135 The Role of a Novel MicroRNA Cluster, C19MC, in Breast Cancer

Abstract

Melanoma: A375 (BRAF V600E) and CHL-1 (BRAF WT) xenografts treated with sorafenib or axitinib and /or MI-319. Mice were treated for 21 days daily by gavage. Tumors were measured daily. Upon sacrifice tumors were frozen in liquid nitrogen for western analysis or fixed in formalin and paraffin embedded for examination of MDSC infiltration by immunofluorescence and proliferation, TUNEL and microvessel density by immunohistochemistry. Results: The addition of MI-319 to any of the VEGF-R antagonists slowed tumor growth and in some cases showed tumor regression. In all xenografts, at the time when tumors were resistant to the VEGFR antagonists, there was increased SDF-1 expression and infiltration of CD11b, GR-1 MDSCs. The addition of MI-319 consistently suppressed SDF-1 production and the infiltration of CD11b, GR-1 MDSCs. Conclusions: The development of resistance to drugs such as sunitinib, sorafenib and axitinib is an inevitable consequence of the hypoxia and nutrient deprivation induced by the involution of the tumor microcirculation. We have shown that resistance in RCC and melanoma is associated with increased expression of SDF-1 and the infiltration of CD11b, GR-1 MDSC. In addition we have shown that the addition of an HDM2 inhibitor enhances the efficacy of VEGF-R antagonists coincident with suppression of both SDF-1 and the infiltration of MDSCs. HDM2 inhibitors are currently in clinical testing and we expect to be able to test these compounds in combination with a VEGF-R inhibitor in the near future.