JultikaUniversity of Oulu repository

Abstract

Neuroblastoma is the most common extracranial solid tumor occurring in infancy and the second most commonly occurring in children. It is the neoplasm of the sympathetic nervous system. (Park et al., 2008). Neuroblastoma is characterized by the complex framework of genetic irregularities interrelated to determine the clinical phenotype. Neuroblastoma is distinguished by somatically gained genetic events that conduct a result of gene overexpression (oncogenes), gene inactivation (tumor suppressor gene), or modifications in gene expression. N-Myc proto-oncogene is known to be amplified in 20% to 25% of neuroblastomas, which plays multiple roles in malignancy and of maintenance of stemness (Maris & Matthay, 1999). In neuroblastoma, the important tumor suppressor gene TP53 is wild type in most of the patients at diagnosis, through overexpression of its negative regulators (Mdm2 or MDMX) and other unknown mechanisms (Tweddle et al., 2003). The p53 has shown to down-regulate N-Myc at protein level in neuroblastoma (Burmakin et al., 2013).

Therefore, it was tempting to study the combinatorial effects of N-Myc inhibition and p53-activation for complete tumor regression in neuroblastoma, as the high-risk neuroblastoma with N-Myc amplification frequently leads to fatal clinical outcome even though multimodal therapy, there is a need to develop more targeted strategies by targeting both oncogene (N-Myc) and tumor suppressor (p53). The combination of two anti-cancer treatments can increase efficiency due to targeting different pathways or by acting in a synergetic or additional manner (Mokhtari et al., 2017).

A number of studies have succeeded to find molecules that appear to restore proper tumor suppressor activity of p53 both in vitro and in vivo (Sanz et al., 2019). Moreover, finding the small molecules to target N-Myc is quite challenging. Recently, small molecules MI-6, which inhibit MYC-MAX (heterodimer important for MYC-driven transcription activation) showed promising in vitro response (Castell, Yan, Fawkner, Hydbring, et al., 2018a). Notably, several studies indicate that the N-Myc amplification in neuroblastoma is associated with repressed cellular immunity (P. Zhang et al., 2017). MYC oncogene represses immune surveillance both directly and indirectly in different cancers (Casey et al., 2017, 2018). Several studies suggest that p53 can influence innate immune responses as part of its tumor suppressor activities (Sanz et al., 2019) but detailed mechanism is still under investigation.

It has been suggested that p53 and Myc inverse regulate several common target genes expression including innate immune genes. In this study, we tried to get a better understanding of the innate immune response by inhibition of N-Myc using MYCMI-6 and activation of p53 using ATSP-7041 and Nutlin-3. Interestingly, monitoring p53 and MYC level, tumor cell expression of endogenous retroviral elements (ERVs) increased which leads to enhanced STAT1 expression, activity and followed by HLA class I expression has been significantly enriched. Our findings suggest that MYC inhibitor and p53 activators increase tumor immunogenicity and provide a rationale for new combination regimens comprising N-Myc inhibitor and p53-activators as an anti-cancer treatment.