E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition

Matsui, Junji; Yamamoto, Yuji; Funahashi, Yasuhiro; Tsuruoka, Akihiko; Watanabe, Tatsuo; Wakabayashi, Toshiaki; Uenaka, Toshimitsu; Asada, Makoto

doi:10.1002/ijc.23131

Cited by 472 publications

(347 citation statements)

References 27 publications

(37 reference statements)

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“…Lenvatinib (Lenvima, E7080, Eisai Co Ltd) is an orally available multi-targeted TKI with reported activity against VEGFR 1-3, FGFR 1-4, PDGFR alpha, RET and KIT (Matsui et al 2008, Bruheim et al 2011, Wiegering et al 2014. Lenvatinib has been approved by the EMA and the FDA for the treatment of patients with progressive radioiodine-refractory DTC recurrent or metastatic (Nair et al 2015).…”

Section: Investigational Drugsmentioning

confidence: 99%

Novel targeted therapeutics for MEN2

Plaza-Menacho

Mologni

2018

Endocrine-Related Cancer

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The rearranged during transfection (RET) proto-oncogene was recognized as the multiple endocrine neoplasia type 2 (MEN2) causing gene in 1993. Since then, much effort has been put into a clear understanding of its oncogenic signaling, its biochemical function and ways to block its aberrant activation in MEN2 and related cancers. Several small molecules have been designed, developed or redirected as RET inhibitors for the treatment of MEN2 and sporadic MTC. However, current drugs are mostly active against several other kinases, as they were not originally developed for RET. This limits efficacy and poses safety issues. Therefore, there is still much to do to improve targeted MEN2 treatments. New, more potent and selective molecules, or combinatorial strategies may lead to more effective therapies in the near future. Here, we review the rationale for RET targeting in MEN2, the use of currently available drugs and novel preclinical and clinical RET inhibitor candidates.

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Section: Investigational Drugsmentioning

confidence: 99%

Novel targeted therapeutics for MEN2

Plaza-Menacho

Mologni

2018

Endocrine-Related Cancer

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“…Lenvatinib (E7080) is an investigational orally active inhibitor of multiple receptor tyrosine kinases, including VEGF, FGF, PDGF and stem cell factor (SCF) receptors [4]. Apart from inhibiting angiogenesis by targeting endothelial cells [4][5][6][7], lenvatinib exerts a direct effect on tumor cells, by inhibiting their migration and invasion [8].…”

Section: Introductionmentioning

confidence: 99%

“…Apart from inhibiting angiogenesis by targeting endothelial cells [4][5][6][7], lenvatinib exerts a direct effect on tumor cells, by inhibiting their migration and invasion [8]. Promising antitumor effects of lenvatinib were observed in Phase I trials [9,10], leading to a number of disease-specific phase 2 and phase 3 trials with lenvatinib as a single agent or in combination with other anticancer agents.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and excretion of 14C-lenvatinib in patients with advanced solid tumors or lymphomas

et al. 2014

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Summary Lenvatinib is an orally available multi-targeted tyrosine kinase inhibitor with anti-angiogenic and antitumor activity. To get more insight into the disposition of lenvatinib, a mass balance study was performed in patients with advanced solid tumors. A single oral 24 mg (100 μCi) dose of 14 Clenvatinib was administered to six patients, followed by collection of blood, plasma, urine and feces for 7 to 10 days. The collected material was analyzed for total radioactivity, unchanged lenvatinib and selected metabolites. The safety and antitumor effect of a daily oral dose of 24 mg non-labeled lenvatinib were assessed in the extension phase of the study. Peak plasma concentrations of lenvatinib and total radioactivity were reached 1.6 and 1.4 h after administration, respectively, and their terminal phase half-lifes were 34.5 and 17.8 h, respectively. Unchanged lenvatinib systemic exposure accounted for 60 % of the total radioactivity in plasma. Peak concentrations of the analyzed metabolite were over 700-fold lower than the peak plasma concentration of lenvatinib. Ten days after the initial dose, the geometric mean (± CV) recovery of administered dose was 89 % ±10 %, with 64 % ±11 % recovered in feces and 25 % ±18 % in urine. Unchanged lenvatinib in urine and feces accounted for 2.5 % ±68 % of the administered dose, indicating a major role of metabolism in the elimination of lenvatinib. In conclusion, lenvatinib is rapidly absorbed and extensively metabolized, with subsequent excretion in urine and, more predominantly, in feces. Additionally, lenvatinib showed acceptable safety and preliminary antitumor activity.

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“…12 Based on previous studies 8,9 and data presented here, 30-100 mg/kg daily may be considered optimal for E7080 in mice. The antitumour activity of E7080 was grossly maintained upon reduction of the dose to 10 mg/kg in two of the human xenograft models applied (ALSKX and MOX).…”

Section: Discussionmentioning

confidence: 87%

Antitumour activity of oral E7080, a novel inhibitor of multiple tyrosine kinases, in human sarcoma xenografts

Bruheim¹,

Kristian²,

Uenaka

et al. 2011

Intl Journal of Cancer

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E7080 is an inhibitor of multiple tyrosine kinases, several of which have pro-angiogenic properties, including receptors for VEGF, FGF, SCF and PDGF. We undertook our study to evaluate the preclinical activity of E7080 in human sarcomas. The antitumour activity of orally administered E7080 was tested in ten human tumour xenografts representing different sarcoma histotypes. Concomitant changes in microvessel density were assayed by immunohistochemistry to CD31. Immunohistochemistry was also used to assess the expression of kinases that E7080 is known to inhibit. The MTS assay was applied to determine effects on tumour cell viability in vitro. At the Q1D5 3 2 schedule, E7080 (30 mg/kg) was active (T/C<40%) in 7/10 xenografts. The effects were accompanied by marked decrease in microvessel densities. Given at the Q1D5 3 4 schedule, E7080 (30, 10, 3 mg/kg) showed antitumour activity in a dose dependent manner in two different xenografts. E7080 growth inhibition did not correlate with the expression of VEGFR1-3, PDGFRA, PDGFRB, FGFR1 or KIT on tumour cells but was significantly correlated with expression of VEGFR2 on tumour microvessels. In vitro E7080 did not show potent effects on tumour cell viability in four different sarcoma cell lines, with IC50 values !10 lM. In conclusion, E7080 showed broad in vivo antitumour activity in sarcoma, mainly attributable to angiogenesis inhibition. E7080 was also active in xenografts resistant to one or more clinically relevant reference drugs given at MTD (doxorubicin, cisplatin or ifosfamide). The present results encourage further investigation of a potential role of E7080 in sarcoma therapy in the clinic.

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E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition

Cited by 472 publications

References 27 publications

Novel targeted therapeutics for MEN2

Novel targeted therapeutics for MEN2

Pharmacokinetics and excretion of 14C-lenvatinib in patients with advanced solid tumors or lymphomas

Antitumour activity of oral E7080, a novel inhibitor of multiple tyrosine kinases, in human sarcoma xenografts

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