Publications by authors named "Yasuhiro Funahashi"

115 Publications

Pharmacodynamic Biomarkers Predictive of Survival Benefit with Lenvatinib in Unresectable Hepatocellular Carcinoma: From the Phase III REFLECT Study.

Clin Cancer Res 2021 Jun 9. Epub 2021 Jun 9.

Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK.

Purpose: In REFLECT, lenvatinib demonstrated an effect on overall survival (OS) by confirmation of noninferiority to sorafenib in unresectable hepatocellular carcinoma. This analysis assessed correlations between serum or tissue biomarkers and efficacy outcomes from REFLECT.

Experimental Design: Serum biomarkers (VEGF, ANG2, FGF19, FGF21, and FGF23) were measured by ELISA. Gene expression in tumor tissues was measured by the nCounter PanCancer Pathways Panel. Pharmacodynamic changes in serum biomarker levels from baseline, and associations of clinical outcomes with baseline biomarker levels, were evaluated.

Results: Four hundred and seven patients were included in the serum analysis set (lenvatinib = 279, sorafenib = 128); 58 patients were included in the gene-expression analysis set (lenvatinib = 34, sorafenib = 24). Both treatments were associated with increases in VEGF; only lenvatinib was associated with increases in FGF19 and FGF23 at all time points. Lenvatinib-treated responders had greater increases in FGF19 and FGF23 versus nonresponders at cycle 4, day 1 (FGF19: 55.2% vs. 18.3%, = 0.014; FGF23: 48.4% vs. 16.4%, = 0.0022, respectively). Higher baseline VEGF, ANG2, and FGF21 correlated with shorter OS in both treatment groups. OS was longer for lenvatinib than sorafenib [median, 10.9 vs. 6.8 months, respectively; HR, 0.53; 95% confidence interval (CI), 0.33-0.85; interaction = 0.0397] with higher baseline FGF21. In tumor tissue biomarker analysis, VEGF/FGF-enriched groups showed improved OS with lenvatinib versus the intermediate VEGF/FGF group (HR, 0.39; 95% CI, 0.16-0.91; = 0.0253).

Conclusions: Higher baseline levels of VEGF, FGF21, and ANG2 may be prognostic for shorter OS. Higher baseline FGF21 may be predictive for longer OS with lenvatinib compared with sorafenib, but this needs confirmation.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4219DOI Listing
June 2021

High Response Rate and Durability Driven by HLA Genetic Diversity in Patients with Kidney Cancer Treated with Lenvatinib and Pembrolizumab.

Mol Cancer Res 2021 May 26. Epub 2021 May 26.

Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, New York.

Immune checkpoint blockade (ICB) therapy has substantially improved the outcomes of patients with many types of cancers, including renal cell carcinoma (RCC). Initially studied as monotherapy, immunotherapy-based combination regimens have improved the clinical benefit achieved by ICB monotherapy and have revolutionized RCC treatment. While biomarkers like PD-L1 and tumor mutational burden (TMB) are FDA approved as biomarkers for ICB monotherapy, there are no known biomarkers for combination immunotherapies. Here, we describe the clinical outcomes and genomic determinants of response from a phase Ib/II clinical trial on patients with advanced RCC evaluating the efficacy of lenvatinib, a multi-kinase inhibitor mainly targeting VEGFR and FGFR plus pembrolizumab, an anti-PD1 immunotherapy. Concurrent treatment with lenvatinib and pembrolizumab resulted in an objective response rate of 79% (19/24) and tumor shrinkage in 96% (23/24) of patients. While tumor mutational burden (TMB) did not predict for clinical benefit, germline HLA-I diversity strongly impacted treatment efficacy. Specifically, HLA-I evolutionary divergence (HED), which measures the breadth of a patient's immunopeptidome, was associated with both improved clinical benefit and durability of response. Our results identify lenvatinib plus pembrolizumab as a highly active treatment strategy in RCC and reveal HLA-I diversity as a critical determinant of efficacy for this combination. HED also predicted better survival in a separate cohort of patients with RCC following therapy with anti-PD-1-based combination therapy. IMPLICATIONS: These findings have substantial implications for RCC therapy and for understanding immunogenetic mechanisms of efficacy and warrants further investigation.
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http://dx.doi.org/10.1158/1541-7786.MCR-21-0053DOI Listing
May 2021

Complex formation of silver(I) ions with a glucosinolate derivative: structural and mechanistic insights into myrosinase-mimicking C-S bond cleavage.

Dalton Trans 2021 Jun;50(24):8292-8296

Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka, 560-0043 Japan.

The crystal structure of an unprecedented silver complex of O-acetylsinigrin has shown chelating bonds of the sulfated thiohydroximate and an η2-bond of the ethylene moiety with Ag(i). Mechanistic studies on the formation and decomposition of the complex by the 1H NMR measurements and theoretical calculations with the DFT method indicated relevance to the glucosinolate degradation in biological systems.
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http://dx.doi.org/10.1039/d1dt00695aDOI Listing
June 2021

Striatal TRPV1 activation by acetaminophen ameliorates dopamine D2 receptor antagonist-induced orofacial dyskinesia.

JCI Insight 2021 May 24;6(10). Epub 2021 May 24.

Department of Molecular Pharmacology, Graduate School and Faculty of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.

