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**Chapter 5**

**Abstract**

**1. Introduction**

Neuroblastoma

*and Masahiro Hirayama*

*Hidemi Toyoda, Dong-Qing Xu, Lei Qi* 

Molecular Target Therapy against

Neuroblastoma, originated from neural crest cells, is the most common extra-

cranial solid tumor in childhood. Treatment is of limited utility for high-risk neuroblastoma and prognosis is poor. The high incidence of resistance of advancedstage neuroblastoma to conventional therapies has prompt investigators to search for novel therapeutic approaches. Activation of IGF-R/PI3K/Akt/mTOR signaling pathway correlates with oncogenesis, poor prognosis, and chemotherapy resistance in neuroblastoma. Therefore, we investigated the effect of IGF-R/PI3K/Akt/mTOR signaling inhibitors in neuroblastoma. Significantly, IGF-R/PI3K/Akt/mTOR signaling inhibitors effectively inhibited cell growth and induced cell cycle arrest, autophagy, and apoptosis in neuroblastoma cells. Moreover, IGF-R/PI3K/Akt/ mTOR signaling inhibitors significantly reduced tumor growth in mice xenograft model without apparent toxicity. Therefore, these results highlight the potential of IGF-R/PI3K/Akt/mTOR signaling pathway as a promising target for neuroblastoma treatment. Therefore, IGF-1R/PI3K/Akt/mTOR signaling inhibitors should be further investigated for treatment in clinical trials for high-risk neuroblastoma.

**Keywords:** neuroblastoma, insulin-like growth factor (IGF), phosphatidylinositol 3-kinase (PI3K), protein kinase-B (Akt), mammalian target of rapamycin (mTOR)

Neuroblastoma (NB) is one of the most common extracranial solid tumors of early childhood [1, 2]. Prognosis of patients with NB depends on tumor stage, patient's age, and biologic feature of the tumor cells [3]. In patients under 1 year of age, NB is curable and sometimes spontaneously regress [4]. However, in older children with advanced stage, often the tumor is very aggressive, and patients have poor prognosis despite treatment with high-dose chemotherapy combined with autologous hematopoietic stem cell transplantation. Although immunotherapeutic therapy such as anti-GD2 monoclonal antibody has improved outcomes of advanced stage of NB, a number of patients still relapse and eventually die of disease [5]. The high incidence of resistance of high-risk NB to conventional therapies

It was reported that phosphorylated protein kinase-B (Akt) correlates with poor patients' prognosis in NB [6], and the phosphatidylinositol-3-kinase (PI3K)/Akt/ mammalian target of rapamycin (mTOR) pathway has subsequently been linked to augmented cell survival [7] and increased resistance to chemotherapy in NB [8].

has prompted us to search for novel therapeutic approaches.
