Treatment options are insufficient in patients with adrenocortical carcinoma. Based on efficacy of sorafenib, a tyrosine kinase inhibitor, and everolimus, an inhibitor of the mammalian target of rapamycin (mTOR) in tumors of different histotype, we aimed at testing these drugs in adrenocortical cancer models. The expression of VEGF and its receptors (VEGFR1-2) was studied in 18 adrenocortical carcinomas, 33 aldosterone-producing adenomas, 12 cortisol-producing adenomas and 6 normal adrenal cortex by real-time PCR and immunohistochemistry, and by immunoblotting in SW13 and H295R cancer cell lines. The effects of sorafenib and everolimus, alone or in combination, were tested on primary adrenocortical cultures and SW13 and H295R cells by evaluating cell viability and apoptosis in vitro, and tumor growth inhibition of tumor cell line xenografts in immunodeficient mice in vivo. VEGF and VEGFR1-2 were detected in all samples and appeared over-expressed in two-thirds of adrenocortical carcinoma specimens. Dose-dependent inhibition of cell viability was observed particularly in SW13 cells after 24h treatment with either drug; drug combination produced markedly synergistic growth inhibition. Increasing apoptosis was observed in tumor cells treated with the drugs, particularly with sorafenib. Finally, a significant mass reduction and increased survival were observed in SW13 xenograft model undergoing treatment with the drugs in combination. Our data suggest that an autocrine VEGF loop may exist within adrenocortical carcinoma. Furthermore, a combination of molecularly-targeted agents may have both antiangiogenic and direct antitumor effects, and thus could represent a new therapeutic tool for the treatment of adrenocortical carcinoma.

Combination of sorafenib and everolimus impacts therapeutically on adrenocortical tumor models.

ROSATO, ANTONIO;RUBIN, BEATRICE;IACOBONE, MAURIZIO;FRIGO, ANNA CHIARA;FASSINA, AMBROGIO;PEZZANI, RAFFAELE;MANTERO, FRANCO
2012

Abstract

Treatment options are insufficient in patients with adrenocortical carcinoma. Based on efficacy of sorafenib, a tyrosine kinase inhibitor, and everolimus, an inhibitor of the mammalian target of rapamycin (mTOR) in tumors of different histotype, we aimed at testing these drugs in adrenocortical cancer models. The expression of VEGF and its receptors (VEGFR1-2) was studied in 18 adrenocortical carcinomas, 33 aldosterone-producing adenomas, 12 cortisol-producing adenomas and 6 normal adrenal cortex by real-time PCR and immunohistochemistry, and by immunoblotting in SW13 and H295R cancer cell lines. The effects of sorafenib and everolimus, alone or in combination, were tested on primary adrenocortical cultures and SW13 and H295R cells by evaluating cell viability and apoptosis in vitro, and tumor growth inhibition of tumor cell line xenografts in immunodeficient mice in vivo. VEGF and VEGFR1-2 were detected in all samples and appeared over-expressed in two-thirds of adrenocortical carcinoma specimens. Dose-dependent inhibition of cell viability was observed particularly in SW13 cells after 24h treatment with either drug; drug combination produced markedly synergistic growth inhibition. Increasing apoptosis was observed in tumor cells treated with the drugs, particularly with sorafenib. Finally, a significant mass reduction and increased survival were observed in SW13 xenograft model undergoing treatment with the drugs in combination. Our data suggest that an autocrine VEGF loop may exist within adrenocortical carcinoma. Furthermore, a combination of molecularly-targeted agents may have both antiangiogenic and direct antitumor effects, and thus could represent a new therapeutic tool for the treatment of adrenocortical carcinoma.
File in questo prodotto:
Non ci sono file associati a questo prodotto.
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11577/2496405
Citazioni
  • ???jsp.display-item.citation.pmc??? 19
  • Scopus 47
  • ???jsp.display-item.citation.isi??? 47
social impact