Abstract 381: Enhancement of efficacy of sorafenib and sunitinib with the HDM2 antagonist MI-319 in RCC tumor xenografts
Authors: Panka David J. , Collins Michael , Atkins Michael B. , Signoretti Sabina , Mier James W. 
Published: February 2011

Abstract
One of the greatest advances in the treatment of renal cell carcinoma (RCC) over the last few years has been the introduction into clinical practice of antitumor agents (e.g. sunitinib, sorafenib) that function primarily as inhibitors of VEGF-driven angiogenesis. Although initially encouraging, there are few if any complete or durable responses to these agents. Typically tumors develop resistance to VEGF-R inhibition within a median of 5-11 months, at which point tumor growth resumes, often at an accelerated pace, despite the continued administration of the drug. In an attempt to assess the biochemical basis for acquired resistance, we have developed several RCC murine xenograft models. Among the genes whose expression in RCC xenografts is altered by sorafenib and sunitinib treatment are the genes that encode certain collagens. Based on this observation, we conjectured that the production of endostatin and other angiostatic collagen fragments might be similarly affected during the course of treatment. Western blot analysis of tumors during resistance revealed a marked reduction in the deposition of endostatin in sorafenib-but not sunitinib-treated 786-0 xenografts. The enzyme necessary for the synthesis of these collagen fragments, proline hydroxylase, is regulated by p53. Treatment with sunitinib induces the sustained up-regulation of p53 which persists with the onset of drug resistance. Conversely, treatment with sorafenib results in only transient p53 activation which is evident only during the period of drug-induced growth arrest and lost with the resumption of tumor growth paralleling the expression of endostatin and prolyl hydroxylase. The extent to which the failure of RCC cells to sustain the activation of p53 during treatment with VEGF-R antagonists accounts for the relative lack of endostatin in the tumor extracellular matrix and the rapid growth characteristic of sorafenib-resistant 786-0 xenografts is currently unknown.
Several small molecule antagonists of HDM2 have been developed which interfere with the interaction between p53 and HDM2, the result of which is enhanced p53 stability. Our preliminary in vitro data shows that although sorafenib is a poor inducer of apoptosis in some RCC cell lines, in combination with the HDM2 antagonist MI-319 sorafenib induces massive cell death. Furthermore the addition of MI-319 to sorafenib dramatically enhances the time to resistance of 786-0 xenografts relative to sorafenib or MI-319 alone. Even more compelling is a nearly 30% regression in tumor volume of 786-0 xenografts treated with the combination of MI-319 and sunitinib for 21 days. Finally the forced suppression of p53 via the use of a tetracycline regulable shRNA to p53 completely blocked the efficacy to sunitinib. These findings lend support for the use of HDM2 antagonists in combination with VEGF receptor antagonists in future RCC clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 381.