Abstract 1785: MET/VEGFR dual inhibition and prominent safety profile of TAS-115 are favorable for the combination with chemotherapeutic drugs
Authors: Fujita Hidenori , Kato Masanori , Fujioka Yayoi , Sato Tsudoi , Ochiiwa Hiroaki , Huang Jinhong , Ito Kimihiro , Aoyagi Yoshimi , Suzuki Takamasa , Ito Satoko , Ito Kenjiro , Hashimoto Akihiro , Nakaya Yoko , Miyadera Kazutaka , Yonekura Kazuhiko 
Published: August 2012

Abstract
MET is known as a proto-oncogene, which involves in growth, migration, metastasis and angiogenesis in tumor progression. Recently, it is reported that MET also functions as chemo and EGFR-TKI resistant factor in cancer cells. Particularly, HGF/MET signal seemed to reduce the potency of conventional chemotherapeutic drugs in clinical. Meanwhile, VEGF/VEGFR signal plays an important role in angiogenesis in tumor growth, and is essential for the survival signal of endothelial cells(ECs) to protect from the damage by chemotherapeutic drugs. Some VEGFR inhibitors have already been approved for the treatment of several carcinomas with monotherapy. Many clinical combination trials with VEGFR inhibitor and chemotherapeutic agents have been tried, but its therapeutic benefit are restricted. It is highly desire for improving therapeutic benefit by combination therapy with VEGFR inhibitor and standard chemotherapy. TAS-115, a novel oral MET/VEGFR dual inhibitor, demonstrated not only potent efficacy but also prominent safety profiles achieved by improvement of PK profile and cellular selectivity. Potent MET/VEGFR dual inhibition provides significant anti-tumor effect from lower dose for TAS-115. On the one hand, the improvement of PK profile and cell selectivity led to better tolerability. As a result, therapeutic window (MTD/ED50) of TAS-115 became wider than that of the pre-existing VEGFR or MET/VEGFR inhibitors. These profiles give TAS-115 the long-term dosing at full effective dose without severe toxicity. Moreover, in vitro study, HGF completely suppressed the induction of apoptosis by 5-FU or Paclitaxel in cancer cells expressed MET. Meanwhile, VEGF abolished the cytotoxic effect by these chemotherapeutic drugs against ECs. It was suggested that harmonization of both HGF and VEGF in tumor greatly contributed to the resistance against conventional chemotherapeutic drugs. The MET/VEGFR dual inhibition by TAS-115 improves the sensitivity of chemotherapeutic drugs for both cancer cells and ECs via suppression of function as chemo-resistance factor by MET and VEGFR. In fact, the combination therapies with TAS-115 and conventional chemotherapeutic drugs caused tumor regression or potent growth inhibition without sever body weight loss in several xenograft models. Notably, TAS-115 markedly enhanced anti-tumor effect of Paclitaxel, and brought tumor shrinkage of approximately 80% in the combination. More important feature is that TAS-115 has disturbed rapid tumor re-growth following Paclitaxel treatment and the higher safety profiles of TAS-115 permits combination therapy with chemotherapeutic drugs in chronic treatment. It is expected TAS-115 demonstrates prominent therapeutic benefit in combination with chemotherapy based on the synergistic action of the potent MET/VEGFR dual inhibition and higher safety profiles.
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 1785. doi:1538-7445.AM2012-1785