Abstract A245: TAS-115, a novel potent dual MET/VEGFRs inhibitor, has highly safer profile leading to more potent efficacy in vivo.
Authors: Kato Masanori , Fujita Hidenori , Miyadera Kazutaka , Fujioka Yayoi , Ochiiwa Hiroaki , Huang Jinhong , Ito Kimihiro , Aoyagi Yoshimi , Takenaka Toru , Suzuki Takamasa , Ito Satoko , Hashimoto Akihiro , Suefuji Takashi , Sato Ayako , Egami Kosuke , Kazuno Hideki , Suda Yoshimitsu , Yonekura Kazuhiko 
Published: June 2012

Abstract
The inhibition of VEGF/VEGFR has been established notable achievement as standard therapy for several cancers. However, unexpectedly success of VEGFR inhibitors (VEGFRI) has been concurrently associated with emerging new type toxicities which result in occasional patient's death and demanding high frequent rates of dose modification including dosing interruption or permanent discontinuations. Those interruptions can easily induce rapid tumor re-growth or tumor metastasis via the aggressive angiogenesis by inductions of various angiogenic factors which can confer the drug resistance to VEGFRI. These issues are considered to be main reason for no success of their combination to other chemotherapies and limiting indications.
MET is a multi-functional receptor tyrosine kinase involved in various malignant phenotypes of diverse cancers. Recent studies suggest that both pathways of MET and VEGFR work in a complementary way on regulation of cancer malignant phenotypes such as angiogenesis, metastasis, or others. Therefore, their dual inhibition minimizing toxicities of VEGFRI seemed to be an attractive strategy for cancer therapy.
TAS-115 is identified as a potent MET and VEGFR dual inhibitor with unique biological and pharmacokinetic properties optimized for minimized toxicities of VEGFR inhibition. In enzyme and cellular phamacodynamic assays, it potently inhibited both MET and VEGFR2 at IC50 of 10–30 nM that is equal or more potent than those of other inhibitors such as crizotinib (METI), sunitinib (VEGFRI), or foretinib (MET/VEGFRI). In cellular growth inhibition assays, it inhibited HGF/MET or VEGF dependent cellular growth at IC50 range of 10 nM. Importantly, the inhibitory effect on cellular growth was less potent under no supplementation of HGF and VEGF condition, the IC50 values were over 20 M. The selectivity between both condition is over 2000-fold while the other well-known inhibitors have only 10–100-fold selectivity.
In vivo studies, orally administered TAS-115 exhibited highly potent anti-tumor activity against MET positive and negative xenografts including complete tumor eradication accompanying by abolishing of MET and VEGFR2 signal cascade. The ED50 values determined in 20 xenograft models were ranged from 3 to 25 mg/kg. The tolerability study of consecutive dosing for 4 weeks revealed no animal death incidence, even at more than 28 times higher exposure to TAS-115, which was sharp contrast to the safety of other VEGFRI including foretinib, sunitinib and sorafenib, whose therapeutic indices (MTD/ED50) were only 1.5–2. Similar safety profile was observed in rats treated for 3 weeks, its therapeutic index was more than 10, while those of other inhibitors were only 0.9–2.5 due to various severe toxicities including myelosuppression, GI, hepatic, renal injury or others. Longer term efficacy studies, for 6 weeks, revealed that this safer profile of TAS-115 resulted in prolonging time to progression much more than any other inhibitors including sunitinib or foretinib.
Taken together, TAS-115 was identified as a highly potent MET/ VEGFR dual inhibitor minimized toxicities of VEGFRI, which will be expected to overcome clinical issues of previous VEGFRI or MET/VEGFRI. Its clinical trial will be initiated in this year.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A245.