c-Met is a receptor tyrosine kinase involved in various malignant phenotypes of diverse cancers. The inhibition of VEGF/VEGFR has been established as a standard therapy for several cancers. Therefore, their dual inhibition is considered to be one of most attractive strategy for cancer therapy. However, unexpectedly success of VEGFR inhibitors (VEGFRI) has been concurrently associated with emerging new type toxicities which result in occasional patient's death and requiring drug off period, frequent interruptions or dose reduction. Moreover, those interruptions resulted in a rapid tumor regrowth due to the aggressive angiogenic signaling which can confer the drug resistance to VEGFRI. These issues are considered to be main reason for the lack of success of their combination with other chemotherapeutics and the limitation of their usage. This sequence of events prompted us to develop a novel c-Met + VEGFRs dual inhibitor TAS-115, which has a high potency and prominent safety profile. A 4wks tolerability study in mice revealed no animal death even at more than 28 times higher drug exposure over the effective doses (ED50). Whereas, therapeutic index (MTD/ED50) of other VEGFRIs including foretinib, sunitinib and sorafenib were only 2-4. Similar safety profile was observed in the tox study in rats treated for 3wks, its therapeutic index was more than 10, while those of other VEGFRIs were only 0.6-2.5 due to severe toxicities. To confirm whether its better safety profile provide more benefit, longer term efficacy studies were conducted. There was no difference in efficacy within the first 2wks, however, over 2wks the animals in foretinib treatment group at MTD began to die and administration could not be continued. In contrast, TAS-115 dosing has continued for over 6wks without any toxic manifestation. The deference in their efficacies at MTD for over 4wks became greater (p<0.001). Moreover, to evaluate how the drug off period of VEGFRIs affect angiogenesis, using sunitinib as a reference, the efficacy study was done with 2wks on / 1wk off dosing regimen, mimicking its clinical setting. Although tumor growth was inhibited with 2wks consecutive dosing of sunitinib via angiogenesis inhibition, the 1wk rest caused a regrowth with recovery of vascularity. And even though its next 2wks dosing re-inhibited tumor growth, repeating these cycles allowed progressive growth with aggressive angiogenic phenotype including higher gene expressions of various angiogenic factors. Meanwhile, TAS-115 could completely inhibit tumor growth for more than 6wks via durable inhibition of angiogenesis. In addition, TAS-115 prolonged the life span in the peritoneal dissemination mouse models of human gastric cancer cell line resistant to sunitinib. Taken together, the prominent safety profile of TAS-115 can lead to more therapeutic benefit via a durable inhibition of angiogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3600. doi:10.1158/1538-7445.AM2011-3600

c-Met is a multi-functional proto-oncogenic receptor tyrosine kinase (RTK) involving various malignant phenotypes and aberrant expressions of HGF/c-Met axis, which are associated with poor prognosis of diverse cancers. On the other hand, VEGF/VEGFR inhibition has achieved a notable status of standard therapy for several cancers. Moreover, recent studies suggest that both RTKs work in a complementary way on cancer malignant phenotypes including angiogenesis, metastasis, and hypoxia reaction. Therefore, their dual inhibition seemed to be an attractive strategy for cancer therapy, and indeed several compounds inhibiting both targets have been subjected to clinical evaluation. However, clinical efficacy appeared to be limited so far, probably due to their poor selective of mode of action and toxicity resulting from VEGFR inhibition which result in poor tolerability restricting the dosage in the clinical setting. The optimized potent c-Met + VEGFRs dual inhibitor with better safety profile may become a successful treatment modality meeting the medical needs. To address this issue, we have developed TAS-115, a novel small molecule c-Met + VEGFRs dual inhibitor. In biochemical assay, it was identified to be a potent ATP competitive inhibitor of both c-Met and VEGFR2 at IC50 of around 10 nM that is equal or more potent than those of other known inhibitors such as crizotinib, foretinib, or sunitinib. In cellular assays, it also potently inhibited the phosophorylation of both kinases with the same potency as HGF/c-Met or VEGF dependent cellular growth at IC50 range of 10 nM. Importantly, the IC50 values under no HGF/c-Met or VEGF dependent condition were over 20,000 nM. The difference between both conditions were more than 2000-fold, while the other inhibitors showed only 10∼300 hold difference when compared to control, not stimulated cells. This selectivity was also confirmed in a panel of 40 cell lines; the IC50 values were highly correlated with HGF, c-Met mRNA expression level as revealed by coefficient value of R2>0.65.In vivo studies, orally administered TAS-115 exhibited highly potent anti-tumor activity against c-Met positive and negative xenografts including complete tumor eradications accompanying by abolishing of c-Met and VEGFR2 signal cascade. The effective doses (ED50) determined in about 12 xenograft models ranged from 4 to 30 mg/kg. The tolerability study of consecutive dosing for 4 wks revealed no animal death incidence, even at more than 28 times higher exposure over the ED50 values of TAS-115, which was surprising when compared with safety of other VEGFR inhibitors including foretinib, sunitinib and sorafenib, whose therapeutic indices (MTD/ED50) were only 2∼4. Taken together, TAS-115 is a highly potent c-Met + VEGFRs dual inhibitor with prominent selectivity and safer profile indicating its therapeutic potentials in human cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3577. doi:10.1158/1538-7445.AM2011-3577

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