1. Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Radiopharmaceutical and Chemical Biology, Dresden, Germany.
2. University Hospital Carl Gustav Carus at the Technische Universität Dresden, Institute of Clinical Chemistry and Laboratory Medicine, Dresden, Germany.
3. National Center for Tumor Diseases/University Cancer Center Dresden, Core Unit for Molecular Tumor Diagnostics, Dresden, Germany.
4. University of Leipzig Medical Center, Institute of Human Genetics, Leipzig, Germany.
5. University Hospital Carl Gustav Carus at the Technische Universität Dresden, Klinik und Poliklinik für Nuklearmedizin, Dresden, Germany.
6. University Hospital Carl Gustav Carus at the Technische Universität Dresden, Department of Medicine III, Dresden, Germany.
7. University Hospital Zurich (USZ) and University of Zurich (UZH), Department of Endocrinology, Diabetology and Clinical Nutrition, Zurich, Switzerland.
8. University Hospital, LMU Munich, Department of Medicine IV, Munich, Germany.
9. Technische Universität Dresden, School of Science, Faculty of Chemistry and Food Chemistry, Dresden, Germany.
10. German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, Germany.
11. National Center for Tumor Diseases (NCT), Partner Site Dresden, University Cancer Center (UCC), Dresden, Germany.
Pheochromocytomas and paragangliomas (PCCs/PGLs) are catecholamine-producing tumors. In inoperable and metastatic cases, somatostatin type 2 receptor (SSTR2) expression allows for peptide receptor radionuclide therapy with [177Lu]Lu-DOTA-TATE. Insufficient receptor levels, however, limit treatment efficacy. This study evaluates whether the epigenetic drugs valproic acid (VPA) and 5-Aza-2'-deoxycytidine (DAC) modulate SSTR2 levels and sensitivity to [177Lu]Lu-DOTA-TATE in two mouse PCC models (MPC and MTT).
Methods: Drug-effects on Sstr2/SSTR2 were investigated in terms of promoter methylation, mRNA and protein levels, and radiotracer binding. Radiotracer uptake was measured in subcutaneous allografts in mice using PET and SPECT imaging. Tumor growth and gene expression (RNAseq) were characterized after drug treatments.
Results: DAC alone and in combination with VPA increased SSTR2 levels along with radiotracer uptake in vitro in MPC (high-SSTR2) and MTT cells (low-SSTR2). MTT but not MPC allografts responded to DAC and VPA combination with significantly elevated radiotracer uptake, although activity concentrations remained far below those in MPC tumors. In both models, combination of DAC, VPA and [177Lu]Lu-DOTA-TATE was associated with additive effects on tumor growth delay and specific transcriptional responses in gene sets involved in cancer and treatment resistance. Effects of epigenetic drugs were unrelated to CpG island methylation of the Sstr2 promoter.
Conclusion: This study demonstrates that SSTR2 induction in mouse pheochromocytoma models has some therapeutic benefit that occurs via yet unknown mechanisms. Transcriptional changes in tumor allografts associated with epigenetic treatment and [177Lu]Lu-DOTA-TATE provide first insights into genetic responses of PCCs/PGLs, potentially useful for developing additional strategies to prevent tumor recurrence.
Keywords: decitabine, neuroendocrine tumors, radiation biology, small animal multimodal imaging, valproic acid