Publications by authors named "Tomoko Shibutani"

7 Publications

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Identification and Therapeutic Targeting of GPR20, Selectively Expressed in Gastrointestinal Stromal Tumors, with DS-6157a, a First-in-Class Antibody-Drug Conjugate.

Cancer Discov 2021 Jun 12;11(6):1508-1523. Epub 2021 Feb 12.

Daiichi Sankyo, Co., Ltd., Tokyo, Japan.

Currently, the only approved treatments for gastrointestinal stromal tumor (GIST) are tyrosine kinase inhibitors (TKI), which eventually lead to the development of secondary resistance mutations in KIT or PDGFRA and disease progression. Herein, we identified G protein-coupled receptor 20 (GPR20) as a novel non-tyrosine kinase target in GIST, developed new GPR20 IHC, and assessed GPR20 expression in cell lines, patient-derived xenografts, and clinical samples from two institutes (United States and Japan). We studied GPR20 expression stratified by treatment line, KIT expression, GIST molecular subtype, and primary tumor location. We produced DS-6157a, an anti-GPR20 antibody-drug conjugate with a novel tetrapeptide-based linker and DNA topoisomerase I inhibitor exatecan derivative (DXd). DS-6157a exhibited GPR20 expression-dependent antitumor activity in GIST xenograft models including a GIST model resistant to imatinib, sunitinib, and regorafenib. Preclinical pharmacokinetics and safety profile of DS-6157a support its clinical development as a potential novel GIST therapy in patients who are refractory or have resistance or intolerance to approved TKIs. SIGNIFICANCE: GPR20 is selectively expressed in GIST across all treatment lines, regardless of / genotypes. We generated DS-6157a, a DXd-based antibody-drug conjugate that exhibited antitumor activity in GIST models by a different mode of action than currently approved TKIs, showing favorable pharmacokinetics and safety profiles..
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http://dx.doi.org/10.1158/2159-8290.CD-20-1434DOI Listing
June 2021

Edoxaban, a direct oral factor Xa inhibitor, ameliorates coagulation, microvascular thrombus formation, and acute liver injury in a lipopolysaccharide-induced coagulopathy model in rats.

J Thromb Thrombolysis 2021 Jul 3;52(1):9-17. Epub 2021 Feb 3.

Pharmacovigilance Department, Daiichi Sankyo Co., Ltd., Tokyo, 103-8426, Japan.

Infection increases the risk of thrombosis through the activation of inflammation and coagulation. Edoxaban, a direct oral factor Xa inhibitor, is used for the prevention and treatment of thrombotic diseases. The aim of this study was to determine the effects of edoxaban on microvascular thrombus formation in a rat model of lipopolysaccharide (LPS)-induced coagulopathy. Rats were intravenously injected with 7.5 mg/kg of LPS (Escherichia coli 055:B5). Immediately after LPS injection, the rats were treated with subcutaneous injection of edoxaban. At 2 and 6 h after the injection of LPS, biomarkers of coagulation and organ damages and inflammatory cytokines were measured. Microvascular thrombus formation in organs was evaluated using I-fibrinogen (human) or by the pathological analysis. Mortality was examined 24 h after LPS injection. After the injection of LPS, D-dimer and thrombin-antithrombin complex increased and platelet numbers decreased, indicating the activation of coagulation. Microvascular thrombi were found in the liver. Markers of liver injury (aspartate aminotransferase and alanine aminotransferase) also increased. Treatment with edoxaban attenuated the changes in the coagulation markers and microvascular thrombus formation in the liver. Edoxaban suppressed the increase in the liver injury markers and reduced the mortality. Edoxaban did not affect the levels of inflammatory cytokines. In conclusions, edoxaban significantly inhibited the activation of coagulation, the formation of microvascular thrombus in the liver and the liver damage, and reduced mortality in rats injected with LPS. These results suggest that the FXa inhibition by edoxaban might be a beneficial therapy for the management of infection-associated thrombosis.
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http://dx.doi.org/10.1007/s11239-021-02381-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856452PMC
July 2021

Tumor B7-H3 (CD276) Expression and Survival in Pancreatic Cancer.

