, Butt Shamus, Karali Christina S, Cawthorne Chris, Archibald Stephen, Aboagye Eric O, Sharma Rohini
Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, UK.
Department of Biomedical Sciences, University of Hull, Hull, UK.
Eur J Cancer. 2022 Nov;176:110-120. doi: 10.1016/j.ejca.2022.09.009. Epub 2022 Oct 5.
Somatostatin receptor-2 (SSTR2) is expressed on cell surface of neuroendocrine neoplasias; its presence is exploited for the delivery of peptide receptor radionuclide therapy (PRRT). Patients with no or low expression of SSTR2 are not candidates for PRRT. SSTR2 promotor undergoes epigenetic modification, known to regulate gene expression. We investigated whether the demethylation agent, guadecitabine, could enhance the expression of SSTR2 in NET models, using radioligand uptake/PET imaging as a biomarker of epigenetic modification.
The effects of guadecitabine on the transcriptional, translational, and functional regulation of SSTR2 both in vitro and in vivo using low (QGP-1) and high (BON-1) methylated neuroendocrine neoplasia models was characterised. Promotor region methylation profiling of clinical samples (n = 61) was undertaken. Safety of combination guadecitabine and PRRT was assessed in vivo.
Pyrosequencing of cell lines illustrated differential methylation indices - BON: 1 94%, QGP: 1 21%. Following guadecitabine treatment, a dose-dependent increase in SSTR2 in BON-1 at a transcriptional, translational, and functional levels using the SSTR2-directed radioligand, F-FET-βAG-TOCA ([F]-FETO) (150% increase [F]-FETO uptake, p < 0.05) was observed. In vivo, guadecitabine treatment resulted in a 70% increase in [F]-FETO uptake in BON-1 tumour models compared models with low baseline percentage methylation (p < 0.05). No additive toxicity was observed with the combination treatment of PRRT and guadecitabine in vivo. Methylation index in clinical samples was 10.5% compared to 5.2% in controls (p = 0.03) and correlated with SSTR2 expression (Wilcoxon rank sign -3.75,p < 0.01).
Guadecitabine increases SSTR2 expression both in vitro and in vivo. The combination of demethylation agents with PRRT warrants further investigation.
生长抑素受体2（SSTR2）在神经内分泌肿瘤的细胞表面表达；利用其存在进行肽受体放射性核素治疗（PRRT）。SSTR2无表达或低表达的患者不适合PRRT。SSTR2启动子发生表观遗传修饰，已知其可调节基因表达。我们研究了去甲基化药物瓜德西他滨是否能在神经内分泌肿瘤模型中增强SSTR2的表达，使用放射性配体摄取/PET成像作为表观遗传修饰的生物标志物。
使用低甲基化（QGP - 1）和高甲基化（BON - 1）神经内分泌肿瘤模型，对瓜德西他滨在体外和体内对SSTR2的转录、翻译和功能调节的影响进行了表征。对临床样本（n = 61）进行启动子区域甲基化分析。在体内评估瓜德西他滨与PRRT联合治疗的安全性。
细胞系焦磷酸测序显示不同的甲基化指数——BON：194%，QGP：121%。瓜德西他滨治疗后，使用针对SSTR2的放射性配体F - FET - βAG - TOCA（[F] - FETO），BON - 1中SSTR2在转录、翻译和功能水平上呈剂量依赖性增加（[F] - FETO摄取增加150%，p < 0.05）。在体内，与基线甲基化百分比低的模型相比，瓜德西他滨治疗使BON - 1肿瘤模型中的[F] - FETO摄取增加了70%（p < 0.05）。在体内，PRRT与瓜德西他滨联合治疗未观察到附加毒性。临床样本中的甲基化指数为10.5%，而对照组为5.2%（p = 0.03），且与SSTR2表达相关（Wilcoxon秩和检验 - 3.75，p < 0.01）。
瓜德西他滨在体外和体内均增加SSTR2表达。去甲基化药物与PRRT联合应用值得进一步研究。
