Winning WNT: Race to Wnt signaling inhibitors

Watanabe, Kazuhide; Dai, Xing

doi:10.1073/pnas.1103102108

Cited by 34 publications

(23 citation statements)

References 20 publications

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“…25 Assessment of three representative Wnt target genes showed that incubation of UCB T cells with iCRT inhibited induction of LEF1, JUN and EOMES by dmPGE2 (Figure 2c). These results provide evidence that PGE2 induced expression of these genes via modulation of the β-catenin-mediated transcriptional activity in UCB T cells.…”

Section: Resultsmentioning

confidence: 97%

Prostaglandin E2 promotes survival of naive UCB T cells via the Wnt/β-catenin pathway and alters immune reconstitution after UCBT

Kim

Nellore

et al. 2014

Blood Cancer Journal

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The outcome of umbilical cord blood transplantation (UCBT) is compromised by low hematopoietic stem cell (HSC) doses leading to prolonged time to engraftment, delayed immunological reconstitution and late memory T-cell skewing. Exposure of UCB to dimethyl-prostaglandin E2 (dmPGE2) increases HSC in vivo. We determined that exposure of UCB T lymphocytes to dmPGE2 modified Wnt signaling resulting in T cell factor (TCF)-mediated transcription. Wnt signaling upregulated interleukin (IL)-7R and IL-2Rβ, resulting in enhanced survival mediated by the homeostatic cytokines IL-7 and IL-15. dmPGE2 also induced components of the Wnt pathway and Wnt receptors, thereby priming UCB T cells to receive signals via Wnt ligands in vivo. We observed that the Wnt transcription factor TCF7 and its target EOMES were elevated in the T cells of patients who received PGE2-treated UCBs. Consistent with the role of Wnt/β-catenin signaling to induce and maintain naive, memory precursors and long-lived central memory CD8+ cells, these patients also had increased fractions of CD8+CD45RO-CD62L+ plus CD8+CD45RO+CD62L+ subsets encompassing these T-cell populations. These effects of the PGE2/Wnt/β-catenin axis may have significant implications for harnessing immunity in the context of UCBT, where impaired immune reconstitution is associated with late memory T-cell skewing.

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Section: Resultsmentioning

confidence: 97%

Prostaglandin E2 promotes survival of naive UCB T cells via the Wnt/β-catenin pathway and alters immune reconstitution after UCBT

Kim

Nellore

et al. 2014

Blood Cancer Journal

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“…In the nucleus, β‐catenin, itself incapable of DNA binding, must interact with TCF/LEF family transcription factors, and recruit other coactivators such as p300 (Rao and Kuhl, ) to modulate Wnt target gene transcription. ICG‐001 and iCRT3,5,14 prevent β‐catenin from binding p300 (Emami et al, ) and TCF/LEF transcription factors (Lepourcelet et al, ), respectively (Watanabe and Dai, ). Another level of regulation occurs through negative or positive feedback by Wnt/β‐catenin target genes.…”

Section: Canonical Wnt/β‐catenin Signaling Pathway and Its Regulationmentioning

confidence: 99%

Canonical Wnt signaling in the oligodendroglial lineage-puzzles remain

Guo

Lang

Sohn

et al. 2015

Glia

100

101

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“…Like several other well characterized oncogenes, β-catenin is very challenging to target by conventional small molecule or monoclonal antibody approaches since it is an intracellular protein with no enzymatic activity (9). Therefore, no approved therapy targeting β-catenin has emerged despite decades of research.…”

Section: Introductionmentioning

confidence: 99%

Direct Pharmacological Inhibition of β-Catenin by RNA Interference in Tumors of Diverse Origin

Ganesh

Koser

Cyr

et al. 2016

Molecular Cancer Therapeutics

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The Wnt/β-catenin pathway is among the most frequently altered signaling networks in human cancers. Despite decades of preclinical and clinical research, efficient therapeutic targeting of Wnt/β-catenin has been elusive. RNA interference (RNAi) technology silences genes at the mRNA level, and therefore can be applied to previously-undruggable targets. Lipid nanoparticles (LNPs) represent an elegant solution for delivery of RNAi-triggering oligonucleotides to disease-relevant tissues, but have been mostly restricted to applications in the liver. In this study, we systematically tuned the composition of a prototype LNP to enable tumor-selective delivery of a Dicer-substrate siRNA (DsiRNA) targeting CTNNB1, the gene encoding β-catenin. This formulation, termed EnCore-R, demonstrated pharmacodynamic activity in subcutaneous human tumor xenografts, orthotopic patient-derived xenograft (PDx) tumors, disseminated hematopoietic tumors, genetically induced primary liver tumors, metastatic colorectal tumors, murine metastatic melanoma. DsiRNA delivery was homogeneous in tumor sections, selective over normal liver and independent of apolipoprotein-E binding. Significant tumor growth inhibition was achieved in Wnt-dependent colorectal and hepatocellular carcinoma models, but not in Wnt-independent tumors. Finally, no evidence of accelerated blood clearance or sustained liver transaminase elevation was observed after repeated dosing in nonhuman primates. These data support further investigation to gain mechanistic insight, optimize dose regimens and identify efficacious combinations with standard-of-care therapeutics.

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Winning WNT: Race to Wnt signaling inhibitors

Cited by 34 publications

References 20 publications

Prostaglandin E2 promotes survival of naive UCB T cells via the Wnt/β-catenin pathway and alters immune reconstitution after UCBT

Prostaglandin E2 promotes survival of naive UCB T cells via the Wnt/β-catenin pathway and alters immune reconstitution after UCBT

Canonical Wnt signaling in the oligodendroglial lineage-puzzles remain

Direct Pharmacological Inhibition of β-Catenin by RNA Interference in Tumors of Diverse Origin

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