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

Yamada, Kazuhiko; Hori, Yusaku; Inoue, Satoshi; Yamamoto, Yuji; Iso, Kentaro; Kono, Hiroshi; Yamaguchi, Atsumi; Kimura, Takayuki; Uesugi, Mai; Ito, Junichi; Matsuki, Masahiro; Nakamoto, Kazutaka; Yoneda, Naoto; Takemura, Atsushi; Kushida, Ikuo; Wakayama, Naomi; Kubara, Kenji; Kato, Yu; Semba, Taro; Yokoi, Akira; Matsukura, Masayuki; Odagami, Takenao; Iwata, Masao; Tsuruoka, Akihiko; Uenaka, Toshimitsu; Matsui, Junji; Matsushima, Tomohiro; Nomoto, Ken’ichi; Kouji, Hiroyuki; Owa, Takashi; Funahashi, Yasuhiro; Ozawa, Yoichi

doi:10.1158/0008-5472.can-20-0782

Cited by 38 publications

(25 citation statements)

References 50 publications

(32 reference statements)

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“…Similarly, the non-responders to anti-PD-1 therapy in our cohort also demonstrated an enriched Wnt/β-catenin pathway. Recently, a selective inhibitor of the interaction between β-catenin and CREB binding protein demonstrated synergistic antitumor activity in combination with PD-1 blockade via modulation of the Wnt/β-catenin pathway and alteration of the tumor immune microenvironments in vivo (27,28). Thus, ICI resistance in MSI-H/dMMR GI tumors can potentially be overcome by targeting the Wnt/β-catenin pathway.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Profiling of MSI-H/dMMR Gastrointestinal Tumors to Identify Determinants of Responsiveness to Anti–PD-1 Therapy

Chida

Kawazoe

Suzuki

et al. 2022

Clinical Cancer Research

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Purpose: Transcriptomic profiling was performed for microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) gastrointestinal (GI) tumors to determine the predictors of response to PD-1 blockade. Experimental Design: Thirty-six patients with MSI-H/dMMR GI tumors, including gastric cancer, colorectal cancer (CRC), cholangiocarcinoma, small intestine cancer, and pancreatic cancer, being treated with PD-1 blockade were analyzed. We conducted the transcriptomic analysis of GI tumors using RNA sequencing data, including the consensus molecular subtypes (CMS) of CRC. Results: Gene set enrichment analysis (GSEA) demonstrated that non-responders had upregulations of epithelial mesenchymal transition, angiogenesis, hypoxia, mTORC1, TNF-α, KRAS, Wnt/β-catenin, TGF-β, and various metabolism-related signaling pathways. Meanwhile, the IFN-γ pathway was enriched in responders. Based on the leading-edge analysis of GSEA, VEGF-A was significantly correlated with enriched pathways in non-responders. Patients with high VEGF-A expression, compared to those with low expression, had significantly shorter progression-free survival (PFS) (median 4.8 months vs. not reached [NR], P = 0.032) and overall survival (median 11.1 months vs. NR, P = 0.045). Among 13 patients with CRC evaluable for CMS classification, the objective response rate was 100%, 0%, 0%, and 16.7% in CMS1, CMS2, CMS3 and CMS4, respectively. Patients with CMS1 had significantly longer PFS (NR vs. 4.8 months, P = 0.017) than those with CMS2, CMS3, or CMS4. Conclusions: Several transcriptomic features, including CMS classification and related genes, were associated with response to PD-1 blockade in MSI-H/dMMR GI tumors. These findings can help develop predictive biomarkers or combination immunotherapies.

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Section: Discussionmentioning

confidence: 99%

Transcriptomic Profiling of MSI-H/dMMR Gastrointestinal Tumors to Identify Determinants of Responsiveness to Anti–PD-1 Therapy

Chida

Kawazoe

Suzuki

et al. 2022

Clinical Cancer Research

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“…On the one hand, abnormal expression of p53 functions as a transcription factor that directly activates the expression of relevant genes in immune cells, thus regulating the proliferation of tumor cells; On the other hand, it can be used as tumor-associated antigen to stimulate an immune response. Studies have shown that abnormal expression of the Wnt signaling may also disrupt tumor immunodetection and promote tumor immune evasion ( 76 ). MAPK signal transduction inhibits the activity of immune cells in the TME by upregulating the release of cytokines such as IL-6 and IL-10 ( 77 ).…”

Section: Jmjd6 Regulates the Innate Immune Responsementioning

confidence: 99%

Role of the Epigenetic Modifier JMJD6 in Tumor Development and Regulation of Immune Response

Wang

Yang

Li³

et al. 2022

Front. Immunol.

