title: Tissue Expression and Pharmacological In Vitro Analyses of mTOR and SSTR Pathways in Adrenocortical Carcinoma.
abstract: New therapies for advanced adrenocortical carcinoma (ACC) are urgently needed, as the majority of the patients experience a rapid and inexorable progression despite surgery and adjuvant mitotane. In vitro data suggest that somatostatin receptors (SSTRs) and mTOR pathway might represent reasonable targets for novel therapies, being involved in functionality and growth of ACC cells. However, in vitro analysis of combination treatments targeting both mTOR and SSTR as compared to mitotane are poorly explored in ACC. This study aimed to investigate in vitro the effects on cell growth of pasireotide, everolimus, and mitotane, alone or combined, in the two ACC cell lines H295R and SW13 (mitotane sensitive and resistant, respectively). Moreover, the tissue expression of mTOR pathway molecules and SSTR (types 1-5) was assessed in 58 ACCs. In both cell lines, only everolimus induced a significant inhibition of cell growth. Conversely, the combinations among mitotane, pasireotide, and everolimus produced antagonistic effects on mitotane-induced growth inhibition on H295R cell line. A heterogeneous profile of mTOR-related molecules and SSTR expression was observed in ACC samples, being the mTOR pathway found activated in approximately 30% of cases. In conclusion, our data suggest caution in designing combinations of mitotane with other drugs potentially active in ACC, such as mTOR inhibitors or somatostatin analogs.
authors.affiliation: Department of Clinical and Biological Sciences and Department of Oncology, University of Turin at San Luigi Hospital, Regione Gonzole 10, 10043 Orbassano, Turin, Italy.
authors.forename: Antonina
authors.initials: A
authors.lastname: Germano
authors.affiliation: Department of Clinical and Biological Sciences and Department of Oncology, University of Turin at San Luigi Hospital, Regione Gonzole 10, 10043 Orbassano, Turin, Italy.
authors.forename: Ida
authors.initials: I
authors.lastname: Rapa
authors.affiliation: Department of Clinical and Biological Sciences and Department of Oncology, University of Turin at San Luigi Hospital, Regione Gonzole 10, 10043 Orbassano, Turin, Italy. eleonora.duregon@unito.it.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Duregon
authors.affiliation: Department of Clinical and Biological Sciences and Department of Oncology, University of Turin at San Luigi Hospital, Regione Gonzole 10, 10043 Orbassano, Turin, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Votta
authors.affiliation: Department of Clinical and Biological Sciences and Department of Oncology, University of Turin at San Luigi Hospital, Regione Gonzole 10, 10043 Orbassano, Turin, Italy.
authors.forename: Jessica
authors.initials: J
authors.lastname: Giorcelli
authors.affiliation: Department of Clinical and Biological Sciences and Department of Oncology, University of Turin at San Luigi Hospital, Regione Gonzole 10, 10043 Orbassano, Turin, Italy.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Buttigliero
authors.affiliation: Department of Clinical and Biological Sciences and Department of Oncology, University of Turin at San Luigi Hospital, Regione Gonzole 10, 10043 Orbassano, Turin, Italy.
authors.forename: Giorgio V
authors.initials: GV
authors.lastname: Scagliotti
authors.affiliation: Department of Clinical and Biological Sciences and Department of Oncology, University of Turin at San Luigi Hospital, Regione Gonzole 10, 10043 Orbassano, Turin, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Volante
authors.affiliation: Department of Clinical and Biological Sciences and Department of Oncology, University of Turin at San Luigi Hospital, Regione Gonzole 10, 10043 Orbassano, Turin, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Terzolo
authors.affiliation: Department of Clinical and Biological Sciences and Department of Oncology, University of Turin at San Luigi Hospital, Regione Gonzole 10, 10043 Orbassano, Turin, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Papotti
mesh_terms: D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000473:pathology*; D018268:Adrenocortical Carcinoma / Q000473:pathology*; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000032:analysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002648:Child; D002675:Child, Preschool; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D017481:Receptors, Somatostatin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Adrenocortical carcinoma cell lines; Everolimus; Mitotane; Pasireotide; Somatostatin receptor; Target therapy; mTOR