Antipsychotics often cause tardive dyskinesia, an adverse symptom of involuntary hyperkinetic movements. Analysis of the US Food and Drug Administration Adverse Event Reporting System and JMDC insurance claims revealed that acetaminophen prevented the dyskinesia induced by dopamine D2 receptor antagonists. In vivo experiments further showed that a 21-day treatment with haloperidol increased the number of vacuous chewing movements (VCMs) in rats, an effect that was inhibited by oral acetaminophen treatment or intracerebroventricular injection of N-(4-hydroxyphenyl)-arachidonylamide (AM404), an acetaminophen metabolite that acts as an activator of the transient receptor potential vanilloid 1 (TRPV1). In mice, haloperidol-induced VCMs were also mitigated by treatment with AM404 applied to the dorsal striatum, an effect not seen in TRPV1-deficient mice. Acetaminophen prevented the haloperidol-induced decrease in the number of c-Fos+preproenkephalin+ striatal neurons in wild-type mice but not in TRPV1-deficient mice. Finally, chemogenetic stimulation of indirect pathway medium spiny neurons in the dorsal striatum decreased haloperidol-induced VCMs. These results suggest that acetaminophen activates the indirect pathway neurons by activating TRPV1 channels via AM404.
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http://dx.doi.org/10.1172/jci.insight.145632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262333PMC
May 2021

Enantioselective Reaction of 2-Azirines with Oxazol-5-(4)-ones Catalyzed by Cinchona Alkaloid Sulfonamide Catalysts.

Org Lett 2021 03 2;23(6):2104-2108. Epub 2021 Mar 2.

Department of Life Science and Applied Chemistry, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan.

The enantioselective reaction of 2-azirines with oxazol-5-(4)-ones (oxazolones) using a cinchona alkaloid sulfonamide catalyst has been developed. The reaction proceeded at the C-2 position of oxazolones to afford products with consecutive tetrasubstituted stereogenic centers in high yield with high diastereo- and enantioselectivity. The obtained aziridines were converted into various chiral compounds without loss of enantiopurity.
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http://dx.doi.org/10.1021/acs.orglett.1c00259DOI Listing
March 2021

Dynamic subcellular localization and transcription activity of the SRF cofactor MKL2 in the striatum are regulated by MAPK.

J Neurochem 2021 Jun 3;157(6):1774-1788. Epub 2021 Feb 3.

Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.

Dopamine type 1 receptor (D1R) signaling activates protein kinase A (PKA), which then activates mitogen-activated protein kinase (MAPK) through Rap1, in striatal medium spiny neurons (MSNs). MAPK plays a pivotal role in reward-related behavior through the activation of certain transcription factors. How D1R signaling regulates behavior through transcription factors remains largely unknown. CREB-binding protein (CBP) promotes transcription through hundreds of different transcription factors and is also important for reward-related behavior. To identify transcription factors regulated by dopamine signaling in MSNs, we performed a phosphoproteomic analysis using affinity beads coated with CBP. We obtained approximately 40 novel candidate proteins in the striatum of the C57BL/6 mouse brain after cocaine administration. Among them, the megakaryoblastic leukemia-2 (MKL2) protein, a transcriptional coactivator of serum response factor (SRF), was our focus. We found that the interaction between CBP and MKL2 was increased by cocaine administration. Additionally, MKL2, CBP and SRF formed a ternary complex in vivo. The C-terminal domain of MKL2 interacted with CBP-KIX and was phosphorylated by MAPK in COS7 cells. The activation of PKA-MAPK signaling induced the nuclear localization of MKL2 and increased SRF-dependent transcriptional activity in neurons. These results demonstrate that dopamine signaling regulates the interaction of MKL2 with CBP in a phosphorylation-dependent manner and thereby controls SRF-dependent gene expression. Cover Image for this issue: https://doi.org/10.1111/jnc.15067.
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http://dx.doi.org/10.1111/jnc.15303DOI Listing
June 2021

E7386, a Selective Inhibitor of the Interaction between β-Catenin and CBP, Exerts Antitumor Activity in Tumor Models with Activated Canonical Wnt Signaling.

Cancer Res 2021 02 6;81(4):1052-1062. Epub 2021 Jan 6.

PRISM BioLab Co., Ltd., Kanagawa, Japan.

The Wnt/β-catenin signaling pathway plays crucial roles in embryonic development and the development of multiple types of cancer, and its aberrant activation provides cancer cells with escape mechanisms from immune checkpoint inhibitors. E7386, an orally active selective inhibitor of the interaction between β-catenin and CREB binding protein, which is part of the Wnt/β-catenin signaling pathway, disrupts the Wnt/β-catenin signaling pathway in HEK293 and adenomatous polyposis coli ()-mutated human gastric cancer ECC10 cells. It also inhibited tumor growth in an ECC10 xenograft model and suppressed polyp formation in the intestinal tract of mice, in which mutation of activates the Wnt/β-catenin signaling pathway. E7386 demonstrated antitumor activity against mouse mammary tumors developed in mouse mammary tumor virus (MMTV)-Wnt1 transgenic mice. Gene expression profiling using RNA sequencing data of MMTV-Wnt1 tumor tissue from mice treated with E7386 showed that E7386 downregulated genes in the hypoxia signaling pathway and immune responses related to the CCL2, and IHC analysis showed that E7386 induced infiltration of CD8 cells into tumor tissues. Furthermore, E7386 showed synergistic antitumor activity against MMTV-Wnt1 tumor in combination with anti-PD-1 antibody. In conclusion, E7386 demonstrates clear antitumor activity via modulation of the Wnt/β-catenin signaling pathway and alteration of the tumor and immune microenvironments, and its antitumor activity can be enhanced in combination with anti-PD-1 antibody. SIGNIFICANCE: These findings demonstrate that the novel anticancer agent, E7386, modulates Wnt/β-catenin signaling, altering the tumor immune microenvironment and exhibiting synergistic antitumor activity in combination with anti-PD-1 antibody.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0782DOI Listing
February 2021

The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors.

Future Oncol 2021 Feb 10;17(6):637-648. Epub 2020 Dec 10.

