Molecularly Guided Therapy of Neuroblastoma: A Review of Different Approaches

Abstract

Neuroblastoma (NB) is the most frequent extra-cranial solid tumor and the first cause of lethality in pre-school age children. NB accounts for 9-10% of pediatric tumors and affects more than ten thousand children a year. It originates from the sympathetic nervous system and is characterized by heterogeneous pathological and clinical presentation. Stage 4 NB represents approximately 50% of the cases and shows metastatic dissemination at onset; its prognosis is grim, with 20% of the patients surviving at 5 years from diagnosis in spite of aggressive chemotherapy with autologous hematopoietic stem cell support. Novel therapeutic strategies are urgently needed to improve the prognosis of stage 4 NB patients. Here we review the most promising approaches to NB treatment that have already reached clinical testing or have proved to be successful in preclinical models of the disease. All of these approaches are molecularly guided, since their rational development has benefited from the enormous amount of information on the biology of neuroblastoma gathered through molecular biology and genetics studies. The following topics are reviewed: MYCN oncogene amplification as parameter for therapeutic decision, minimal residual disease, immunotherapy, gene therapy, differentiation and apoptotic therapy, anti-angiogenic therapy, gene expression profiling as tool for generating novel therapeutic approaches. Although several efforts are still needed to reach a significant cure of patients with neuroblastoma, molecularly guided approaches have opened new ways to neuroblastoma treatment and can represent useful models for other cancers of either childhood or adulthood.

NT-polyplex: a new tool for therapeutic gene delivery to neuroblastoma tumors

“…30 Although the neuroblastoma has spontaneous remission or progresses to a differentiated tumor such as ganglioneuroma in children aged less than 1 year, 31 this tumor has aggressive behavior in children older than 1 year. 32 At the time of diagnosis in the latter case, 50% of these patients have already developed metastatic dissemination, and only 20% of these patients have a 5-year survival despite intensive multimodal therapy.…”

“…32 At the time of diagnosis in the latter case, 50% of these patients have already developed metastatic dissemination, and only 20% of these patients have a 5-year survival despite intensive multimodal therapy. 30 To date, treatment with chemotherapy, surgery and radiation therapy has resulted in suboptimal outcomes in patients with advanced disease. 33 Surgery is not effective on the disseminated neuroblastoma and neither are radiation and chemotherapy, which additionally cause severe toxic side effects on healthy tissues.…”

Vitamin K3 Analogs Induce Selective Tumor Cytotoxicity in Neuroblastoma

“…The 5-year survival rate of patients with stage 4 is as low as 20-25%. 4) Therefore, novel therapeutic strategies are urgently needed to improve the overall survival of these patients.…”

Differentiation induced by physiological and pharmacological stimuli leads to increased antigenicity of human neuroblastoma cells

“…A number of other complementary therapeutic approaches, such as antiangiogenic and apoptosis-inducing agents, gene therapy and immunotherapy (reviewed in [19]), have shown some success, but only in pre-clinical models of NB, whereas retinoid-based differentiation therapy already demonstrated effectiveness in clinical settings (reviewed in [4]). …”