Abstract 4132: Anti-tumor and anti-metastatic effect of sunitinib in a patient derived metastatic clear cell renal cell carcinoma xenograft model

Abstract

Abstract Background: Sunitinib, a multi-tyrosine kinase inhibitor, is considered first-line therapy for patient with advanced renal cell carcinoma. The mechanism by which sunitinib harnesses angiogenesis is by targeting receptors of pro-angiogenic growth factors such as VEGF, PDGF and kit. Recently, it has been speculated that sunitinib may have a direct anti-tumor effect. Our previous studies have shown that tumors resistant to sunitinib still present decreased tumor vasculature compared to untreated tumors, suggesting that sunitinib anti-tumor effect may be in part independent from its anti-angiogenic effect. Hence, we wanted to further investigate the anti-tumor effect of sunitinib in human renal cell carcinoma (RCC) cell lines and a patient derived clear cell RCC xenograft model. In addition, we examined the effect of sunitinib on early and late stage metastasis in a spontaneous metastatic human ccRCC model. Methods: Human ccRCC PDX RP-R-02 was implanted into SCID mice subcutaneously. Spontaneous metastatic ccRCC model, RP-R-02LM was developed from RP-R-02. RP-R-02LM tumor bearing mice were treated with sunitinib (40mg/kg; 5days/week). Tumor tissues and lungs were collected for immunohistochemistry analysis. In parallel, human RCC cell lines were treated in vitro with varying concentrations of sunitinib and cell viability was assessed. Results: Human RCC cells lines treated in vitro with sunitinib at pharmacological achievable concentrations showed a decrease in cell proliferation, suggesting a direct anti-tumor effect of sunitinib in RCC. RP-R-02LM but not parental RP-R-02 implanted either subcutaneous or orthotopically in the kidney, spontaneously metastasize to the lungs and closely mimics what is seen in the clinic. PCR results indicated that both xenografts still maintain human origin. In our in vivo system, RP-R-02LM treated with sunitinib had no anti-tumor effect on tumor at the primary site; however, we observed an inhibition of dissemination to the metastatic lung site as indicated by significantly low numbers of metastasis compared to the controls. Immunohistochemical analysis showed decrease in tumor vasculature with sunitinib treatment compared to the control, with increased tumor cell proliferations. Conclusion: Our studies suggest that sunitinib has a direct anti-tumor in vitro and eventually tumor cells acquire drug resistance. Our in vivo studies show that tumors resistant to sunitinib have decreased vessel density as compared to the untreated tumors, suggesting that sunitinib is still a potent anti-angiogenic agent. In addition, we show the anti-metastatic effect of sunitinib in a spontaneous metastatic human clear cell renal cell carcinoma. Overall our data suggest that sunitinib maintains an anti-metastatic effect in sunitinib resistant tumor bearing animals that is independent from its anti-angiogenic effect. Citation Format: Remi M. Adelaiye-Ogala, Li Shen, Sreenivasulu Chintala, Eric Ciamporcero, Ashley Orillion, May Elbanna, Shengyu Ku, Kiersten Marie Miles, Bryan Gillard, Michael Buck, Roberto Pili. Anti-tumor and anti-metastatic effect of sunitinib in a patient derived metastatic clear cell renal cell carcinoma xenograft model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4132. doi:10.1158/1538-7445.AM2015-4132