The START Center for Cancer Care, San Antonio, TX 78229, USA.

Tumor progression and immune evasion result from multiple oncogenic and immunosuppressive signals within the tumor microenvironment. The combined blockade of VEGF and inhibitory immune checkpoint signaling has been shown to enhance immune activation and tumor destruction in preclinical models. The LEAP clinical trial program is evaluating the safety and efficacy of lenvatinib (a multikinase inhibitor) plus pembrolizumab (a PD-1 inhibitor) across several solid tumor types. Preliminary results from ongoing trials demonstrate robust antitumor activity and durable responses across diverse tumor types with a manageable safety profile. Thus, lenvatinib plus pembrolizumab is anticipated to be an important potential new regimen for several solid cancers that currently have limited therapeutic options. NCT03884101, NCT03713593, NCT03820986, NCT03776136, NCT03797326, NCT03829319, NCT03829332, NCT03976375, NCT04428151, NCT04199104, NCT03898180, NCT04246177 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-0937DOI Listing
February 2021

Antitumor Activity of Eribulin After Fulvestrant Plus CDK4/6 Inhibitor in Breast Cancer Patient-derived Xenograft Models.

Anticancer Res 2020 Dec;40(12):6699-6712

Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan;

Background/aim: There is no established standard chemotherapy after administration of the combination endocrine plus CDK4/6 inhibitor therapy for luminal-type breast cancer. We used patient-derived xenograft (PDX) models to determine the antitumor activity of eribulin and capecitabine after endocrine therapy plus CDK4/6 inhibitor.

Materials And Methods: We examined the antitumor activity of fulvestrant, palbociclib, eribulin, and capecitabine in 4 luminal-type breast cancer PDX models (OD-BRE-0188, -0438, -0450, -0745). In OD-BRE-0438, we determined the antitumor activity of chemotherapy after fulvestrant-palbociclib treatment. We also performed immunohistochemical analysis to explore the effects of treatment on E-cadherin in tumor tissues.

Results: Fulvestrant, fulvestrant-palbociclib and chemotherapy had antitumor activity in the 4 PDX models. In OD-BRE-0438 (the most resistant to fulvestrant-palbociclib), eribulin had superior antitumor activity to capecitabine after fulvestrant plus palbociclib. Only eribulin tended to increase E-cadherin expression.

Conclusion: Eribulin had superior antitumor activity to capecitabine after fulvestrant-palbociclib in the OD-BRE-0438 model.
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http://dx.doi.org/10.21873/anticanres.14693DOI Listing
December 2020

Correlative serum biomarker analyses in the phase 2 trial of lenvatinib-plus-everolimus in patients with metastatic renal cell carcinoma.

Br J Cancer 2021 01 7;124(1):237-246. Epub 2020 Oct 7.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: No biomarkers have been established to predict treatment efficacy in renal cell carcinoma (RCC). In an exploratory retrospective analysis of a Phase 2 study, we constructed composite biomarker scores (CBSs) to predict progression-free survival (PFS) and overall survival (OS) in patients with metastatic RCC randomised to receive lenvatinib-plus-everolimus.

Methods: Of 40 biomarkers tested, the 5 most strongly associated with PFS (HGF, MIG, IL-18BP, IL-18, ANG-2) or OS (TIMP-1, M-CSF, IL-18BP, ANG-2, VEGF) were used to make a 5-factor PFS-CBS or OS-CBS, respectively. A 2-factor CBS was generated with biomarkers common to PFS-CBS and OS-CBS. Patients were divided into groups accordingly (5-factor-CBS high: 3-5, CBS-low: 0-2; 2-factor-CBS high: 1-2, CBS-low: 0).

Results: PFS/OS with lenvatinib-plus-everolimus were significantly longer in the 5-factor CBS-high group versus the CBS-low group (P = 0.0022/P < 0.0001, respectively). In the CBS-high group, PFS/OS were significantly longer with lenvatinib-plus-everolimus versus everolimus (P < 0.001/P = 0.0079, respectively); PFS was also significantly longer with lenvatinib-plus-everolimus versus lenvatinib (P = 0.0046). The 5-factor-CBS had a predictive role in PFS and OS after multivariate analysis. Similar trends were observed with the 2-factor-CBS for PFS (i.e., lenvatinib-plus-everolimus versus everolimus).

Conclusions: The 5-factor CBS may identify patients with metastatic RCC who would benefit from lenvatinib-plus-everolimus versus everolimus; additional validation is required.

Clinical Trial Registration: The clinical trial registration number is NCT01136733.
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http://dx.doi.org/10.1038/s41416-020-01092-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782770PMC
January 2021

Activated FGF2 signaling pathway in tumor vasculature is essential for acquired resistance to anti-VEGF therapy.

Sci Rep 2020 02 19;10(1):2939. Epub 2020 Feb 19.

Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, 5-1-3 Tokodai, Tsukuba, Ibaraki, 300-2635, Japan.

Anti-vascular endothelial growth factor (VEGF) therapy shows antitumor activity against various types of solid cancers. Several resistance mechanisms against anti-VEGF therapy have been elucidated; however, little is known about the mechanisms by which the acquired resistance arises. Here, we developed new anti-VEGF therapy-resistant models driven by chronic expression of the mouse VEGFR2 extracellular domain fused with the human IgG4 fragment crystallizable (Fc) region (VEGFR2-Fc). In the VEGFR2-Fc-expressing resistant tumors, we demonstrated that the FGFR2 signaling pathway was activated, and pericytes expressing high levels of FGF2 were co-localized with endothelial cells. Lenvatinib, a multiple tyrosine kinase inhibitor including VEGFR and FGFR inhibition, showed marked antitumor activity against VEGFR2-Fc-expressing resistant tumors accompanied with a decrease in the area of tumor vessels and suppression of phospho-FGFR2 in tumors. Our findings reveal the key role that intercellular FGF2 signaling between pericytes and endothelial cells plays in maintaining the tumor vasculature in anti-VEGF therapy-resistant tumors.
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http://dx.doi.org/10.1038/s41598-020-59853-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031295PMC
February 2020

Enantioselective Vinylogous Mannich Reaction of Acyclic Vinylketene Silyl Acetals with Ketimines Using Chiral Bis(imidazoline)-Cu(II) Catalysts.

