Targeting the DNA Damage Response for the Treatment of High Risk Neuroblastoma

Abstract

Despite intensive multimodal therapy, the survival rate for high risk neuroblastoma (HR-NB) remains <50%. Most cases initially respond to treatment but almost half will subsequently relapse with aggressive treatment resistant disease. Novel treatments exploiting the molecular pathology of NB and/or overcoming resistance to current genotoxic therapies are needed before survival rates can significantly improve. DNA damage response (DDR) defects are frequently observed in HR-NB including allelic deletion and loss of function mutations in key DDR genes, oncogene induced replication stress and cell cycle checkpoint dysfunction. Exploiting defects in the DDR has been a successful treatment strategy in some adult cancers. Here we review the genetic features of HR-NB which lead to DDR defects and the emerging molecular targeting agents to exploit them.

Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

“…Consistently, either a single treatment of a PARP inhibitor or combined treatment with a CHK1 inhibitor was demonstrated to increase RS or further potentiate the increased RS in neuroblastoma cells with MYCN amplification [ 84 ], supporting the compatibility between PARP inhibitors and inhibitors of the ATR-CHK1 pathway for effectively inducing catastrophic cell death. Taken together with the strategy for treating 11q loss neuroblastomas, the identification of genetic aberrations in genes orchestrating the two core pillars of DDR pathways, the HR and NHEJ, might be worth evaluating to develop a combination treatment with these inhibitors (targeting the DDR for the treatment of high-risk neuroblastoma is reviewed in [ 73 ]).…”

“…Therefore, G2 checkpoint inhibition in tumor cells by the CHK1 inhibitor is thought to “accelerate” the cell cycle and leads to mitotic catastrophe caused by premature mitosis with lethal levels of genomic instability ( Figure 2 ). To date, several selective inhibitors of ATR, M6620 (VX-970 or berzosertib), M4344 (VX-803), AZD6738 and BAY1895344, and CHK1, prexasertib (LY2606368), GDC-575 (ARRY-575; RG7741) and CCT245737 (SRA737), have been tested in clinical trials, but have not yet been approved [ 72 , 73 ]. For instance, prexasertib, which is a second-generation small-molecule inhibitor of CHK1, has been evaluated as both a single agent and in combination with other targeted agents or cytotoxic chemotherapies in adults and pediatric patients with tumors [ 74 ].…”

Heterogeneities in Cell Cycle Checkpoint Activation Following Doxorubicin Treatment Reveal Targetable Vulnerabilities in TP53 Mutated Ultra High-Risk Neuroblastoma Cell Lines

“…However, many clinical trials targeting the checkpoint proteins have been terminated due to toxicity and/or low target specificity [ 28 ]. One explanation could be that the DNA damage response is a highly orchestrated network that might render the cells relatively insensitive to the antiproliferative effect of a single cell cycle checkpoint protein inhibitor [ 40 ]. Therefore it has been proposed to use a combination of these agents in order to enhance the efficiency of conventional CT [ 28 ].…”

A GD2-aptamer-mediated, self-assembling nanomedicine for targeted multiple treatments in neuroblastoma theranostics

“… 1 , 2 NB is classified into risk groups (low, intermediate, and high) according to the International Neuroblastoma Risk Group (INRG) classification. 3 Although high-risk NB (HRNB) is the most prevalent, when compared with the low-risk and intermediate-risk groups, outcomes in the high-risk group are considerably poorer. 3 , 4 , 5 Clinical HRNB primarily comprises children older than 18 months with distant metastatic spread and/or amplification of the MYCN oncogene.…”

“… 3 Although high-risk NB (HRNB) is the most prevalent, when compared with the low-risk and intermediate-risk groups, outcomes in the high-risk group are considerably poorer. 3 , 4 , 5 Clinical HRNB primarily comprises children older than 18 months with distant metastatic spread and/or amplification of the MYCN oncogene. 6 At present, despite multiple combination treatments, including conventional or high-dose chemotherapy, surgical resection, radiotherapy, differentiation therapy, and immunotherapy, 1 , 7 the 5-year overall survival (OS) from HRNB has not yet changed substantially (<50%).…”