Chemoprevention of neuroblastoma: progress and promise beyond uncertainties

Abstract

Neuroblastoma is the most common extracranial solid tumor in children and comprises one-tenth of all childhood cancer deaths. The current clinical therapy for this deadly disease is multimodal, involving an induction phase with alternating regimens of high-dose chemotherapeutic drugs and load reduction surgery; a consolidation phase with more intensive chemotherapy, radiotherapy, and stem cell transplant; and a maintenance phase with immunotherapy and immune-activating cytokine treatment. Despite such intensive treatment, children with neuroblastoma have unacceptable life quality and survival, warranting preventive measures to regulate the cellular functions that orchestrate tumor progression, therapy resistance, metastasis, and tumor relapse/recurrence. Globally, active efforts are underway to identify novel chemopreventive agents, define their mechanism(s) of action, and assess their clinical benefit. Some chemoprevention strategies (e.g., retinoids, difluoromethylornithine) have already been adopted clinically as part of maintenance phase therapy. Several agents are in the pipeline, while many others are in preclinical characterization. Here we review the classes of chemopreventive agents investigated for neuroblastoma, including cellular events targeted, mode(s) of action, and the level of development. Our review: (i) highlights the pressing need for new and improved chemopreventive strategies for progressive neuroblastoma; (ii) lists the emerging classes of chemopreventive agents for neuroblastoma; and (iii) recognizes the relevance of targeting dynamically evolving hallmark functions of tumor evolution (e.g., survival, differentiation, lineage transformation). With recent gains in the understanding of tumor evolution processes and preclinical and clinical efforts, it is our strong opinion that effective chemopreventive strategies for aggressive neuroblastoma are a near reality.

Keywords: DFMO; Neuroblastoma; apoptosis; chemoprevention; phytochemicals; polyphenols; retinoids; secondary and tertiary chemopreventive; terpenes.

Figure 1.

Schema showing the classification of chemopreventive strategies and the specific cellular functions targeted by each class of chemopreventive agent.

Figure 2.

3D molecular structures, molecular formula and molecular weight of 9-cisRA, 13-ciRA, ATRA, 4-HPR, and 4-Oxo-4-HPR (a metabolite of 4-HPR) molecules. Images were adapted from PubChem^® (Available from: https://pubchem.ncbi.nlm.nih.gov/), National Library of Medicine, NIH.

Figure 3.

Simplified pathway map showing targeted signaling events altered or rearranged with retinoid treatment, their mechanism(s) of action, and the effect on key cellular functions involved in neuroblastoma evolution. Significantly, retinoids-regulated signaling converges on targeting the signaling pathways that regulate the hallmarks of neuroblastoma progression.

Figure 4.

Cartoon showing diverse classes of phytochemicals investigated in vitro and in vivo for neuroblastoma chemoprevention, their mode of action and targeted cellular functions that dictate prevention of tumor progression, metastasis and disease evolution. Chemopreventive drugs target targets and/or signaling pathways, but largely the mode of action converge in defined sets of cellular/biological functions and conceptually supports the chemopreventive cocktail strategy for the development of effective molecular targeted maintenance therapy for neuroblastoma. Independent approaches displayed the systemic delivery feasibility, selective effect on tumor cells while sparing normal neural cells and neural stem cells, and excellent chemopreventive benefit of phytochemicals in the preclinical models of neuroblastoma.

Figure 5.

Pyramid showing the evolution profile of chemopreventive agents for neuroblastoma. While some retinoids and DFMO are used as part of maintenance therapy, some are still being characterized in clinical trials. A large group of lead candidates that show excellent chemopreventive properties are in the pipeline for clinical translation. In addition, a sizable group of potential candidates for neuroblastoma chemoprevention are currently being characterized.