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 2 ). 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 2 on transcriptional, translational, and functional levels in a time-and dose-dependent manner. Thereby, their combinations revealed synergistic effects. In vivo, drug-based sstr 2 upregulation improved the tumor-to-background and tumor-tokidney ratios, which are the key determinants of successful sstr 2 -targeted imaging and radiopeptide therapy. Conclusion: We present an approach that uses epigenetic modifiers to improve sstr 2 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.

Meningiomas express members of the somatostatin receptor family. The present study assessed the long-term benefits and harm of somatostatin-based radiopeptide therapy in meningioma patients. Methods: Patients with progressive unresectable meningioma were treated with 90 Y-DOTATOC and 177 Lu-DOTATOC until tumor progression or permanent toxicity occurred. Multivariable Cox regression analyses were used to study predictors of survival. Results: Overall, 74 treatment cycles were performed on 34 patients. Stable disease was achieved in 23 patients. Severe hematotoxicity occurred in 3 patients, and severe renal toxicity in 1 patient. Mean survival was 8.6 y from the time of recruitment. Stable disease after treatment (hazard ratio, 0.017 vs. progressive disease; 95% confidence interval, 0.001-0.35; n 5 34; P 5 0.01) and high tumor uptake (hazard ratio, 0.046 vs. intermediate or low tumor uptake; 95% confidence interval, 0.004-0.63; n 5 34; P 5 0.019) were associated with longer survival. Conclusion: 90 Y-DOTATOC and 177 Lu-DOTATOC are promising tools for treating progressive unresectable meningioma, especially in cases of high tracer uptake in the tumor.

Our results suggest sstr as an independent prognostic marker in NETs. Sstr-immunohistochemistry correlates with sstr-imaging; however, sstr-imaging is more accurate for determining the individual prognosis.

IMPORTANCE Multiple therapies are currently available for patients with neuroendocrine tumors (NETs), yet many therapies have not been compared head-to-head within randomized clinical trials (RCTs). OBJECTIVE To assess the relative safety and efficacy of therapies for NETs. DATA SOURCES PubMed, Embase, the Cochrane Central Register of Controlled Trials, trial registries, meeting abstracts, and reference lists from January 1, 1947, to March 2, 2018, were searched. Key search terms included neuroendocrine tumors, gastrointestinal neoplasms, therapy, and randomized controlled trial. STUDY SELECTION Randomized clinical trials comparing 2 or more therapies in patients with NETs (primarily gastrointestinal and pancreatic) were evaluated. Thirty RCTs met the selection criteria. DATA EXTRACTION AND SYNTHESIS Pairs of independent reviewers screened studies, extracted data, and assessed the risk of bias. A network meta-analysis with a frequentist approach was used to compare the efficacy of therapies; the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was used. MAIN OUTCOMES AND MEASURES Disease control, progression-free survival, overall survival, adverse events, and quality of life. RESULTS The systematic review identified 30 relevant RCTs comprising 3895 patients (48.4% women) assigned to 22 different therapies for NETs. These therapies showed a broad range of risk for serious and nonserious adverse events. The network meta-analyses included 16 RCTs with predominantly a low risk of bias; nevertheless, precision-of-treatment estimates and estimated heterogeneity were limited. The network meta-analysis found 7 therapies for pancreatic NETs: everolimus (hazard ratio [HR], 0.35 [95% CI, 0.28-0.45]), everolimus plus somatostatin analogue (HR, 0.35 [95% CI, 0.25-0.51]), everolimus plus bevacizumab plus somatostatin analogue (HR, 0.44 [95% CI, 0.26-0.75]), interferon (HR, 0.37 [95% CI, 0.16-0.83]), interferon plus somatostatin analogue (HR, 0.31 [95% CI, 0.13-0.71]), somatostatin analogue (HR, 0.46 [95% CI, 0.33-0.66]), and sunitinib (HR, 0.42 [95% CI, 0.26-0.67]), and 5 therapies for gastrointestinal NETs: bevacizumab plus somatostatin analogue (HR, 0.22 [95% CI, 0.05-0.99]), everolimus plus somatostatin analogue (HR, 0.31 [95% CI, 0.11-0.90]), interferon plus somatostatin analogue (HR, 0.27 [95% CI, 0.07-0.96]), Lu 177-dotatate plus somatostatin analogue (HR, 0.08 [95% CI, 0.03-0.26], and somatostatin analogues (HR, 0.40 [95% CI, 0.21-0.78]) with higher efficacy than placebo and suggests an overall superiority of combination therapies. CONCLUSIONS AND RELEVANCE The findings from this study suggest that a range of efficient therapies with different safety profiles is available for patients with NETs.