869 - Angiogenic and signalling proteins correlate resistance and sequence of treatment in renal cell cancer

Date 28 September 2012
Event ESMO Congress 2012
Session Publication Only
Topics Renal Cell Cancer
Translational Research
Presenter Roberta Rosa
Authors R. Rosa1, V. Damiano2, L. Nappi3, L. Formisano3, F. Massari4, A. Scarpa5, G. Martignoni6, R. Bianco2, G. Tortora4
  • 1University Federico II, Napoli/IT
  • 2Medical Oncology, University Federico II, Napoli/IT
  • 3Endocrinologia Ed Oncologia Molecolare E Clinica, University Federico II, Napoli/IT
  • 4Oncologia Medica, Azienda Ospedaliera Universitaria Integrata Verona-"Borgo Roma", 37134 - Verona/IT
  • 5Patologia E Diagnostica, Anatomia Patologica, Universit, 37134 - Verona/IT
  • 6Pathology And Diagnostics, University of Verona, Verona/IT

Abstract

Background

The multi-tyrosine kinases inhibitors and the mammalian target of rapamycin (mTOR) inhibitors have dramatically changed the management of metastatic renal cell carcinoma (RCC). However, a relevant issue in RCC treatment is still the lack of a biological and molecular rationale able to establish the most effective sequence of the different therapeutic options available.

Methods

To address this issue, we systematically assessed the effect of different agents, alone and in sequence, on the growth, expression and secretion of key angiogenic and signalling proteins involved in tumor growth and resistance to treatment, in a panel of human RCC cell lines with different VHL status and in tumors xenografted in nude mice.

Results

We demonstrated that sunitinib, sorafenib and everolimus are equally active as single agents in inhibiting cell proliferation, signal transduction and VEGF secretion, both in vitro and in tumors grown in mice. Pre-treatment of tumor cells with sunitinib reduced the response to subsequent sunitinib and sorafenib but not to everolimus. Lack by sunitinib of a persistent inhibition of key proteins including HIF-1, VEGF and MAPK anticipates onset of resistance in xenografted tumors. After first line sunitinib, second line everolimus was more effective than sorafenib or sunitinib rechallenge to interfere with critical signalling proteins and VEGF and Interleukin-8 secretion, translating into an advantage in the long-lasting inhibition of tumor growth and significant prolongation of mice survival.

Conclusions

Our study demonstrates that angiogenic and signalling proteins predict treatment failure with sunitinib and that the use of mTOR inhibitor everolimus in second line is substantiated by a persistent control of proteins responsible for RCC growth and resistance to treatment.

Disclosure

All authors have declared no conflicts of interest.