Retinoid Therapy for Neuroblastoma: Historical Overview, Regulatory Challenges, and Prospects

Abstract

Retinoids are vitamin A derivatives and include trans-retinoic acid, isotretinoin, tamibarotene, and bexarotene, all of which are currently available for clinical use. The clinical development of retinoid therapy for neuroblastoma has a history spanning more than four decades. The most promising agent is isotretinoin, which can contribute to improving event-free survival in patients with high-risk neuroblastoma by approximately 10% when administered over six months as maintenance therapy. Although isotretinoin is regarded as an essential component in the standard clinical management of high-risk neuroblastoma, its use for this purpose in the US and EU is off-label. To promote isotretinoin use in Japan as a treatment for neuroblastoma, our clinical research team is planning to launch an investigator-initiated, registration-directed clinical trial. The present review article discusses the basic science behind retinoid therapy, pre-clinical/clinical evidence on neuroblastoma, the concept of the proposed clinical trial, and prospects for this therapy.

Keywords: high-risk; isotretinoin; maintenance therapy; neuroblastoma; off-label issue; retinoic acids; retinoid therapy; retinoids; tumor differentiation therapy.

Figure 1

Chemical structure of retinoids used in clinical practice. A natural retinoid molecule consists of four isoprenoid units containing a hydrophobic part, the central polyene linker, and the polar region. Synthetic retinoids are generated by modifying the hydrophobic part and the central polyene linker to increase molecular stability. This figure was designed by authors using Ketcher 2.4.

Figure 2

Coregulator exchange at RXR/RAR heterodimers. RARs function as modulators of transcription by recruiting coregulator complexes having HDAC activity. Retinoids function as a ligand activating or blocking gene transcription mediated via RXR/RAR heterodimers. This figure was designed by the authors. HDAC, histone deacetylase; NCoR, nuclear receptor corepressor complex; RA, retinoic acid; RARE, retinoic acid-response element; SMRT, silencing mediator of retinoic acid and thyroid hormone receptor.

Figure 3

Promises, challenges, and countermeasures of a new tumor differentiation therapy based on retinoids. This figure was designed by the authors based on an illustration by Takashi Mifune with his permission. CAR-T cell, chimeric antigen receptor (CAR)-expressing T cells; DDS, drug delivery system; Rx, treatment.