CUDC-907, a dual PI3K/histone deacetylase inhibitor, increases meta-iodobenzylguanidine uptake (123/131I-mIBG) in vitro and in vivo: a promising candidate for advancing theranostics in neuroendocrine tumor

**Background:** Neuroblastoma (NB) and pheochromocytoma/paraganglioma (PHEO/PGL) are types of neuroendocrine tumors. Imaging for these tumors is typically conducted using scintigraphy after the administration of radiolabeled meta-iodobenzylguanidine (mIBG), a norepinephrine analog that tumor cells absorb through monoamine transporters. Enhancing the activity of these transporters pharmacologically presents a promising strategy to improve the imaging and treatment (theranostics) of these tumors.

**Methods:** To identify the transporters involved in mIBG uptake, transfected Human Embryonic Kidney (HEK) cells were utilized. Histone deacetylase inhibitors (HDACi) and inhibitors targeting the PI3K/AKT/mTOR pathway were tested on various cell lines to evaluate their impact on mIBG internalization. Further studies were conducted on xenografted mice to determine the effect of the most promising HDACi on 123I-mIBG uptake.

**Results:** Studies with transfected HEK cells revealed that the norepinephrine and dopamine transporters (NET and DAT) are highly effective at internalizing mIBG. Treatment with sodium-4-phenylbutyrate (an HDACi), CUDC-907 (a dual HDACi and PI3K inhibitor), BGT226 (a PI3K inhibitor), as well as VS-5584 and rapamycin (two mTOR inhibitors), led to significant increases in mIBG internalization in a neuroblastoma cell line (IGR-NB8), enhancing uptake by 2.9-, 2.1-, 2.5-, 1.5-, and 1.3-fold, respectively, compared to untreated cells. CUDC-907 also enhanced mIBG uptake in two other NB cell lines and one PHEO cell line. The primary mechanism of mIBG internalization was identified as NET. In xenografted mice with IGR-NB8 cells, oral administration of 5 mg/kg of CUDC-907 resulted in a 2.3- and 1.9-fold increase in tumor uptake of 123I-mIBG at 4 and 24 hours post-injection, respectively, compared to untreated controls.

**Conclusions:** CUDC-907-mediated upregulation of NET enhances mIBG internalization both in vitro and in vivo, leading to improved imaging and potential therapeutic outcomes.