The insulin-like growth factor receptor 2 (IGF2R) as a new potential therapeutic target in adrenocortical carcinoma: in vitro and in vivo studies

Adrenocortical carcinoma (ACC) is a rare endocrine cancer with a poor prognosis for which novel therapies are urgently needed. The IGF2 overexpression is a frequent event in ACC. IGF2 acts on a complex pathway leading to growth of ACC cells, however until now researchers focused the attention mainly on IGF1R. Despite the centrality of this pathway, the IGF1R inhibition in clinical trial failed, suggesting the need of a deeper understanding of multiple players modulating IGF pathway. IGF2R traditional acts degrading IGF2 in lysosomes and transporting lysosomal enzymes. An IGF2R soluble form is also present in human and rodents fluids. IGF2R function as tumor suppressor in different type of cancers was demonstrated however, its oncogenic role in cervical and triple-negative breast cancers was observed. To date, its role in ACC has been poorly investigated and findings are in contrast. Our preliminary results indicated IGF2R as a pro- oncogenic factor in ACC. In this regard, the goals of the study will be to evaluate in ACC: 1. The IGF2R pro-oncogenic role and the impact of its inhibition on tumor behaviour and sensibility to EDP-M in vitro and in vivo studies; 2. The connection between IGF2R and sphingosine pathway and the co-treatment with inhibitors of both pathways also evaluating the effects on the sensibility to EDP-M in vitro and in vivo studies; 3. The IGF2R role in internalizing and degrading IGF2 in primary tumors and its metastasis, trying to switch IGF2R function toward IGF2 degradation as an alternative therapeutic strategy; 4. The IGF2R function in transporting lysosomal enzymes with the aim to identify a new therapeutic strategy; 5. The cross-talk between IGF2R multiple functions and IGF2R soluble form The results are expected to deeply investigate IGF2R role in ACC and evaluate it as a new therapeutic target from several points of view.