Nothing but NET: a review of norepinephrine transporter expression and efficacy of 131I-mIBG therapy

Abstract

Neuroblastoma is unique amongst common pediatric cancers for its expression of the norepinephrine transporter (NET), enabling tumor-selective imaging and therapy with radioactive analogues of norepinephrine. The majority of neuroblastoma tumors are avid for (123)I-metaiodobenzaguanidine (mIBG) on imaging, yet the therapeutic response to (131) I-mIBG is only 30% in clinical trials, and off-target effects cause short- and long-term morbidity. We review the contemporary understanding of the tumor-selective uptake, retention, and efflux of meta-iodobenzylguanidine (mIBG) and strategies currently in development for improving its efficacy. Combination treatment strategies aimed at enhancing NET are likely necessary to reach the full potential of (131)I-mIBG therapy.

Keywords: meta-iodobenzylguanidine; neuroblastoma; norepinephrine transporter.

Figure 1

Representation of the mechanisms involved in ¹³¹I-mIBG uptake, retention, and efflux. Along with a passive diffusion phenomenon and exocytosis, ¹³¹I-mIBG may be released by the uptake carrier working in a reverse mode. The latter mechanism can be triggered either by the inversion of the sodium gradient across the cell membrane or by trans-stimulation by a ligand outside the cell membrane. Red text and lines represent the mechanisms being explored to enhance ¹³¹I-mIBG uptake, retention, and cytotoxicity. Some therapies radiosensitize neuroblastomas (HDAC inhibitors, gamma radiation, topoisomerase inhibitors, proteasome inhibitors) while others directly increase NET expression or enhance its function. Circle = ¹³¹I-mIBG, triangle = norepinephrine. HDAC = histone deacetylase; VMAT = vesicular monoamine transporter.