Combining Molecular Targeted Drugs To Inhibit Both Cancer Cells And Activated Stromal Cells In Colon Cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Recent studies 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, 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 have not been studied. In the present study, the effects of nilotinib (PDGF-R tyrosine kinase inhibitor) and everolimus (mTOR inhibitor) on tumor development and metastasis, were examined using orthotopic and experimental liver metastatic models of human colon cancer, whereby KM12SM cells were implanted into the cecum and spleen of nude mice, respectively. Groups of mice 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, primary tumors and metastatic lesions were resected, and specimens were analyzed histologically and immunohistochemically for comparison between the treatment group and control group. After treatment with nilotinib, 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. 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 liver lesions. Therefore, concurrent inhibition of tumor cells and activated stromal cells by combination therapy may represent a novel molecular-targeted approach for patients with colon cancer. Citation Format: Ryo Yuge, Yasuhiko Kitadai, Kei Shinagawa, Mieko Onoyama, Yuichiro Tanaka, Shinji Tanaka, Wataru Yasui, Kazuaki Chayama. Combining molecular targeted drugs to inhibit both cancer cells and activated stromal cells in colon cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 146. doi:10.1158/1538-7445.AM2014-146