Org Lett 2020 04 12;22(8):2868-2872. Epub 2020 Feb 12.

Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan.

The enantioselective vinylogous Mannich reaction of ketimines derived from isatins with acyclic vinylketene silyl acetals has been developed using a chiral bis(imidazoline)-Cu(II) catalyst. A series of chiral 3-aminooxindole derivatives bearing tetra-substituted stereogenic centers with an α,β-unsaturated ester moiety were obtained in excellent yields (up to 99%) with high enantioselectivities (up to 98% ee). Enantioselective bisvinylogous Mannich reaction to ketimines derived from isatins also afforded product with high enantioselectivity. Based on the experimental investigations, a possible transition state has been proposed to explain the origin of the asymmetric induction.
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http://dx.doi.org/10.1021/acs.orglett.0c00289DOI Listing
April 2020

Advances in defining signaling networks for the establishment of neuronal polarity.

Curr Opin Cell Biol 2020 04 1;63:76-87. Epub 2020 Feb 1.

Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan; Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi, 470-1192, Japan. Electronic address:

Neurons are highly polarized cells that have structurally and functionally distinct processes called axons and dendrites. How neurons establish polarity is one of the fundamental questions of neuroscience. In the last decade, significant progress has been made in identifying and understanding the molecular mechanisms responsible for neuronal polarization, primarily through researches conducted on cultured neurons. Advances in phosphoproteomics technologies and molecular tools have enabled comprehensive signal analysis and visualization and manipulation of signaling molecules for analyzing neuronal polarity. Furthermore, advances in gene transfer techniques have revealed the role of extracellular and intracellular signaling molecules in neuronal polarization in vivo. This review discusses the latest insights and techniques for the elucidation of the molecular mechanisms that control neuronal polarity.
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http://dx.doi.org/10.1016/j.ceb.2019.12.009DOI Listing
April 2020

Second-line lenvatinib in patients with recurrent endometrial cancer.

Gynecol Oncol 2020 03 17;156(3):575-582. Epub 2020 Jan 17.

Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA.

Objective: This study assessed the efficacy of lenvatinib, a multitargeted tyrosine kinase inhibitor, as second-line therapy in patients with unresectable endometrial cancer. The primary end point was the objective response rate (ORR) as assessed by independent radiologic review (IRR). Secondary end points included median progression-free survival (PFS), overall survival (OS), and clinical benefit rate. Exploratory end points examined the association of baseline levels of plasma biomarkers (50 circulating cytokine and/or angiogenic factors measured by immunoassays) with efficacy outcomes.

Methods: An international, open-label, single-arm, multicenter, phase 2 trial was conducted. Eligible patients had histologically confirmed unresectable endometrial cancer that relapsed after 1 prior systemic platinum-based chemotherapy. Patients received once-daily oral lenvatinib 24 mg in a 28-day dosing cycle.

Results: There were 133 patients in the study. By IRR, 19 patients had a confirmed objective response for an ORR of 14.3% (95% CI: 8.8-21.4). Durable stable disease (≥23 weeks) was observed in 31 patients (23.3%) and the clinical benefit rate was 37.6% (95% CI: 29.3-46.4). Median PFS was 5.6 months (95% CI: 3.7-6.3), and median OS was 10.6 months (95% CI: 8.9-14.9). The most common (any grade) treatment-related adverse events were fatigue/asthenia (48%), hypertension (49%), nausea/vomiting (32%), decreased appetite (32%), and diarrhea (31%). Lower baseline levels of angiopoietin-2 were associated with longer PFS, OS, and a higher ORR.

Conclusions: Patients with recurrent endometrial cancer treated with second-line lenvatinib experienced modest antitumor activity and treatment was generally well tolerated, with a safety profile consistent with previous studies.
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http://dx.doi.org/10.1016/j.ygyno.2019.12.039DOI Listing
March 2020

Phosphorylation of Npas4 by MAPK Regulates Reward-Related Gene Expression and Behaviors.

Cell Rep 2019 12;29(10):3235-3252.e9

Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya 466-8550, Japan; Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan. Electronic address:

Dopamine (DA) activates mitogen-activated protein kinase (MAPK) via protein kinase A (PKA)/Rap1 in medium spiny neurons (MSNs) expressing the dopamine D1 receptor (D1R) in the nucleus accumbens (NAc), thereby regulating reward-related behavior. However, how MAPK regulates reward-related learning and memory through gene expression is poorly understood. Here, to identify the relevant transcriptional factors, we perform proteomic analysis using affinity beads coated with cyclic AMP response element binding protein (CREB)-binding protein (CBP), a transcriptional coactivator involved in reward-related behavior. We identify more than 400 CBP-interacting proteins, including Neuronal Per Arnt Sim domain protein 4 (Npas4). We find that MAPK phosphorylates Npas4 downstream of PKA, increasing the Npas4-CBP interaction and the transcriptional activity of Npas4 at the brain-derived neurotrophic factor (BDNF) promoter. The deletion of Npas4 in D1R-expressing MSNs impairs cocaine-induced place preference, which is rescued by Npas4-wild-type (WT), but not by a phospho-deficient Npas4 mutant. These observations suggest that MAPK phosphorylates Npas4 in D1R-MSNs and increases transcriptional activity to enhance reward-related learning and memory.
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http://dx.doi.org/10.1016/j.celrep.2019.10.116DOI Listing
December 2019

Behavioral analysis in mice deficient for GAREM2 (Grb2-associated regulator of Erk/MAPK subtype2) that is a subtype of highly expressing in the brain.

