Adrenocortical cancer (ACC) is a rare tumor optimally treated with surgical resection. Unfortunately in many patients tumors are not amenable to surgical resection, while others suffer a subsequent relapse, so that there is a need for more effective systemic therapies. The availability of agents directed at novel targets offers the opportunity to identify new agents with activity in ACC. The recent approval of both sunitinib and sorafenib for renal cell carcinoma offers multi-targeted kinase inhibitors that may be active in other malignancies. A putative target for these drugs is the VEGF receptor. VEGF, often produced in tumors can be secreted and can activate the VEGFR in both tumor cells and vascular endothelium. We examined VEGF expression in 16 adrenal tumors by immunohistochemistry (IHC). Compared with a p53 mutant colon cancer used as the positive control, VEGF levels were much higher in 3/16, intermediate defined as comparable to that in the colon cancer cells in an additional 10, and low in 3 ACC tumors. Analysis of HIF1α in a subset of the patients found high to very high levels of nuclear HIF1α in some providing a potential pathway for VEGF activation. N-cadherin a member of a superfamily of transmembrane proteins responsible for cell-to-cell adhesion in vertebrate is expressed predominantly in neural and mesodermal epithelia. Over-expression of N-cadherin is associated with tumor progression and metastasis in breast, prostate, lung and bladder cancer and agents targeting this pathway are in development. Little is known about the role of cadherins in ACC. The adrenal gland is composed of the cortex and medulla, arising from the mesoderm and neuroectoderm respectively. We examined expression of N-cadherin by IHC and immunoblot in 16 ACC tumors, and in H-295R cells grown in vitro and as xenografts with SK-N-SH neuroblastoma cells as positive control. Ki 67 a marker of proliferation was also analyzed. N-cadherin was expressed in 5/16 tumors, and 2/2 xenografts by IHC. Expression was principally membranous, but also cytoplasmic. 4/16 tumors, and 2/2 H295R xenografts were positive by immnunoblotting. There was no correlation Ki 67 and N-cadherin expression. These results show that VEGF and N-cadherin are expressed in a significant fraction of ACC and targeting these proteins may offer an alternative treatment. Studies are ongoing to determine the in vivo efficacy of agents targeting VEGF and N-cadherin using the H-295R xenograft model.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA