Author: Namisaki, Tadashi ; Yoshiji, Hitoshi ; Abe, Masanori ; Ohira, Hiromasa ; Kawano, Tetsu ; Ido, Akio ; Harada, Kenichi ; Higashine, Yukari ; Tanaka, Atsushi ; Tsubouchi, Hirohito ; Kamiya, Yuki ; Shimoda, Shinji ; Nakanuma, Yasuni ; Kakuda, Yuko ; Imai, Toshio ; Zeniya, Mikio ; Hojo, Seiichiro ; Umeda, Atsushi

BackgroundWhile ursodeoxycholic acid (UDCA) remains the first-line therapy for primary biliary cholangitis (PBC), the autoimmune nature of PBC underscores the need for treatments targeting immunological pathways that may achieve a cure. E6011, a novel humanized anti-fractalkine monoclonal antibody, has emerged as a potential therapeutic option for PBC. We conducted a randomized, placebo-controlled, double-blind study to evaluate the efficacy and safety of E6011 in patients with PBC with an incomplete response to UDCA.MethodsThe study was composed of 12-week Double-Blind Phase (placebo, E6011 10 mg/kg/month, 15 mg/kg/month, or 10 mg/kg/every other week [eow]) followed by a 52-week Open-Label Phase. The primary endpoint was the percent change in alkaline phosphatase (ALP) at Week 12.ResultsA total of 29 patients were enrolled. Histological evaluation at screening revealed that 83 % of the enrolled patients were classified as Stage 4 according to the Nakanuma Classification. The mean percent changes in ALP at Week 12 were +0.45 % in the placebo, +0.65 % in the 10 mg/kg/month, +1.23 % in the 15 mg/kg/month and +1.19 % in the 10 mg/kg/eow, with no observed trends toward ALP reduction in the E6011 treatment. Based on the interim analysis, the study was discontinued due to a lack of the efficacy. E6011 was generally safe and well tolerated.ConclusionThis study of E6011 failed to meet the primary endpoint in patients with PBC with an incomplete response to UDCA. The advanced histological severity present in more than 80 % of patients at baseline may have contributed to these findings.

01 Nov 2024·Pathology - Research and Practice

Cultures derived from pancreatic cancer xenografts with long-term gemcitabine treatment produce chemoresistant secondary xenografts: Establishment of isogenic gemcitabine-sensitive and -resistant models

Article

Author: Yanagita, Emmy ; Sasai, Ken ; Ito, Tomo ; Sukezane, Taiko ; Itoh, Tomoo ; Kobayashi-Ooka, Yasuyo ; Akagi, Tsuyoshi

In attempts to establish sophisticated models to reproduce the process of acquired drug resistance, we transformed normal human pancreatic ductal epithelial cells by introducing genes for multiple cellular factors. We also created isogenic gemcitabine-sensitive and -resistant models by short- and long-term gemcitabine treatment, respectively. These models demonstrated differences in drug resistance in vivo, but not in vitro. Gemcitabine treatment also induced squamous transdifferentiation in xenografts in mice. The transcription factor p63 was identified as a possible resistance-determining factor but was unlikely to be solely responsible for the resistance to gemcitabine. This system would prove useful to discover novel molecular targets to overcome chemotherapy resistance, by allowing the evaluation of molecules of interest in xenograft models after in vitro genetic ablation.

01 Oct 2024·Nature Cell Biology

Wnt-deficient and hypoxic environment orchestrates squamous reprogramming of human pancreatic ductal adenocarcinoma

Article

Author: Kodama, Yuzo ; Kitagawa, Yuko ; Hirano, Tomonori ; Iwasaki, Eisuke ; Kakiuchi, Nobuyuki ; Tamagawa, Hiroki ; Takano, Ai ; Seino, Takashi ; Kitago, Minoru ; Matano, Mami ; Togasaki, Kazuhiro ; Fujii, Masayuki ; Sasai, Ken ; Toshimitsu, Kohta ; Kawasaki, Kenta ; Machinaga, Akihito ; Ogawa, Seishi ; Machida, Yujiro ; Kawasaki, Shintaro ; Ohta, Yuki ; Seno, Hiroshi ; Takahashi, Sirirat ; Sato, Toshiro ; Sekine, Shigeki ; Kanai, Takanori

Human pancreatic cancer is characterized by the molecular diversity encompassing native duct-like and squamous cell-like identities, but mechanisms underlying squamous transdifferentiation have remained elusive. To comprehensively capture the molecular diversity of human pancreatic cancer, we here profiled 65 patient-derived pancreatic cancer organoid lines, including six adenosquamous carcinoma lines. H3K27me3-mediated erasure of the ductal lineage specifiers and hijacking of the TP63-driven squamous-cell programme drove squamous-cell commitment, providing survival benefit in a Wnt-deficient environment and hypoxic conditions. Gene engineering of normal pancreatic duct organoids revealed that GATA6 loss and a Wnt-deficient environment, in concert with genetic or hypoxia-mediated inactivation of KDM6A, facilitate squamous reprogramming, which in turn enhances environmental fitness. EZH2 inhibition counterbalanced the epigenetic bias and curbed the growth of adenosquamous cancer organoids. Our results demonstrate how an adversarial microenvironment dictates the molecular and histological evolution of human pancreatic cancer and provide insights into the principles and significance of lineage conversion in human cancer.

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