MYCN deregulation plays a key role in leading childhood and adulthood cancers. Particularly, MYCN amplification (MNA) is an independent poor prognosis marker for many tumor types, including neuroblastoma (NB), where it identifies 50% of the high-risk cases with very poor prognosis. Direct MYCN targeting is effective in preclinical models, but not yet achievable in patients. Most importantly, the mechanisms of MYCN-induced therapy resistance are largely not understood.
A number of scientific reports suggest that enduring anticancer effects are only achieved when (re)activation of immune responses is obtained, regardless of the therapeutic approach employed (chemo/radio therapy, target therapy or immune checkpoint blockade). Unfortunately, MNA NBs are mostly characterized by a "cold" phenotype, that is lack of tumor infiltrating leukocytes, low type-I interferon transcriptomics and reduced chemokine expression. In these settings, reactivation of immune responses might not be an easy task. Indeed, initial reports on the outcome of immune checkpoint blockade were rather discouraging.
By causing replication stress, PARP inhibitors are able to trigger the cytosolic DNA sensing pathway (STING pathway) and promote innate immune responses, as part of their anticancer activity. Although PARP inhibitors increase replication stress, they appeared unable to activate the STING pathway, in MNA NB tumors. Rather, our data support the hypothesis that MNA NB enforce repression of STING activity to escape its cell-intrinsic and/or immune-mediated tumor suppressive effects, which would be otherwise triggered by MYCN-dependent replication stress.
This proposal aims to provide significant proofs of principle for this hypothesis, by addressing the consequences of STING reactivation in MNA NB models.
Our hypothesis is that MYCN enforce repression of STING activity to escape its cell-intrinsic and/or immune- mediated tumor suppressive effects, which would be otherwise triggered by MYCN-dependent replication stress. The proposal presented here is composed by one work packages with the objectives to address the consequences of STING reactivation in MNA NB models. It can be further extended (as mentioned in `Hypothesis and aims¿ section) by adding significant in vitro investigation aimed to elucidate the molecular mechanisms of STING pathway repression by MYCN. More specifically, we could further elucidate the epigenetic and non-epigenetic mechanisms of STING pathway repression by MYCN in NB.
By revealing the causes of the immune `cold¿ phenotype of MNA NB, we might provide an explanation for current therapeutic failures as well as new avenues for the cure of these tumors.