The mammalian target of rapamycin (mTOR) plays a key role in cellular growth and homeostasis and its regulation is frequently altered in tumors. Vascular endothelial growth factor (VEGF) is known to mediate its biological functions via activation of the protein tyrosine kinase receptors, VEGF receptor 1 (VEGFR-1/Flt1) and VEGFR-2 (KDR/Flk1). Recently, mTOR inhibitors and multi-targeted kinase inhibitors have entered late-phase clinical trials in a heterogenous set of neuroendocrine neoplasms. To identify new biomarkers to predict patient outcome, we studied the expressions of AKT-mTOR pathway and VEGFR-2 in 290 gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We performed immunoshistochemistry of phospho-Akt (pAkt), phospho-mTOR (pmTOR), VEGFR-2, Chromogranin A (Chr A), and Somatostatin receptors (SSTRs) 1, 2, and 5 and analyzed the association with AJCC stage and WHO grade. All cases were re-graded and re-staged according to WHO 2010 classification and AJCC 7th edition. The cases were composed of 131 foregut (49 stomach, 32 duodenum, and 50 pancreas) and 159 hindgut (20 colon and 139 rectum); 204 (70%) Stage I, 40 (14%) Stage II, 33 (12%) Stage III, and 13 (4%) Stage IV; 179 (62%) NET G1, 61 (21%) NET G2, 20 (7%) NEC, 16 (5%) mixed adenoneuroendocrine carcinoma, and 14 (5%) grade not available. We found that 43%, 41%, and 72% of GEP-NET were positive for pAkt, pmTOR, and VEGFR-2 respectively. In hindgut tumors, the frequencies of pAkt, pmTOR, and VEGFR-2 were significantly higher than foregut tumors (P<0.001, 64%, 54%, and 85% in hindgut vs. 18%, 24%, and 56% in foregut). The activated status of mTOR pathway was proved by the strong correlation of pmTOR with pAkt and SSTRs (P<0.001). There was a strong intercorrelation between pmTOR and VEGFR-2 expressions (P<0.001). The expression of pmTOR were inversely associated with AJCC stage and WHO grade (P<0.05), however the expression of VEGFR-2 was not associated with them. The expressions of pmTOR and VEGFR-2 showed a significant correlation with expression Chr A (P<0.05). Inverse association between pmTOR with AJCC stage or WHO grade was noted in hindgut tumors, but no association was noted in foregut tumors. Regarding to VEGFR-2, in hindgut tumors, there was a positive correlation between VEGFR-2 with Chr A. None of pAkt, pmTOR or VEGFR-2 had an impact on survival. In foregut tumors, VEGFR-2 was associated with N stage. In conclusion, pmTOR and VEGFR-2 were inversely associated with AJCC stage or WHO grade. Our results showed that pmTOR and VEGFR-2 showed considerable variations in expression in GEP-NET in dependence of tumor location. These differences in expressions of pmTOR and VEGFR-2 might possibly influence response to mTOR inhibitiors or multi-targeted receptor tyrosine kinase inhibitors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5576. doi:1538-7445.AM2012-5576