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JMJD6 is a member of the Jumonji (JMJC) domain family of histone demethylases that contributes to catalyzing the demethylation of H3R2me2 and/or H4R3me2 and regulating the expression of specific genes. JMJD6-mediated demethylation modifications are involved in the regulation of transcription, chromatin structure, epigenetics, and genome integrity. The abnormal expression of JMJD6 is associated with the occurrence and development of a variety of tumors, including breast carcinoma, lung carcinoma, colon carcinoma, glioma, prostate carcinoma, melanoma, liver carcinoma, etc. Besides, JMJD6 regulates the innate immune response and affects many biological functions, as well as may play key roles in the regulation of immune response in tumors. Given the importance of epigenetic function in tumors, targeting JMJD6 gene by modulating the role of immune components in tumorigenesis and its development will contribute to the development of a promising strategy for cancer therapy. In this article, we introduce the structure and biological activities of JMJD6, followed by summarizing its roles in tumorigenesis and tumor development. Importantly, we highlight the potential functions of JMJD6 in the regulation of tumor immune response, as well as the development of JMJD6 targeted small-molecule inhibitors for cancer therapy.

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“…In a phase I clinical study, for example, PRI-724, an inhibitor of the β-catenin interaction with the transcriptional coactivator cyclic AMP response element-binding protein (CBP), converted eight patients (40%) into stable disease with a median progression-free survival (PFS) of two months [44]. Another antagonist of the β-catenin-CBP complex, E7386, significantly attenuated Wnt signaling in patient-derived hepatocellular carcinoma (HCC) xenograft models, and is being tested in early phase clinical studies [45]. Besides, antagonistic antibodies of Frizzled receptors, such as Vantictumab and Lpafricept, and anti-ROR1 antibody Cirmtuzumab are still in phase I trials without convincing outcomes [46][47][48][49][50][51].…”

Section: Targeting Wnt Pathway With Rnai Therapeuticsmentioning

confidence: 99%

Nanoparticle-Based RNAi Therapeutics Targeting Cancer Stem Cells: Update and Prospective

et al. 2021

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Cancer stem cells (CSCs) are characterized by intrinsic self-renewal and tumorigenic properties, and play important roles in tumor initiation, progression, and resistance to diverse forms of anticancer therapy. Accordingly, targeting signaling pathways that are critical for CSC maintenance and biofunctions, including the Wnt, Notch, Hippo, and Hedgehog signaling cascades, remains a promising therapeutic strategy in multiple cancer types. Furthermore, advances in various cancer omics approaches have largely increased our knowledge of the molecular basis of CSCs, and provided numerous novel targets for anticancer therapy. However, the majority of recently identified targets remain ‘undruggable’ through small-molecule agents, whereas the implications of exogenous RNA interference (RNAi, including siRNA and miRNA) may make it possible to translate our knowledge into therapeutics in a timely manner. With the recent advances of nanomedicine, in vivo delivery of RNAi using elaborate nanoparticles can potently overcome the intrinsic limitations of RNAi alone, as it is rapidly degraded and has unpredictable off-target side effects. Herein, we present an update on the development of RNAi-delivering nanoplatforms in CSC-targeted anticancer therapy and discuss their potential implications in clinical trials.

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

Cited by 38 publications

References 50 publications

Transcriptomic Profiling of MSI-H/dMMR Gastrointestinal Tumors to Identify Determinants of Responsiveness to Anti–PD-1 Therapy

Transcriptomic Profiling of MSI-H/dMMR Gastrointestinal Tumors to Identify Determinants of Responsiveness to Anti–PD-1 Therapy

Role of the Epigenetic Modifier JMJD6 in Tumor Development and Regulation of Immune Response

Nanoparticle-Based RNAi Therapeutics Targeting Cancer Stem Cells: Update and Prospective

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