Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Mps One Binder Kinase Activator (MOB)1A/1B are core components of the Hippo pathway. These proteins, which coactivate LArge Tumor Suppressor homolog (LATS) kinases, are also tumor suppressors. To investigate MOB1A/B’s roles in normal physiology and lung cancer, we generated doxycycline (Dox)-inducible, bronchioalveolar epithelium–specific, null mutations of MOB1A/B in mice [SPC-rtTA/(tetO)7-Cre/Mob1aflox/flox/Mob1b-/-; termed luMob1DKO) mice]. Most mutants (70%) receiving Dox in utero [luMob1DKO (E6.5-18.5) mice] died of hypoxia within 1hr post-birth. Their alveolar epithelial cells showed increased proliferation, impaired YAP1/TAZ-dependent differentiation, and decreased surfactant protein production, all features characteristic of human respiratory distress syndrome　(RDS). Intriguingly, mutant mice that received Dox postnatally [luMob1DKO (P21–41) mice] did not develop spontaneous lung adenocarcinomas, and urethane treatment-induced lung tumor formation was decreased (rather than increased). Lungs of luMob1DKO (P21–41) mice exhibited increased detachment of bronchiolar epithelial cells and decreased numbers of the bronchioalveolar stem cells (BASCs) thought to initiate lung adenocarcinomas. YAP1/TAZ-NKX2.1-dependent expression of collagen XVII, a key hemidesmosome component, was also reduced. Thus, a MOB1-YAP1/TAZ-NKX2.1 axis is essential for normal lung homeostasis and expression of the collagen XVII protein necessary for alveolar stem cell maintenance in the lung niche.

Language：English  

DOI： 10.1111/1759-7714.70107

PubMed

Language：English   Publisher：Cancer Immunology Immunotherapy  

The development of immune checkpoint inhibitors has changed treatment strategies for some patients with non-small cell lung cancer (NSCLC). However, resistance remains a major problem, requiring the elucidation of resistance mechanisms, which might aid the development of novel therapeutic strategies. The upregulation of CD155, a primary ligand of the immune checkpoint receptor TIGIT, has been implicated in a mechanism of resistance to PD-1/PD-L1 inhibitors, and it is therefore important to characterize the mechanisms underlying the regulation of CD155 expression in tumor cells. The aim of this study was to identify a Nectin that might regulate CD155 expression in NSCLC and affect anti-tumor immune activity. In this study, we demonstrated that NECTIN4 regulated the cell surface expression and stabilization of CD155 by interacting and co-localizing with CD155 on the cell surface. In a syngeneic mouse model, NECTIN4-overexpressing cells exhibited increased cell surface CD155 and resistance to anti-PD-1 antibodies. Of note, combination therapy with anti-PD-1 and anti-TIGIT antibodies significantly suppressed tumor growth. These findings provide new insights into the mechanisms of resistance to anti-PD-1 antibodies and suggest that NECTIN4 could serve as a valuable marker in therapeutic strategies targeting TIGIT.

DOI： 10.1007/s00262-025-04079-z

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Language：English   Publisher：エルゼビア・ジャパン(株)  

Language：English   Publisher：Respiratory Investigation  

Background: Osimertinib is a standard treatment for non–small cell lung cancer (NSCLC) positive for EGFR activating mutations. Although renal dysfunction associated with osimertinib treatment is reported to be rare, detailed information on this adverse effect is needed because cytotoxic drugs such as pemetrexed are also widely administered for NSCLC but cannot be used in individuals with renal dysfunction. Methods: We retrospectively collected clinical data including the serum creatinine concentration and estimated glomerular filtration rate (eGFR) during osimertinib treatment for 130 NSCLC patients. Results: Serum creatinine and eGFR worsened gradually during osimertinib treatment, with the median value of creatinine at the point of greatest deterioration differing significantly from that at baseline (0.93 versus 0.72 mg/dL, P < 0.01). Seventy patients (54 %) experienced worsening of the CTCAE grade for creatinine increased, with the frequency of patients with grade 1 or 2 being increased significantly (P < 0.01) at the point of greatest deterioration relative to baseline (grade 1, 46.9 % versus 14.6 %; grade 2, 14.6 % versus 0.8 %, respectively). A higher serum creatinine level at baseline was a significant risk factor for worsening of the CTCAE grade (odds ratio of 1.66, P < 0.001). The median serum creatinine and eGFR at 4 weeks after osimertinib discontinuation had improved to levels similar to those for baseline. Conclusions: Renal dysfunction occurred frequently during osimertinib treatment but was ameliorated after drug discontinuation, suggesting that, although renal function should be carefully monitored, its impairment is not likely to affect subsequent chemotherapy in most patients.

DOI： 10.1016/j.resinv.2025.03.015

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DOI： 10.1016/j.annonc.2024.10.681

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

Yes関連蛋白質1(YAP1)とPDZ結合モチーフを有する転写コアクチベーター(TAZ)の活性がどのように制御されているのか解明するのに役立てるレポーター細胞システム(RCS)を開発した。そのため、YAP1/TAZの主要な結合パートナーである転写因子TEADも考慮に入れ、YAP1/TAZ/TEADに応答する高感度なDNAエレメントを構築してレンチウイルス利用のRCSへ組み入れた。こうすることで内因性のYAP1/TAZを、in vitro系ではルシフェラーゼ活性として、in vivo系ではVenus蛍光として感度高く特異的にモニタリングできるように図った。また上記の応答エレメントをT細胞因子(TCF)結合エレメントへ置き換えることでWnt/β-カテニン/TCFシグナル伝達を標的とするRCSに転用でき、NF-κB結合エレメントへ置換すればIL-1β/NF-κBシグナル伝達のRCSとして転用可能であることも実証された。本RCSを用い、既知の阻害薬364種に対しスクリーニングを実施した。その結果、YAP1/TAZ経路およびβカテニン経路を調節する阻害薬が、新規なものも含め多数同定された。そしてYAP1/TAZの新規な調節因子が、実際に内因性YAP1/TAZの蛋白質レベルを変化させることなどを確認した。本RCSは生細胞にも適用できる強力なツールになると結論された。

Language：English   Publisher：Cancer Science  

The activation of yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ) has been implicated in both regeneration and tumorigenesis, thus representing a double-edged sword in tissue homeostasis. However, how the activity of YAP1/TAZ is regulated or what leads to its dysregulation in these processes remains unknown. To explore the upstream stimuli modulating the cellular activity of YAP1/TAZ, we developed a highly sensitive YAP1/TAZ/TEAD-responsive DNA element (YRE) and incorporated it into a lentivirus-based reporter cell system to allow for sensitive and specific monitoring of the endogenous activity of YAP1/TAZ in terms of luciferase activity in vitro and Venus fluorescence in vivo. Furthermore, by replacing YRE with TCF- and NF-κB-binding DNA elements, we demonstrated the applicability of this reporter system to other pathways such as Wnt/β-catenin/TCF- and IL-1β/NF-κB-mediated signaling, respectively. The practicality of this system was evaluated by performing cell-based reporter screening of a chemical compound library consisting of 364 known inhibitors, using reporter-introduced cells capable of quantifying YAP1/TAZ- and β-catenin-mediated transcription activities, which led to the identification of multiple inhibitors, including previously known as well as novel modulators of these signaling pathways. We further confirmed that novel YAP1/TAZ modulators, such as potassium ionophores, Janus kinase inhibitors, platelet-derived growth factor receptor inhibitors, and genotoxic stress inducers, alter the protein level or phosphorylation of endogenous YAP1/TAZ and the expression of their target genes. Thus, this reporter system provides a powerful tool to monitor endogenous signaling activities of interest (even in living cells) and search for modulators in various cellular contexts.

DOI： 10.1111/cas.16316

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Language：English   Publisher：Lung Cancer  

Objectives: Predicting the prognosis of lung cancer is crucial for providing optimal medical care. However, a method to accurately predict the overall prognosis in patients with stage IV lung cancer, even with the use of machine learning, has not been established. Moreover, the inter-institutional generalizability of such algorithms remains unexplored. This study aimed to establish machine learning-based algorithms with inter-institutional generalizability to predict prognosis. Materials and Methods: This multicenter, retrospective, hospital-based cohort study included consecutive patients with stage IV lung cancer who were randomly categorized into the training and independent test cohorts with a 2:1 ratio, respectively. The primary metric to assess algorithm performance was the area under the receiver operating characteristic curve in the independent test cohort. To assess the inter-institutional generalizability of the algorithms, we investigated their ability to predict patient outcomes in the remaining facility after being trained using data from 15 other facilities. Results: Overall, 6,751 patients (median age, 70 years) were enrolled, and 1,515 (22 %) showed mutated epidermal growth factor receptor expression. The median overall survival was 16.6 (95 % confidence interval, 15.9–17.5) months. Algorithm performance metrics in the test cohort showed that the areas under the curves were 0.90 (95 % confidence interval, 0.88–0.91), 0.85 (0.84–0.87), 0.83 (0.81–0.85), and 0.85 (0.82–0.87) at 180, 360, 720, and 1,080 predicted survival days, respectively. The performance test of 16 algorithms for investigating inter-institutional generalizability showed median areas under the curves of 0.87 (range, 0.84–0.92), 0.84 (0.78–0.88), 0.84 (0.76–0.89), and 0.84 (0.75–0.90) at 180, 360, 720, and 1,080 days, respectively. Conclusion: This study developed machine learning algorithms that could accurately predict the prognosis in patients with stage IV lung cancer with high inter-institutional generalizability. This can enhance the accuracy of prognosis prediction and support informed and shared decision-making in clinical settings.

DOI： 10.1016/j.lungcan.2024.107896

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Language：English   Publisher：Thoracic Cancer  

Tracheomediastinal fistula is a rare but life-threatening complication of cancer. We report a case of tracheomediastinal fistula induced by concurrent chemoradiotherapy in limited stage small cell lung cancer. Despite the treatment response, the metastatic paratracheal lymph node increased gradually during concurrent chemoradiotherapy, resulting in the occurrence of tracheomediastinal fistula and mediastinitis. Without any surgical intervention, the patient achieved successful recovery from mediastinitis through antibiotic treatment, although the tracheomediastinal fistula remained open. In this report, we also review previous studies of tracheomediastinal and bronchomediastinal fistulas and summarize the clinical features.

DOI： 10.1111/1759-7714.15270

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Language：English   Publisher：Pharmacology and Therapeutics  

The treatment of interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF), remains challenging as current available antifibrotic agents are not effective in halting disease progression. Connective tissue growth factor (CTGF), also known as cellular communication factor 2 (CCN2), is a member of the CCN family of proteins that regulates cell signaling through cell surface receptors such as integrins, the activity of cytokines/growth factors, and the turnover of extracellular matrix (ECM) proteins. Accumulating evidence indicates that CTGF plays a crucial role in promoting lung fibrosis through multiple processes, including inducing transdifferentiation of fibroblasts to myofibroblasts, epithelial-mesenchymal transition (EMT), and cooperating with other fibrotic mediators such as TGF-β. Increased expression of CTGF has been observed in fibrotic lungs and inhibiting CTGF signaling has been shown to suppress lung fibrosis in several animal models. Thus, the CTGF signaling pathway is emerging as a potential therapeutic target in IPF and other pulmonary fibrotic conditions. This review provides a comprehensive overview of the current evidence on the pathogenic role of CTGF in pulmonary fibrosis and discusses the current therapeutic agents targeting CTGF using a systematic review approach.