Mol Brain 2019 11 12;12(1):94. Epub 2019 Nov 12.

The Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, 5562 Nanatsuka, Shobara, Hiroshima, 727-0023, Japan.

Grb2-associated regulator of Erk/MAPK (GAREM), is an adaptor protein related to the several cell growth factor receptor-signaling. The GAREM family has two subtypes, GAREM1 and GAREM2, both encoded in the human and mouse genome. Recent genome-wide research identified GAREM2 as a candidate of neurodegenerative diseases. Here, we use knockout (KO) mice to show the role of GAREM2, that is highly expressed in the brain. According to the comprehensive behavioral battery, they exhibited less anxiety both in elevated plus maze and open field tests, mildly increased social approaching behavior in the reciprocal social interaction test, and longer latency to immobility in the tail suspension test as compared to wild-type (WT). Additionally, the extension of neurites in the primary cultured neurons was suppressed in ones derived from GAREM2 KO mice. Furthermore, we also identified Intersectin, as a binding partner of GAREM2 in this study. Intersectin is also a multi-domain adaptor protein that regulates endocytosis and cell signaling, which can potentially alter the subcellular localization of GAREM2. The important molecules, such as the neurotrophin receptor and Erk family, that are involved in the signaling pathway of the neural cell growth in the mouse brain, have been reported to participate in emotional behavior. As GAREM plays a role in the cellular growth factor receptor signaling pathway, GAREM2 may have a common role related to the transduction of Erk signaling in the higher brain functions.
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http://dx.doi.org/10.1186/s13041-019-0512-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852768PMC
November 2019

Neuronal Polarity: Positive and Negative Feedback Signals.

Front Cell Dev Biol 2019 24;7:69. Epub 2019 Apr 24.

Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Establishment and maintenance of neuronal polarity are critical for neuronal development and function. One of the fundamental questions in neurodevelopment is how neurons generate only one axon and several dendrites from multiple minor neurites. Over the past few decades, molecular and cell biological approaches have unveiled a large number of signaling networks regulating neuronal polarity in cultured hippocampal neurons and the developing cortex. Emerging evidence reveals that positive and negative feedback signals play a crucial role in axon and dendrite specification. Positive feedback signals are continuously activated in one of minor neurites and result in axon specification and elongation, whereas negative feedback signals are propagated from a nascent axon terminal to all minor neurites and inhibit the formation of multiple axon, thereby leading to dendrite specification, and maintaining neuronal polarity. This current insight provides a holistic picture of the signaling mechanisms underlying neuronal polarization during neuronal development. Here, our review highlights recent advancements in this fascinating field, with a focus on the positive, and negative feedback signals as key regulatory mechanisms underlying neuronal polarization.
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http://dx.doi.org/10.3389/fcell.2019.00069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491837PMC
April 2019

Antitumor and Antiangiogenic Activities of Lenvatinib in Mouse Xenograft Models of Vascular Endothelial Growth Factor-Induced Hypervascular Human Hepatocellular Carcinoma.

Cancer Invest 2019 22;37(4-5):185-198. Epub 2019 Apr 22.

b Eisai Inc , Woodcliff Lake , New Jersey , USA.

High expression of vascular endothelial growth factor (VEGF) in patients with hepatocellular carcinoma (HCC) is associated with poor prognosis. Here, we investigated the antitumor activity of lenvatinib, a multiple receptor tyrosine kinase inhibitor, in VEGF-overexpressing HCC models. In human umbilical vein endothelial cells, lenvatinib showed potent inhibitory activities against VEGF-induced proliferation and VEGF/basic fibroblast growth factor-induced tube formation. In VEGF-overexpressing HCC xenograft models, characterized by aggressive tumor growth and hypervascularity, lenvatinib had significant antitumor and antiangiogenic activities. These results suggest that potent activity of lenvatinib against VEGF signaling underlies its antitumor and antiangiogenic activities in the hypervascular HCC models.
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http://dx.doi.org/10.1080/07357907.2019.1601209DOI Listing
July 2019

Lenvatinib induces death of human hepatocellular carcinoma cells harboring an activated FGF signaling pathway through inhibition of FGFR-MAPK cascades.

Biochem Biophys Res Commun 2019 05 31;513(1):1-7. Epub 2019 Mar 31.

Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan. Electronic address:

Lenvatinib inhibits VEGF- and FGF-driven angiogenesis, and proliferation of tumor cells with activated FGF signaling pathways in preclinical models, and we previously demonstrated antitumor activity in human HCC xenograft tumor models. Here, we examined the inhibitory activity of lenvatinib against FGF-driven survival of human HCC cell lines. First, we conducted a histological analysis of FGF19-overexpressing Hep3B2.1-7 xenograft tumors collected from mice treated with lenvatinib. Second, we examined the effects of pharmacological inhibition on survival of cultured HCC cells with an activated FGF signaling pathway under nutrient-starved culture condition to mimic tumor microenvironments induced by angiogenesis inhibition. In the first analysis, area of histological focal necrosis was greater in Hep3B2.1-7 xenograft tumors with the lenvatinib treatment than that after the treatment with sorafenib, which does not inhibit FGFRs. Lenvatinib and E7090 (a selective FGFR1-3 inhibitor), but not sorafenib, induced death of Hep3B2.1-7, and another FGF19 overexpressing HuH-7 cells. Lenvatinib and E7090 decreased phosphorylation of downstream molecules of the FGF signaling pathway (such as FRS2, Erk, and p38 MAPK), and induced PARP cleavage, even under limited nutrients. PD0325901, MEK inhibitor, caused the same changes in HCC cells as those described above for lenvatinib and E7090. These results reveal that the FGF signaling pathway through MAPK cascades plays an important role in survival of HCC cell lines with an activated FGF signaling pathway under limited nutrients, and FGFR-MAPK cascades likely contribute to survival of HCC cells with an activated FGF signaling pathway under tumor microenvironments with limited nutrients, where tumor angiogenesis is inhibited.
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http://dx.doi.org/10.1016/j.bbrc.2019.02.015DOI Listing
May 2019

Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway.

