Upregulation of Key Molecules for Targeted Imaging and Therapy.

UNLABELLED

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 (sstr). 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 sstr on transcriptional, translational, and functional levels in a time- and dose-dependent manner. Thereby, their combinations revealed synergistic effects. In vivo, drug-based sstr upregulation improved the tumor-to-background and tumor-to-kidney ratios, which are the key determinants of successful sstr-targeted imaging and radiopeptide therapy.

CONCLUSION

We present an approach that uses epigenetic modifiers to improve sstr 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.