Potential for Increasing Uptake of Radiolabeled 68Ga-DOTATOC and 123I-MIBG in Patients with Midgut Neuroendocrine Tumors Using a Histone Deacetylase Inhibitor Vorinostat

Background: Histone deacetylase (HDAC) inhibitors have been shown in preclinical studies to upregulate norepinephrine transporters in neuroblastoma and pheochromocytoma, and somatostatin receptors in pulmonary carcinoid, small cell lung cancer, and pancreatic neuroendocrine malignancies. This pilot imaging study in humans focuses on midgut neuroendocrine carcinoma metastatic to the liver, evaluating the effect of pretreatment with the HDAC inhibitor vorinostat on uptake of I-123-MIBG and Ga-68-DOTATOC. Materials and Methods: Multiple midgut neuroendocrine liver metastases in clinically stable subjects were imaged with I-123-MIBG and Ga-68-DOTATOC before and after a 4-d course of vorinostat. Scans were performed with strict attention to detail and timed about 1 month apart occurring just before monthly long-acting octreotide administrations. Uptake changes in tumor and normal liver parenchyma were assessed on positron emission computed tomography (PET/CT) with standardized uptake values and on single photon emission computed tomography (SPECT) with qualitative ratio images. Results: The experimental units were metastatic liver lesions within patients (n = 50). There was no significant difference in administered activity or uptake time between pairs of scans for either radiotracer. Statistically significant increase in maximum standardized uptake values (SUVmax) averaged over all lesions was noted on the Ga-68-DOTATOC PET scans (+11%, p < 0.01). SUVmax in normal liver showed no significant change (p = 0.12). There was no qualitative change in uptake of I-123-MIBG after vorinostat. Conclusions: In this pilot imaging study in patients with midgut neuroendocrine liver metastases, a short course of the HDAC inhibitor vorinostat induced a statistically significant increase in SUVmax on Ga-68-DOTATOC PET/computed tomography (CT) imaging in some hepatic neuroendocrine tumor metastases. There was no significant effect of vorinostat on tumor uptake of I-123-MIBG on SPECT/CT imaging. Given the pilot nature of this trial, the findings merit further investigation with a more rigorous protocol evaluating longer pretreatment and different dosages of vorinostat or other HDAC inhibitors, as well as effects on the therapeutic capability of Lu-177- or Y-90-somatostatin analogs.

Automated summary

This pilot imaging study focused on midgut neuroendocrine carcinoma metastatic to the liver, evaluating the effect of pretreatment with the HDAC inhibitor vorinostat on uptake of I-123-MIBG and Ga-68-DOTATOC. The study found a statistically significant increase in SUVmax on Ga-68-DOTATOC PET/CT imaging in some hepatic neuroendocrine tumor metastases after a short course of vorinostat, suggesting potential therapeutic implications for somatostatin analogs.