The challenge of developmental therapeutics for adrenocortical carcinoma

Abstract

Adrenocortical carcinoma (ACC) is a rare disease with an estimated incidence of only 0.7 new cases per million per year. Approximately 30-70% of the patients present with advanced disease with very poor prognosis and without effective therapeutic options. In the recent years, unprecedented progresses in cancer biology and genomics have fostered the development of numerous targeted therapies for various malignancies. Immunotherapy has also transformed the treatment landscape of malignancies such as melanoma, among others. However, these advances have not brought meaningful benefits for patients with ACC. Extensive genomic analyses of ACC have revealed numerous signal transduction pathway aberrations (e.g., insulin growth factor receptor and Wnt/β-catenin pathways) that play a central role in pathophysiology. These molecular alterations have been explored as potential therapeutic targets for drug development. This manuscript summarizes recent discoveries in ACC biology, reviews the results of early clinical studies with targeted therapies, and provides the rationale for emerging treatment strategies such as immunotherapy.

Keywords: IGF-1R; VEGFR; adrenocortical carcinoma; targeted therapy; β-catenin.

Figure 1. IGF-1R and Wnt/Frizzled receptor pathways

A. In adrenocortical carcinoma cells IGF2 binds to IGF1 receptor (IGF1R) family. IGF-1R has a tetrameric structure in which the intra-cellular β-chain tyrosine kinase activity regulated by ligand binding to extra-cellular α chain. Downstream of these receptors are the well-known Akt and MAPK intracellular signaling networks, which when activated promote cell proliferation. B. The Wnt proteins, by binding to frizzled receptors and the LRP co-receptor, act to suppress the activity of glycogen synthase kinase-3β (GSK-3β). ZNRF3 promotes degradation of Wnt receptor functioning as tumor suppressors. This prevents phosphorylation of downstream molecules allowing β-catenin association with Tcf/Lef in the nucleus and subsequent increased cell proliferation.

Figure 2. Targeted agents and immune checkpoint inhibitors studied and under development in ACC