担当区分：筆頭著者   記述言語：英語   出版者・発行元：Biochimica Et Biophysica Acta Molecular Basis of Disease  

Background: Helicobacter pylori infection and subsequent atrophic gastritis (AG) and intestinal metaplasia (IM) are regarded as precursor conditions for gastric cancer (GC). Though diverse mechanisms of carcinogenesis from AG and IM have been clarified using mouse models, few studies using human models have been reported. Here, we describe in vitro modeling of IM, as well as in vivo modeling of the oncogenic transformation from AG using human gastric organoids. Methods: Organoids derived from patients with AG were established and characterized by immunohistochemistry and in situ hybridization. Niche factor withdrawal and genetic engineering using CRISPR/Cas9 were conducted for modeling IM, and manipulated organoids were xenografted subcutaneously in mice to establish a GC model. Results: AG organoids (AGOs) were maintained by Wnt niche factors; withdrawal of these factors led to differentiation toward foveolar cells. Knockout of Runt-related transcription factor 3 (RUNX3), or activation of bone morphogenetic protein (BMP) signaling, resulted in accumulation of the key IM markers caudal-type homeobox 2 (CDX2) and mucin 2 (MUC2) in AGOs; disruption of SMAD4 counteracted the induction of these markers. Organoids doubly deficient for TP53 and SMAD4 formed larger and more proliferative p21 -negative subcutaneous tumors than did RUNX3-deficient organoids, suggesting that induction of a senescent state is a key barrier in stepwise carcinogenesis from AG. Conclusions: Wnt signaling is essential for homeostasis of AG, and SMAD4-dependent activation of BMP signaling promotes intestinal differentiation. Combined disruption of TP53 and SMAD4 confers tumorigenic potential to AGOs by inhibiting p21 induction.

DOI： 10.1016/j.bbadis.2025.167843

Web of Science

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PubMed

担当区分：筆頭著者   記述言語：英語   出版者・発行元：Cancer Science  

Microtubule targeting agents (MTAs) such as taxanes are broadly used for the treatment of patients with cancer. Although MTAs are not effective for treatment of colorectal cancer (CRC), preclinical studies suggest that a subset of patients with CRC, especially those with cancers harboring the BRAF mutation, could benefit from such agents. However, two MTAs, eribulin (Eri) and vinorelbine, have shown limited clinical efficacy. Here, we report that insulin-like growth factor 1 receptor (IGF-1R) signaling is involved in Eri resistance. Using CRC cell lines, we showed that Eri induces activation and subsequent translocation of IGF-1R to the nucleus. When the activation and/or nuclear translocation of IGF-1R was inhibited, Eri induced DNA damage and enhanced G<inf>2</inf>/M arrest. In a xenograft model using the Eri-resistant SW480 cell line, the combination of Eri and the IGF-1R inhibitor linsitinib suppressed tumor growth more efficiently than either single agent. Thus, our results indicated that combination dosing with Eri and an IGF-1R inhibitor could overcome Eri resistance and offer a therapeutic opportunity in CRC.

DOI： 10.1111/cas.15558

Web of Science

Scopus

PubMed

記述言語：英語  

DOI： 10.1007/s13691-025-00768-9

Web of Science

PubMed

出版者・発行元：ESMO Gastrointestinal Oncology  

Background: Nanoliposomal irinotecan with fluorouracil and folinic acid (NFF) is a standard second- or later-line regimen after gemcitabine-based therapy for patients with unresectable or recurrent pancreatic cancer (urPC). However, limited prospective clinical data on the efficacy and safety of NFF in a real-world setting have been presented. Therefore, we conducted this observational, real-world study to investigate the efficacy and safety of NFF. Patients and methods: We collected prospective data of urPC patients treated with NFF in 17 hospitals in Japan from 2021 to 2023. The primary endpoint was overall survival (OS). Secondary endpoints were overall response rate, disease control rate, progression-free survival, dose intensity, and adverse events (AEs). Results: NFF was administered to 150 patients with a mean age of 72 years. The median follow-up period was 7.2 months. All patients had previously received gemcitabine-based therapy. The median OS was 7.8 months; median progression-free survival was 3.7 months; median overall response rate was 11%; and median disease control rate was 56%. Median relative dose intensity was 72.7% with nanoliposomal irinotecan and 79.4% with fluorouracil. Grade 3/4 hematological and nonhematological AEs occurred in 52 and 70 patients, respectively. Neutropenia (28%) and anorexia (19%) were common grade 3/4 AEs. Subanalysis of patients with second-line and third- or later-line therapy demonstrated no significant difference in OS (7.4 versus 7.8 months, respectively; P = 0.88). Integrated analysis of the prospective and retrospective phases of the study showed that median OS was 8.0 months. Conclusions: NFF has an appropriate efficacy and safety profile and is a candidate for second- or later-line therapy for urPC.

DOI： 10.1016/j.esmogo.2025.100150

Scopus

出版者・発行元：Therapeutic Advances in Medical Oncology  

Background: Nanoliposomal irinotecan with fluorouracil and folinic acid (NFF) is a standard regimen for patients with unresectable or recurrent pancreatic cancer (urPC) after gemcitabine-based chemotherapy. However, little is known about the clinical impact of previous chemotherapy on the effects of NFF in the real world. Objectives: We retrospectively evaluated whether the efficacy and safety of NFF differed depending on the history of prior chemotherapy among urPC patients receiving NFF. Design: This study was conducted using the real-world data of Japanese patients with urPC who received NFF in the multicenter NAPOLEON-2 study. Methods: We compared the efficacy and adverse events (AEs) after NFF initiation between previous irinotecan users and non-users, fluorouracil users and non-users, and platinum users and non-users. We also investigated whether the treatment duration of gemcitabine plus nab-paclitaxel (GnP) influenced the efficacy of NFF among patients treated with NFF as a second-line therapy after GnP. Results: Overall, 161 patients were enrolled, all of whom had previously received gemcitabine. In the efficacy analysis between irinotecan users and non-users, the median overall survival (OS) was 9.2 and 8.0 months, respectively (hazard ratio (HR) 0.88; p = 0.66). For fluorouracil, the median OS was 9.1 months for users and 7.6 months for non-users (HR 0.98; p = 0.93). For platinum, the median OS was 9.1 months for users and 8.0 months for non-users (HR 0.88; p = 0.67). There was no clinical difference in AEs between irinotecan users and non-users, which affected ⩾10% of patients in both groups. The median OS in the group with previous GnP for ⩾7.8 months was 9.5 months, while it was 4.8 months in the group with GnP for <7.8 months (HR 0.50; p < 0.01). Conclusion: NFF may be effective and tolerable, even in patients previously treated with irinotecan-, fluorouracil-, or platinum-based chemotherapy, in the real world.

DOI： 10.1177/17588359251393156

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