Upregulation of Key Molecules for Targeted Imaging and Therapy.
- Taelman VF Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland.
- Radojewski P Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland.
- Marincek N Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland.
- Ben-Shlomo A Pituitary Center, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California.
- Grotzky A Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland.
- Olariu CI Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland.
- Perren A Institute of Pathology, University Bern, Bern, Switzerland.
- Stettler C Division of Diabetes, Endocrinology, Nutritional Medicine & Metabolism, University Hospital and Inselspital, Bern, Switzerland; and.
- Krause T Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland.
- Meier LP Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland.
- Cescato R Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland.
- Walter MA Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland m.a.walter@gmx.net.
- 2016-07-02
Published in:
- Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - 2016
DOTATATE
DOTATOC
PRRT
molecular imaging
neuroendocrine tumors
Animals
Azacitidine
Biomarkers, Tumor
Cell Line, Tumor
Decitabine
Drug Evaluation, Preclinical
Gene Expression Regulation, Neoplastic
Mice
Mice, Nude
Molecular Targeted Therapy
Neoplasms, Experimental
Organometallic Compounds
Pathology, Molecular
Positron-Emission Tomography
Receptors, Somatostatin
Reproducibility of Results
Sensitivity and Specificity
Up-Regulation
English
Targeted diagnosis and therapy enable precise tumor detection and treatment. Successful examples for precise tumor targeting are diagnostic and therapeutic radioligands. However, patients with tumors expressing low levels of the relevant molecular targets are deemed ineligible for such targeted approaches.
METHODS
We performed a screen for drugs that upregulate the somatostatin receptor subtype 2 (sstr2). Then, we characterized the effects of these drugs on transcriptional, translational, and functional levels in vitro and in vivo.
RESULTS
We identified 9 drugs that act as epigenetic modifiers, including the inhibitor of DNA methyltransferase decitabine as well as the inhibitors of histone deacetylase tacedinaline and romidepsin. In vitro, these drugs upregulated sstr2 on transcriptional, translational, and functional levels in a time- and dose-dependent manner. Thereby, their combinations revealed synergistic effects. In vivo, drug-based sstr2 upregulation improved the tumor-to-background and tumor-to-kidney ratios, which are the key determinants of successful sstr2-targeted imaging and radiopeptide therapy.
CONCLUSION
We present an approach that uses epigenetic modifiers to improve sstr2 targeting in vitro and in vivo. Translation of this method into the clinic may potentially convert patients ineligible for targeted imaging and therapy to eligible candidates.
METHODS
We performed a screen for drugs that upregulate the somatostatin receptor subtype 2 (sstr2). Then, we characterized the effects of these drugs on transcriptional, translational, and functional levels in vitro and in vivo.
RESULTS
We identified 9 drugs that act as epigenetic modifiers, including the inhibitor of DNA methyltransferase decitabine as well as the inhibitors of histone deacetylase tacedinaline and romidepsin. In vitro, these drugs upregulated sstr2 on transcriptional, translational, and functional levels in a time- and dose-dependent manner. Thereby, their combinations revealed synergistic effects. In vivo, drug-based sstr2 upregulation improved the tumor-to-background and tumor-to-kidney ratios, which are the key determinants of successful sstr2-targeted imaging and radiopeptide therapy.
CONCLUSION
We present an approach that uses epigenetic modifiers to improve sstr2 targeting in vitro and in vivo. Translation of this method into the clinic may potentially convert patients ineligible for targeted imaging and therapy to eligible candidates.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.2967/jnumed.115.165092
- PMID 27363833
- Persistent URL
- https://sonar.ch/global/documents/107123
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