DOI： 10.1016/j.pharmthera.2023.108578

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DOI： 10.1183/13993003.congress-2023.PA1232

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Language：English   Publisher：American journal of respiratory and critical care medicine  

Rationale: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by progressive lung scarring. IPF-related pulmonary vascular remodeling and pulmonary hypertension (PH) result in a particularly poor prognosis. Objectives: To study the pathogenesis of vascular remodeling in fibrotic lungs and its contribution to progression of fibrosis. Methods: We used an experimental model of lung fibrosis associated with PH by transient overexpression of active TGF-β1 (transforming growth factor-β1). Samples from patients with fibrotic lung diseases were analyzed in depth using immunostaining, gene expression, and gene mutations. Measurements and Main Results: We found a reduction in endothelial cells (ECs) and activation of vascular smooth muscle cells (VSMCs) in fibrotic lungs. Coculturing fibroblasts with VSMCs or ECs from fibrotic lungs induced fibrotic phenotypes in fibroblasts. IPF fibroblasts induced EC death and activation of VSMCs in coculture systems. Decreased concentrations of BMPR2 (bone morphogenic protein receptor 2) and its signaling were observed in ECs and VSMCs from fibrotic lungs in both rats and humans. On fibroblasts treated with media from VSMCs, BMPR2 suppression in VSMCs led to fibrogenic effects. Tacrolimus activated BMPR2 signaling and attenuated fibrosis and PH in rodent lungs. Whole-exome sequencing revealed rare mutations in PH-related genes, including BMPR2, in patients with IPF undergoing transplantation. A unique missense BMPR2 mutation (p.Q721R) was discovered to have dysfunctional effects on BMPR2 signaling. Conclusions: Endothelial dysfunction and vascular remodeling in PH secondary to pulmonary fibrosis enhance fibrogenesis through impaired BMPR2 signaling. Tacrolimus may have value as a treatment of advanced IPF and concomitant PH. Genetic abnormalities may determine the development of PH in advanced IPF.

DOI： 10.1164/rccm.202109-2174OC

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Language：English   Publisher：European Respiratory Journal  

Background Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease implicated as an independent risk factor for lung cancer. However, optimal treatment for advanced lung cancer with IPF remains to be established. We performed a randomised phase 3 trial (J-SONIC) to assess the efficacy and safety of nintedanib plus chemotherapy (experimental arm) compared with chemotherapy alone (standard-of-care arm) for advanced nonsmall cell lung cancer (NSCLC) with IPF. Methods Chemotherapy-naïve advanced NSCLC patients with IPF were allocated to receive carboplatin (area under the curve of 6 on day 1) plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) (100 mg·m⁻² on days 1, 8 and 15) every 3 weeks with or without nintedanib (150 mg twice daily, daily). The primary end-point was exacerbation-free survival (EFS). Results Between May 2017 and February 2020, 243 patients were enrolled. Median EFS was 14.6 months in the nintedanib plus chemotherapy group and 11.8 months in the chemotherapy group (hazard ratio (HR) 0.89, 90% CI 0.67–1.17; p=0.24), whereas median progression-free survival was 6.2 and 5.5 months, respectively (HR 0.68, 95% CI 0.50–0.92). Overall survival was improved by nintedanib in patients with nonsquamous histology (HR 0.61, 95% CI 0.40–0.93) and in those at GAP (gender–age–physiology) stage I (HR 0.61, 95% CI 0.38–0.98). Seven (2.9%) out of 240 patients experienced acute exacerbation during study treatment. Conclusions The primary end-point of the study was not met. However, carboplatin plus nab-paclitaxel was found to be effective and tolerable in advanced NSCLC patients with IPF. Moreover, nintedanib in combination with such chemotherapy improved overall survival in patients with nonsquamous histology.

DOI： 10.1183/13993003.00380-2022

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Language：English   Publisher：European Journal of Cancer  

Background: We previously validated in European patients with NSCLC treated with programmed death-1 (PD-1) checkpoint inhibitors the cumulative detrimental effect of concomitant medications. Materials and methods: We evaluated the prognostic ability of a “drug score” computed on the basis of baseline corticosteroids, proton pump inhibitors, and antibiotics, in an independent cohort of Japanese patients with advanced NSCLC treated with PD-1 monotherapy. Subsequently, we assessed the impact of baseline probiotics on the score's diagnostic ability and their interaction with antibiotics in influencing survival. Results: Among the 293 eligible patients, good (19.5 months), intermediate (13.4 months), and poor (3.7 months) risk groups displayed a significantly different overall survival (OS) (log-rank test for trend: p = 0.016), but with a limited diagnostic ability (C-index: 0.57, 95%CI: 0.53–0.61), while no significant impact on progression-free survival (PFS) was reported (log-rank test for trend: p = 0.080; C-index: 0.55, 95%CI: 0.52–0.58). Considering the impact of the probiotics∗antibiotics interaction (p-value 0.0510) on OS, we implemented the drug score by assigning 0 points to concomitant antibiotics and probiotics. With the adapted drug score good, intermediate, and poor risk patients achieved a median OS of 19.6 months, 13.1 months, and 3.7 months, respectively, with a similar diagnostic ability (log-rank test for trend: p = 0.006; C-index: 0.58, 95%CI: 0.54–0.61). However, the diagnostic ability for PFS of the adapted score was improved (log-rank test for trend: p = 0.034; C-index: 0.62, 95%CI: 0.54–0.69). Conclusions: Although we failed to validate the drug score in this independent Japanese cohort, we showed that probiotics may have an antibiotic-dependent impact on its prognostic value. Further investigation looking at the effect of concomitant medications and probiotics across cohorts of different ethnicities is warranted.

DOI： 10.1016/j.ejca.2022.06.002

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Language：English   Publisher：BMC Cancer  

Background: Many studies have recently reported the association of concomitant medications with the response and survival in patients with non-small-cell lung cancer (NSCLC) treated with cancer immunotherapy. However, the clinical impact of statin therapy on the outcome of cancer immunotherapy in patients with NSCLC is poorly understood. Methods: In our database, we retrospectively identified and enrolled 390 patients with advanced or recurrent NSCLC who were treated with anti-programmed cell death-1 (PD-1) monotherapy in clinical practice between January 2016 and December 2019 at 3 medical centers in Japan to examine the clinical impact of statin therapy on the survival of patients with NSCLC receiving anti-PD-1 monotherapy. A propensity score-matched analysis was conducted to minimize the bias arising from the patients’ backgrounds. Results: The Kaplan–Meier curves of the propensity score-matched cohort showed that the overall survival (OS), but not the progression-free survival (PFS), was significantly longer in patients receiving statin therapy. However, a Cox regression analysis in the propensity score-matched cohort revealed that statin therapy was not an independent favorable prognostic factor, although it tended to be correlated with a favorable outcome. Conclusions: Statin therapy may be a combination tool for cancer immunotherapy in patients with NSCLC. These findings should be validated in further prospective studies with larger sample sizes.

DOI： 10.1186/s12885-022-09385-8

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Language：English   Publisher：ESMO Open  