PLoS One 2019 27;14(2):e0212513. Epub 2019 Feb 27.

Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan.

Lenvatinib is a multiple receptor tyrosine kinase inhibitor targeting mainly vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) receptors. We investigated the immunomodulatory activities of lenvatinib in the tumor microenvironment and its mechanisms of enhanced antitumor activity when combined with a programmed cell death-1 (PD-1) blockade. Antitumor activity was examined in immunodeficient and immunocompetent mouse tumor models. Single-cell analysis, flow cytometric analysis, and immunohistochemistry were used to analyze immune cell populations and their activation. Gene co-expression network analysis and pathway analysis using RNA sequencing data were used to identify lenvatinib-driven combined activity with anti-PD-1 antibody (anti-PD-1). Lenvatinib showed potent antitumor activity in the immunocompetent tumor microenvironment compared with the immunodeficient tumor microenvironment. Antitumor activity of lenvatinib plus anti-PD-1 was greater than that of either single treatment. Flow cytometric analysis revealed that lenvatinib reduced tumor-associated macrophages (TAMs) and increased the percentage of activated CD8+ T cells secreting interferon (IFN)-γ+ and granzyme B (GzmB). Combination treatment further increased the percentage of T cells, especially CD8+ T cells, among CD45+ cells and increased IFN-γ+ and GzmB+ CD8+ T cells. Transcriptome analyses of tumors resected from treated mice showed that genes specifically regulated by the combination were significantly enriched for type-I IFN signaling. Pretreatment with lenvatinib followed by anti-PD-1 treatment induced significant antitumor activity compared with anti-PD-1 treatment alone. Our findings show that lenvatinib modulates cancer immunity in the tumor microenvironment by reducing TAMs and, when combined with PD-1 blockade, shows enhanced antitumor activity via the IFN signaling pathway. These findings provide a scientific rationale for combination therapy of lenvatinib with PD-1 blockade to improve cancer immunotherapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212513PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392299PMC
December 2019

In Vivo Identification of Protein Kinase Substrates by Kinase-Oriented Substrate Screening (KIOSS).

Curr Protoc Chem Biol 2019 03 7;11(1):e60. Epub 2019 Jan 7.

Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, Nagoya, Japan.

Protein phosphorylation plays a critical role in the regulation of cellular function. Information on protein phosphorylation and the responsible kinases is important for understanding intracellular signaling. A method for in vivo screening of kinase substrates named KIOSS (kinase-oriented substrate screening) has been developed. This protocol provides a method that utilizes phosphoprotein-binding modules such as 14-3-3 protein, the pin1-WW domain, and the chek2-FHA domain as biological filters to successfully enrich phosphorylated proteins related to intracellular signaling rather than housekeeping and/or structural proteins. More than 1000 substrate candidates for PKA, PKC, MAPK, and Rho-kinase in HeLa cells, as well as phosphorylation downstream of D1R, NMDAR, adenosine A2a receptor, PKA, PKC, MAPK, and Rho-kinase in mouse brain slice cultures have been identified by this method. An online database named KANPHOS (Kinase-Associated Neural Phospho-Signaling) provides the phosphorylation signals identified by these studies, as well as those previously reported in the literature. © 2019 by John Wiley & Sons, Inc.
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http://dx.doi.org/10.1002/cpch.60DOI Listing
March 2019

Comprehensive analysis of kinase-oriented phospho-signalling pathways.

J Biochem 2019 Apr;165(4):301-307

Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Showa-ku, Nagoya, Aichi, Japan.

Accumulating information on eukaryotic protein phosphorylation implies a large and complicated phospho-signalling network in various cellular processes. Although a large number of protein phosphorylation sites have been detected, their physiological consequences and the linkage between each phosphorylation site and the responsible protein kinase remain largely unexplored. To understand kinase-oriented phospho-signalling pathways, we have developed novel substrate screening technologies. In this review, we described the in vitro and in vivo screening methods named kinase-interacting substrate screening analysis and kinase-oriented substrate screening analysis, respectively.
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http://dx.doi.org/10.1093/jb/mvy115DOI Listing
April 2019

Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model.

Cancer Sci 2018 Dec 16;109(12):3993-4002. Epub 2018 Nov 16.

Oncology Business Group, Eisai, Woodcliff Lake, New Jersey.

