Dataset Information

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 tumors.

ABSTRACT:

Background

Neuroblastoma (NB) and pheochromocytoma/paraganglioma (PHEO/PGL) are neuroendocrine tumors. Imaging of these neoplasms is performed by scintigraphy after injection of radiolabeled meta-iodobenzylguanidine (mIBG), a norepinephrine analog taken up by tumoral cells through monoamine transporters. The pharmacological induction of these transporters is a promising approach to improve the imaging and therapy (theranostics) of these tumors.

Methods

Transporters involved in mIBG internalization were identified by using transfected Human Embryonic Kidney (HEK) cells. Histone deacetylase inhibitors (HDACi) and inhibitors of the PI3K/AKT/mTOR pathway were tested in cell lines to study their effect on mIBG internalization. Studies in xenografted mice were performed to assess the effect of the most promising HDACi on ¹²³I-mIBG uptake.

Results

Transfected HEK cells demonstrated that the norepinephrine and dopamine transporter (NET and DAT) avidly internalizes mIBG. Sodium-4-phenylbutyrate (an HDACi), CUDC-907 (a dual HDACi and PI3K inhibitor), BGT226 (a PI3K inhibitor) and VS-5584 and rapamycin (two inhibitors of mTOR) increased mIBG internalization in a neuroblastoma cell line (IGR-NB8) by 2.9-, 2.1-, 2.5-, 1.5- and 1.3-fold, respectively, compared with untreated cells. CUDC-907 also increased mIBG internalization in two other NB cell lines and in one PHEO cell line. We demonstrated that mIBG internalization occurs primarily through the NET. In xenografted mice with IGR-NB8 cells, oral treatment with 5 mg/kg of CUDC-907 increased the tumor uptake of ¹²³I-mIBG by 2.3- and 1.9-fold at 4 and 24 h post-injection, respectively, compared to the untreated group.

Conclusions

Upregulation of the NET by CUDC-907 lead to a better internalization of mIBG in vitro and in vivo.

SUBMITTER: Grand-Guillaume J

PROVIDER: S-EPMC10485979 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Publications

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

Grand-Guillaume Joana J Mansi Rosalba R Gaonkar Raghuvir H RH Zanger Sandra S Fani Melpomeni M Eugster Philippe J PJ Beck Popovic Maja M Grouzmann Eric E Abid Karim K

Journal of translational medicine 20230907 1

<h4>Background</h4>Neuroblastoma (NB) and pheochromocytoma/paraganglioma (PHEO/PGL) are neuroendocrine tumors. Imaging of these neoplasms is performed by scintigraphy after injection of radiolabeled meta-iodobenzylguanidine (mIBG), a norepinephrine analog taken up by tumoral cells through monoamine transporters. The pharmacological induction of these transporters is a promising approach to improve the imaging and therapy (theranostics) of these tumors.<h4>Methods</h4>Transporters involved in mIB ...[more]

PMID: 37679770

Similar Datasets

Project description:BackgroundHigh-risk neuroblastoma (HR-NB) has a variable response to preoperative chemotherapy. It is not possible to differentiate viable vs. nonviable residual tumor before surgery.PurposeTo explore the association between apparent diffusion coefficient (ADC) values from diffusion-weighted magnetic resonance imaging (DW-MRI), 123 I-meta-iodobenzyl-guanidine (123 I-mIBG) uptake, and histology before and after chemotherapy.Study typeRetrospective.SubjectsForty patients with HR-NB.Field strength/sequence1.5T axial DW-MRI (b = 0,1000 s/mm2 ) and T2 -weighted sequences. 123 I-mIBG scintigraphy planar imaging (all patients), with additional 123 I-mIBG single-photon emission computed tomography / computerized tomography (SPECT/CT) imaging (15 patients).AssessmentADC maps and 123 I-mIBG SPECT/CT images were coregistered to the T2 -weighted images. 123 I-mIBG uptake was normalized with a tumor-to-liver count ratio (TLCR). Regions of interest (ROIs) for primary tumor volume and different intratumor subregions were drawn. The lower quartile ADC value (ADC25prc ) was used over the entire tumor volume and the overall level of 123 I-mIBG uptake was graded into avidity groups.Statistical testsAnalysis of variance (ANOVA) and linear regression were used to compare ADC and MIBG values before and after treatment. Threshold values to classify tumors as viable/necrotic were obtained using ROC analysis of ADC and TLCR values.ResultsNo significant difference in whole-tumor ADC25prc values were found between different 123 I-mIBG avidity groups pre- (P = 0.31) or postchemotherapy (P = 0.35). In the "intratumor" analysis, 5/15 patients (prechemotherapy) and 0/14 patients (postchemotherapy) showed a significant correlation between ADC and TLCR values (P < 0.05). Increased tumor shrinkage was associated with lower pretreatment tumor ADC25prc values (P < 0.001); no association was found with pretreatment 123 I-mIBG avidity (P = 0.17). Completely nonviable tumors had significantly lower postchemotherapy ADC25prc values than tumors with >10% viable tumor (P < 0.05). Both pre- and posttreatment TLCR values were significantly higher in patients with >50% viable tumor than those with 10-50% viable tumor (P < 0.05). DATA CONCLUSION: 123 I-mIBG avidity and ADC values are complementary noninvasive biomarkers of therapeutic response in HR-NB.Level of evidence4.Technical efficacy stage3.

Dataset Information

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 tumors.

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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 tumors.

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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 tumors.