Dual Targeting of PI3K and HDAC by CUDC-907 Inhibits Pediatric Neuroblastoma Growth.

Rameswari Chilamakuri,Saurabh Agarwal

doi:10.3390/cancers14041067

Abstract

The dysregulation of PI3K, HDACs, and MYCN are well known for promoting multiple cancer types, including neuroblastoma (NB). Targeting the upstream regulators of MYCN, including HDACs and PI3K, was shown to suppress cancer growth. In the present study, we analyze different NB patient datasets to reveal that high PI3K and HDAC expression is correlated with overall poor NB patient survival. High PI3K level is also found to be associated with high MYCN level and NB stage progression. We repurpose a dual inhibitor CUDC-907 as a single agent to directly target both PI3K and HDAC in NB. We use in vitro methodologies to determine the efficacy and selectivity of CUDC-907 using six NB and three control fibroblast cell lines. Our results show that CUDC-907 significantly inhibits NB proliferation and colony growth, induces apoptosis, blocks cell cycle progression, inhibits MYCN, and enhances H3K9Ac levels by inhibiting the PI3K/AKT signaling pathway and HDAC function. Furthermore, CUDC-907 significantly inhibits NB tumor growth in a 3D spheroid tumor model that recapitulates the in vivo tumor growth. Overall, our findings highlight that the dual inhibition of PI3K and HDAC by CUDC-907 is an effective therapeutic strategy for NB and other MYC-dependent cancers.

Highlights

IntroductionHigh-risk neuroblastoma (NB) is the most common extracranial solid tumor that accounts for almost 10% of all childhood-related cancers [1]
HDAC2 gene expression showed an inverse correlation with overall and event-free survival of NB patients (Supplementary Figure S1). These findings suggest the oncogenic role of phosphoinositide-3 kinase (PI3K) and histone deacetylases (HDAC) in NB and highlight an effective therapeutic targeting strategy of using a dual inhibitor CUDC-907 for NB
Our results showed that CUDC-907-mediated PI3K and HDAC inhibition leads to inhibiting NB

Summary

Introduction

High-risk neuroblastoma (NB) is the most common extracranial solid tumor that accounts for almost 10% of all childhood-related cancers [1]. Despite major advancements in intensive multi-modal therapies, the overall 5-year survival rate of NB is less than 50% [2]. Current NB therapy follows an induction chemotherapy regimen that is often associated with disease comorbidities and increased risk of secondary malignancies [3]. Developing novel single-agent therapeutic strategies targeting multiple oncogenic pathways such as PI3K/AKT, histone deacetylases, and MYCN, is important for NB and other cancers

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