Assuntos
Formação de Anticorpos/efeitos dos fármacos , Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , SARS-CoV-2/imunologia , Vacinação , Adulto , Idoso , Idoso de 80 Anos ou mais , Vacina BNT162 , COVID-19/imunologia , Vacinas contra COVID-19/imunologia , ChAdOx1 nCoV-19 , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Leucemia Mielogênica Crônica BCR-ABL Positiva/virologia , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: 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. METHODS: 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. RESULTS: 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, 18F-FET-ßAG-TOCA ([18F]-FETO) (150% increase [18F]-FETO uptake, p < 0.05) was observed. In vivo, guadecitabine treatment resulted in a 70% increase in [18F]-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). CONCLUSION: Guadecitabine increases SSTR2 expression both in vitro and in vivo. The combination of demethylation agents with PRRT warrants further investigation.