Introduction: The albumin-bilirubin (ALBI) grade is a novel indicator of the liver function. Some studies showed that the ALBI grade was a prognostic and predictive biomarker for the efficacy of chemotherapy in cancer patients. The association between the ALBI grade and outcomes in patients with non-small-cell lung cancer (NSCLC) treated with cancer immunotherapy, however, is poorly understood. Methods: We retrospectively enrolled 452 patients with advanced or recurrent NSCLC who received anti-programmed cell death protein 1 (PD-1)-based therapy between 2016 and 2019 at three medical centers in Japan. The ALBI score was calculated from albumin and bilirubin measured at the time of treatment initiation and was stratified into three categories, ALBI grade 1-3, with reference to previous reports. We examined the clinical impact of the ALBI grade on the outcomes of NSCLC patients receiving anti-PD-1-based therapy using Kaplan–Meier survival curve analysis with log-rank test and Cox proportional hazards regression analysis. Results: The classifications of the 452 patients were as follows: grade 1, n = 158 (35.0%); grade 2, n = 271 (60.0%); and grade 3, n = 23 (5.0%). Kaplan–Meier survival curve analysis showed that the ALBI grade was significantly associated with progression-free survival and overall survival. Moreover, Cox regression analysis revealed that the ALBI grade was an independent prognostic factor for progression-free survival and overall survival. Conclusion: The ALBI grade was an independent prognostic factor for survival in patients with advanced or recurrent NSCLC who receive anti-PD-1-based therapy. These findings should be validated in a prospective study with a larger sample size.

DOI： 10.1016/j.esmoop.2021.100348

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Language：English   Publisher：Cancer Science  

Considering the increasing number of identified driver oncogene alterations, additional genetic tests are required to determine the treatment for advanced non-small-cell lung cancer (NSCLC). Next-generation sequencing can detect multiple driver oncogenes simultaneously, enabling the analysis of limited amounts of biopsied tissue samples. In this retrospective, multicenter study (UMIN ID000039523), we evaluated real-world clinical data using the Oncomine Dx Target Test Multi-CDx System (Oncomine DxTT) as a companion diagnostic system. Patients with NSCLC who were tested for a panel of 46 genes using the Oncomine DxTT between June 2019 and January 2020 were eligible for enrollment. Patients from 19 institutions affiliated to the West Japan Oncology Group were recruited. The primary endpoint of the study was the success rate of genetic alteration testing in four driver genes (EGFR, ALK, ROS1, and BRAF) using the Oncomine DxTT. In total, 533 patients were enrolled in the study. The success rate of genetic alteration testing for all four genes was 80.1% (95% CI 76.5%-83.4%). Surgical resection was associated with the highest success rate (88.0%), which was significantly higher than that for bronchoscopic biopsy (76.8%, P =.005). Multivariate analysis revealed a significant difference for surgical resection alone (P =.006, 95% CI 1.36-6.18, odds ratio 2.90). Although the success rate of genetic alteration testing immediately after Oncomine DxTT induction was not sufficient in this study, optimizing specimen quantity and quality may improve the use of driver gene testing in clinical settings.

DOI： 10.1111/cas.15176

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

非小細胞肺癌(NSCLC)へのコンパニオン診断プラットフォームとして日本で承認されたオンコマインDx Target TestマルチCDxシステム(オンコマインDxTT)の実臨床使用データを評価した。本研究は後方視的研究として国内19施設で施行した。2019年6月～2020年1月に本システムを使用し、遺伝子46種について次世代シーケンス解析(NGS)パネル検査されたNSCLC患者533名(男性345名、年齢25～94歳)を組入れた。主要評価項目は、本システムで行った4種のドライバー遺伝子(EGFR、ALK、ROS1、BRAF)における遺伝子変化検査の成功率に設定した。その4種の遺伝子全てで検査に成功した率は80.1%(95%CI 76.5～83.4%)であった。検査検体が手術切除検体であることは高い成功率(88.0%)と関連しており、気管支鏡生検検体での成功率(76.8%)よりも有意に高かった。検体の種類や処理条件(組織固定処理の時間)に関して2者間を比較した場合、多変量解析によって成功率に有意差が示されたのは上記の2種の検体を比較した場合のみであった(オッズ比2.9、95%CI 1.4～6.2)。本システムが導入された直後の時期に本試験で評価した検査成功率は十分に高いものではなかったが、検体の量と質を最適化すれば実臨床でもドライバー遺伝子検査の利用が改善されると考えられた。

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