Angiogenesis inhibitors such as lenvatinib and sorafenib, and an immune checkpoint inhibitor (ICI), nivolumab, are used for anticancer therapies against advanced hepatocellular carcinoma (HCC). Combination treatments comprising angiogenesis inhibitors plus ICIs are promising options for improving clinical benefits in HCC patients, and clinical trials are ongoing. Here, we investigated the antitumor and immunomodulatory activities of lenvatinib (a multiple receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 1-3, fibroblast growth factor receptor 1-4, platelet-derived growth factor receptor α, KIT and RET) and the combined antitumor activity of lenvatinib plus anti-programmed cell death 1 (PD-1) antibody in the Hepa1-6 mouse HCC syngeneic model. We found that the antitumor activities of lenvatinib and sorafenib were not different in immunodeficient mice, but lenvatinib showed more potent antitumor activity than sorafenib in immunocompetent mice. The antitumor activity of lenvatinib was greater in immunocompetent mice than in immunodeficient mice and was attenuated by CD8 T cell depletion. Treatment with lenvatinib plus anti-PD-1 antibody resulted in more tumor regression and a higher response rate compared with either treatment alone in immunocompetent mice. Single-cell RNA sequencing analysis demonstrated that treatment with lenvatinib with or without anti-PD-1 antibody decreased the proportion of monocytes and macrophages population and increased that of CD8 T cell populations. These data suggest that lenvatinib has immunomodulatory activity that contributes to the antitumor activity of lenvatinib and enhances the antitumor activity in combination treatment with anti-PD-1 antibody. Combination treatment of lenvatinib plus anti-PD-1 antibody therefore warrants further investigation against advanced HCC.
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http://dx.doi.org/10.1111/cas.13806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6272102PMC
December 2018

Balance between dopamine and adenosine signals regulates the PKA/Rap1 pathway in striatal medium spiny neurons.

Neurochem Int 2019 01 15;122:8-18. Epub 2018 Oct 15.

Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, Nagoya, Aichi, 466-8550, Japan. Electronic address:

Medium spiny neurons (MSNs) expressing dopamine D1 receptor (D1R) or D2 receptor (D2R) are major components of the striatum. Stimulation of D1R activates protein kinase A (PKA) through G to increase neuronal activity, while D2R stimulation inhibits PKA through G. Adenosine A2A receptor (A2AR) coupled to G is highly expressed in D2R-MSNs within the striatum. However, how dopamine and adenosine co-operatively regulate PKA activity remains largely unknown. Here, we measured Rap1gap serine 563 phosphorylation to monitor PKA activity and examined dopamine and adenosine signals in MSNs. We found that a D1R agonist increased Rap1gap phosphorylation in striatal slices and in D1R-MSNs in vivo. A2AR agonist CGS21680 increased Rap1gap phosphorylation, and pretreatment with the D2R agonist quinpirole blocked this effect in striatal slices. D2R antagonist eticlopride increased Rap1gap phosphorylation in D2R-MSNs in vivo, and the effect of eticlopride was blocked by the pretreatment with the A2AR antagonist SCH58261. These results suggest that adenosine positively regulates PKA in D2R-MSNs through A2AR, while this effect is blocked by basal dopamine in vivo. Incorporating computational model analysis, we propose that the shift from D1R-MSNs to D2R-MSNs or vice versa appears to depend predominantly on a change in dopamine concentration.
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http://dx.doi.org/10.1016/j.neuint.2018.10.008DOI Listing
January 2019

Lenvatinib inhibits angiogenesis and tumor fibroblast growth factor signaling pathways in human hepatocellular carcinoma models.

Cancer Med 2018 06 7;7(6):2641-2653. Epub 2018 May 7.

Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.

Unresectable hepatocellular carcinoma (uHCC) is one of the most lethal and prevalent cancers worldwide, and current systemic therapeutic options for uHCC are limited. Lenvatinib, a multiple receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors (VEGFRs) and fibroblast growth factor receptors (FGFRs), recently demonstrated a treatment effect on overall survival by statistical confirmation of noninferiority to sorafenib in a phase 3 study of uHCC. Here, we investigated mechanisms underlying the antitumor activity of lenvatinib in preclinical HCC models. In vitro proliferation assay of nine human HCC cell lines showed that lenvatinib selectively inhibited proliferation of FGF signal-activated HCC cells including FGF19-expressing Hep3B2.1-7. Lenvatinib suppressed phosphorylation of FRS2, a substrate of FGFR1-4, in these cells in a concentration-dependent manner. Lenvatinib inhibited in vivo tumor growth in Hep3B2.1-7 and SNU-398 xenografts and decreased phosphorylation of FRS2 and Erk1/2 within the tumor tissues. Lenvatinib also exerted antitumor activity and potently reduced tumor microvessel density in PLC/PRF/5 xenograft model and two HCC patient-derived xenograft models. These results suggest that lenvatinib has antitumor activity consistently across diverse HCC models, and that targeting of tumor FGF signaling pathways and anti-angiogenic activity underlies its antitumor activity against HCC tumors.
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http://dx.doi.org/10.1002/cam4.1517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010799PMC
June 2018

Co(III) Complexes with NS-Type Ligands as Structural/Functional Models for the Isocyanide Hydrolysis Reaction Catalyzed by Nitrile Hydratase.

Inorg Chem 2018 Apr 27;57(8):4277-4290. Epub 2018 Mar 27.

Department of Frontier Materials, Graduate School of Engineering , Nagoya Institute of Technology , Gokiso-cho, Showa-ku, Nagoya 466-8555 , Japan.