J Clin Med 2018 Jul 10;7(7). Epub 2018 Jul 10.

Division of Pathology, The Cancer Institute, Department of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.

B7-H3 (CD276), a member of the family of immune modulators, orchestrates antitumor immunity. To date, only small-sized studies have examined the association of B7-H3 expression with survival in pancreatic cancer, yielding inconclusive results. We evaluated tumor B7-H3 expression in 150 consecutive patients with pancreatic ductal adenocarcinoma using immunohistochemistry. B7-H3 expression was positive (≥10% tumor cells) in 99 of 150 (66%) cases of pancreatic cancer. We classified the tumors into four groups depending on B7-H3 expression (negative, low, intermediate, and high) and found that higher B7-H3 expression was independently associated with lower disease-free survival (DFS; for high vs. negative B7-H3 expression: multivariable hazard ratio (HR) = 3.12; 95% confidence interval (CI) = 1.48⁻6.15; = 0.0026). Furthermore, the association of B7-H3 expression with survival differed according to the pathological stage (p-stage) ( = 0.048, between p-stages I⁻II and III⁻IV). The association of B7-H3 positivity with lower DFS was stronger in tumors with p-stage I⁻II (multivariable HR = 3.10, 95% CI = 1.75⁻5.69; < 0.0001) than in those with p-stage III⁻IV (multivariable HR = 1.20, 95% CI = 0.67⁻2.28; = 0.55). We demonstrated that tumor high B7-H3 expression is independently associated with poor survival in patients with pancreatic cancer and that this association is stronger in tumors with p-stage I⁻II than in those with p-stage III⁻IV. B7-H3 expression may be a useful prognostic biomarker for identifying aggressive early-stage pancreatic cancer.
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http://dx.doi.org/10.3390/jcm7070172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069252PMC
July 2018

Association of tumor TROP2 expression with prognosis varies among lung cancer subtypes.

Oncotarget 2017 Apr;8(17):28725-28735

Division of Pathology, The Cancer Institute; Department of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.

TROP2 is a transmembrane glycoprotein that is overexpressed in various cancers. Emerging evidence suggests that TROP2-targeting therapies are efficacious and safe in patients with multiple prior treatments. TROP2 is a promising target for lung cancer treatment; however, little is known regarding the association of TROP2 expression with clinicopathological/molecular features, including prognosis, in lung cancer. We examined consecutive cases of adenocarcinoma, squamous cell carcinoma (SqCC), and high-grade neuroendocrine tumor (HGNET) for the membranous expression of TROP2 using immunohistochemistry. High TROP2 expression was observed in 64% (172/270) of adenocarcinomas, 75% (150/201) of SqCCs, and 18% (21/115) of HGNETs. Intriguingly, the association of TROP2 expression with mortality was dependent on the lung cancer subtype. High TROP2 expression was associated with higher lung cancer-specific mortality in adenocarcinomas [univariable hazard ratio (HR) = 1.60, 95% confidence interval (CI) = 1.07-2.44, P = 0.022)], but not in SqCCs (univariable HR = 0.79, 95% CI = 0.35-1.94, P = 0.79). In HGNETs, high TROP2 expression was associated with lower lung cancer-specific mortality in both univariable and multivariable analyses (multivariable HR = 0.13, 95% CI = 0.020-0.44, P = 0.0003). Our results suggest a differential role for TROP2 in different lung cancer subtypes.
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http://dx.doi.org/10.18632/oncotarget.15647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438686PMC
April 2017

Tumor B7-H3 (CD276) expression and smoking history in relation to lung adenocarcinoma prognosis.

Lung Cancer 2017 01 17;103:44-51. Epub 2016 Nov 17.

Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan. Electronic address:

Objectives: Compared with non-smoking counterparts, smoking-associated lung cancers have a higher mutational load, resulting in the creation of more tumor neoantigens and increased immunogenicity. B7-H3 (also known as CD276) belongs to a family of immune modulators that includes PD-1 and PD-L1 (also known as B7-H1 or CD274). Considering the evidence that PD-L1 inhibitors have been shown to be more effective against lung cancer in smokers, we herein examined the prognostic interaction of tumor B7-H3 expression level with smoking history in lung adenocarcinoma patients.

Materials And Methods: Using tissue microarrays comprising 270 consecutive cases of lung adenocarcinoma, we evaluated tumor B7-H3 expression by immunohistochemistry. We examined the prognostic association between B7-H3 expression levels and smoking history, using Cox proportional hazards regression analysis and the log-rank test. Additionally, we used logistic regression analysis to examine the correlations between B7-H3 expression levels and clinicopathological/molecular features of lung adenocarcinoma.

Results: The association of B7-H3 expression with survival differed by smoking history (P=0.014); high B7-H3 expression was associated with decreased lung cancer-specific survival in moderate/heavy-smoking patients (smoking index [SI]≥400) (hazard ratio [HR]=3.07, 95% confidence interval [CI]=1.74-5.49, P=0.0001; log-rank: P<0.0001), but not in non/light-smoking patients (SI<400) (HR=1.14, 95% CI=0.63-1.96, P=0.64; log-rank: P=0.64). Interestingly, in moderate/heavy-smoking patients, high B7-H3 expression was associated with decreased survival in stage I cancer (log-rank; P=0.0005), whereas it showed no significant difference of survival in stage II-IV cancer (P=0.37). High B7-H3 expression was associated with smokers (univariable odds ratio [OR]=2.63, 95% CI=1.51-4.65; P=0.0005) and independently associated with EGFR wild-type status (multivariable OR=2.80, 95% CI=1.38-5.84; P=0.0042).

Conclusions: We demonstrated that the prognostic association of B7-H3 expression indeed differed according to smoking history. Our study also showed the significant association of high B7-H3 expression with EGFR wild-type and smoking patients, indicating the potential effectiveness of anti-B7-H3 therapy for EGFR wild-type or smokers' lung adenocarcinoma.
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http://dx.doi.org/10.1016/j.lungcan.2016.11.013DOI Listing
January 2017

Novel anti-EPHA2 antibody, DS-8895a for cancer treatment.

Cancer Biol Ther 2016 11 21;17(11):1158-1167. Epub 2016 Sep 21.

a Biologics & Immuno-Oncology Laboratories , Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo , Japan.

Overexpression of EPHA2 has been observed in multiple cancers and reported to be associated with poor prognosis. Here, we produced an afucosylated humanized anti-EPHA2 monoclonal antibody (mAb), DS-8895a for cancer treatment. The antibody recognizes the extracellular juxtamembrane region of EPHA2 and therefore can bind to both full-length and truncated forms of EPHA2, which are anchored to cell membranes and recently reported to be produced by post-translational cleavage in tumors. DS-8895a exhibited markedly increased antibody dependent cellular cytotoxicity (ADCC) in vitro and also inhibited tumor growth in EPHA2-positive human breast cancer MDA-MB-231 and human gastric cancer SNU-16 xenograft mouse models. Moreover, DS-8895a in combination with cisplatin (CDDP) showed better efficacy than each of the monotherapies did in the human gastric cancer model. These results suggest that a novel antibody, DS-8895a has therapeutic potential against EPHA2-expressing tumors.
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http://dx.doi.org/10.1080/15384047.2016.1235663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5137487PMC
November 2016

WITHDRAWN: Tumor B7-H3 (CD276) expression and smoking history in relation to lung adenocarcinoma prognosis.

Lung Cancer 2016 12 1;243:21-28. Epub 2016 Oct 1.

Division of Pathology, The Cancer Institute; Department of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan. Electronic address:

The Publisher regrets that this article is an accidental duplication of an article that has already been published in The Journal of Lung Cancer - http://dx.doi.org/10.1016/j.lungcan.2016.11.013. Please see online announcement for additional details. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.
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http://dx.doi.org/10.1016/j.lungcan.2016.09.016DOI Listing
December 2016
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