Abstract 2074: Blockade mTOR and PDGF pathways by combination of molecular-targeted drugs inhibited cancer-stromal cell interaction in colon cancer.

Abstract

Abstract Recent studies in molecular and cellular biology have shown that tumor growth and metastasis are not determined by cancer cells alone but also by a variety of stromal cells. We have shown previously that platelet-derived growth factor receptors (PDGF-Rs) are overexpressed by various stromal cell populations, including carcinoma-associated fibroblasts and pericytes, but not by cancer cells themselves in human colon cancer tissues. Blockade of PDGF-R signaling pathways in tumor-associated stromal cells has been shown to inhibit the stromal reaction. Activation of phosphoinositide 3-kinase (PI3K)/Akt/ mammalian target of rapamycin (mTOR) signaling is frequently observed in many cancer types and has been implicated in the pathogenesis of various diseases. mTOR is a central regulatory kinase that increases the production of proteins that stimulate key cellular processes such as cell proliferation, metabolism, survival, and angiogenesis. However, the effects of mTOR inhibitors on the stromal component of tumor tissues has not been studied. In the present study, the effects of PDGF-R tyrosine kinase inhibitors (nilotinib) and mTOR inhibitor (everolimus) on tumor development and spread, were examined using an orthotopic model of human colon cancer, whereby KM12SM cells were implanted into the cecum of nude mice. Groups of mice (n=7 each) received saline (control), nilotinib (100mg/kg/day) or everolimus (1mg/kg/day), or a combination of nilotinib (100mg/kg/day) and everolimus (1mg/kg/day) by daily oral gavage. After 4 weeks of treatment, tumors and lymph nodes were resected, and specimens were analyzed histologically and immunohistochemically for comparison between the treatment group and control group. After treatment with nilotinib(vs. saline), the stromal reaction was significantly decreased. After treatment with everolimus, the stromal reaction was not decreased, but tumor cell proliferation and microvessel density were decreased, and the proportion of apoptotic tumor cells was increased. With the combination therapy, both tumor cell proliferation and the stromal reaction were decreased and apoptosis of tumor cells was increased, resulting in a remarkable decrease in tumor size and the number of metastatic lymph nodes. Therefore, concurrent inhibition of tumor cells and activated stromal cells by combination therapy using PDGF-R tyrosine kinase inhibitor and mTOR inhibitor may represent a novel molecular-targeted approach for patients with colon cancer. Citation Format: Ryo Yuge, Yasuhiko Kitadai, Kei Shinagawa, Mieko Onoyama, Mayu Ohnishi, Shinji Tanaka, Wataru Yasui, Kazuhisa Chayama. Blockade mTOR and PDGF pathways by combination of molecular-targeted drugs inhibited cancer-stromal cell interaction in colon cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2074. doi:10.1158/1538-7445.AM2013-2074