It has been before reported that, in addition to hydration of nitriles, the Fe-type nitrile hydratase (NHase) also catalyzes the hydrolysis of tert-butylisocyanide ( tBuNC). In order to investigate the unique isocyanide hydrolysis by NHase, we prepared three related Co(III) model complexes, PPh[Co(L)] (1), PPh[Co(L-O)] (2), and PPh[Co(L-O)] (3), where L is bis( N-(2-mercapto-2-methylpropionyl)aminopropyl)sulfide. The suffixes L-O and L-O indicate ligands with a sulfenate and a sulfinate and with two sulfinates, respectively, instead of the two thiolates of L. The X-ray analyses of 1 and 3 reveal trigonal bipyramidal and square pyramidal structures, respectively. Complex 2, however, has five-coordinate trigonal-bipyramidal geometry with η-type S-O coordination by a sulfenyl group. Addition of tBuNC to 1, 2, and 3 induces an absorption spectral change as a result of formation of an octahedral Co(III) complex. This interpretation is also supported by the crystal structures of PPh[Co(L-O)( tBuNC)] (4) and (PPh)[Co(L-O)(CN)] (5). A water molecule interacts with 3 but cannot be activated as reported previously, as demonstrated by the lack of absorption spectral change in the pH range of 5.5-10.2. Interestingly, the coordinated tBuNC is hydrolyzed by 2 and 3 at pH 10.2 to produce tBuNH and CO molecule, but 1 does not react. These findings provide strong evidence that hydrolysis of tBuNC by NHase proceeds not by activation of the coordinated water molecule but by coordination of the substrate. The mechanism of the hydrolysis reaction of tBuNC is explained with support provided by DFT calculations; a positively polarized C atom of tBuNC on the Co(III) center is nucleophilically attacked by a hydroxide anion activated through an interaction of the sulfenyl/sulfinyl oxygen with the nucleophile.
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http://dx.doi.org/10.1021/acs.inorgchem.6b02324DOI Listing
April 2018

Enantioselective aza-Friedel-Crafts reaction of cyclic ketimines with indoles using chiral imidazoline-phosphoric acid catalysts.

Chem Commun (Camb) 2018 Apr;54(31):3811-3814

Department of Life Science and Applied Chemistry, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan.

An enantioselective aza-Friedel Crafts reaction of cyclic 4-aryl-3-oxo-1,2,5-thiadiazol-1,1-oxides as cyclic ketimines with indoles was developed. High enantioselectivities were observed for the reaction of various cyclic ketimines with indoles using chiral imidazoline-phosphoric acid catalysts. The obtained products can be converted to chiral α-amino amide and hydantoin.
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http://dx.doi.org/10.1039/c8cc00594jDOI Listing
April 2018

Catalytic Enantioselective Reaction of 2H-Azirines with Thiols Using Cinchona Alkaloid Sulfonamide Catalysts.

Org Lett 2018 02 19;20(3):856-859. Epub 2018 Jan 19.

Department of Chemistry, Graduate School of Science, Osaka University 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan.

The first catalytic enantioselective reaction of 2H-azirines with thiols has been developed. The obtained aziridines can be converted to optically active oxazolines, aziridylamides, or α-sulfonyl esters. Transformation of these optically active aziridines showed that 2H-azirines act as β,β-dicarbocationic amine synthons.
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http://dx.doi.org/10.1021/acs.orglett.7b04022DOI Listing
February 2018

Catalytic Enantioselective Reaction of Allenylnitriles with Imines Using Chiral Bis(imidazoline)s Palladium(II) Pincer Complexes.

Angew Chem Int Ed Engl 2017 07 19;56(30):8677-8680. Epub 2017 Jun 19.

Department of Life Science and Applied Chemistry, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya, 466-8555, Japan.

The first highly enantioselective reaction of allenylnitriles with imines has been developed. Excellent yields and enantioselectivities were observed for the reaction with various imines using chiral Phebim-Pd complexes. This process offers a simple and efficient synthetic route for various functionalized α-vinylidene-β-aminonitriles and their derivatives.
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http://dx.doi.org/10.1002/anie.201702429DOI Listing
July 2017

Exploratory analysis of biomarkers associated with clinical outcomes from the study of lenvatinib in differentiated cancer of the thyroid.

Eur J Cancer 2017 04 24;75:213-221. Epub 2017 Feb 24.

Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Lenvatinib significantly prolonged progression-free survival (PFS) versus placebo in the phase III Study of (E7080) LEnvatinib in differentiated Cancer of the Thyroid (SELECT) of patients with radioiodine-refractory differentiated thyroid cancer. This exploratory analysis investigated potential predictive biomarkers of lenvatinib efficacy and target engagement.

Patients And Methods: Circulating cytokine/angiogenic factors (CAFs) in blood samples collected at baseline and throughout treatment were analysed from patients randomised to receive lenvatinib or placebo from August 5, 2011 to October 4, 2012. For CAF biomarker analyses, patients were dichotomised by baseline levels. Tumour tissues were analysed for BRAF and NRAS/KRAS/HRAS mutations.

Results: Tumours and CAFs were analysed from 183/392 (47%) and 387/392 (99%) patients, respectively. Lenvatinib PFS benefit was maintained in all assessments. For lenvatinib-treated patients, interaction-term analyses revealed that low baseline Ang2 level was predictive of tumour shrinkage (P = 0.016) and PFS (P = 0.018). Vascular endothelial growth factor and fibroblast growth factor 23 (FGF23) were significantly upregulated with lenvatinib, and FGF23 upregulation on cycle 1/day 15 was associated with longer PFS. In mutation analyses, no significant differences in clinical outcomes were observed. BRAF may be a negative prognostic factor for PFS in placebo-treated patients with papillary thyroid cancer (P = 0.019).

Conclusion: The lenvatinib PFS benefit was maintained regardless of baseline CAF or BRAF/RAS status. Baseline Ang2 was predictive of PFS in a subgroup of lenvatinib-treated patients, indicating that Ang2 may be predictive of lenvatinib sensitivity. BRAF may be a poor prognostic factor in patients with radioiodine-refractory papillary thyroid cancer. Improved PFS associated with upregulated FGF23 suggests that lenvatinib-induced FGF receptor inhibition contributes to lenvatinib efficacy. Trial registration ID of the main study, SELECT: ClinicalTrials.gov: NCT01321554.
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http://dx.doi.org/10.1016/j.ejca.2017.01.013DOI Listing
April 2017