Targeting ligand-dependent wnt pathway dysregulation in gastrointestinal cancers through porcupine inhibition

Flanagan, Dustin J.; Woodcock, Simon; Phillips, Caroline; Eagle, Catherine; Sansom, Owen J.

doi:10.1016/j.pharmthera.2022.108179

Cited by 15 publications

(14 citation statements)

References 172 publications

(219 reference statements)

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“…Targeting the β-catenin-dependent pathway has been the focus of multiple drug discovery programs both in academia and industry, but only a few have reached clinical trials ( Blagodatski et al, 2014 ; Liu et al, 2021 ). Among them, there are five small molecules acting as Porcupine inhibitors ( e.g., 1 and 2 , in Figure 1 ), which are profiled in phase 1/2 clinical trials for different cancer indications ( Flanagan et al, 2022 ), while CWP232291, PRI-724, and SM08502 target downstream components of the Wnt-pathway ( Shaw et al, 2019a ). CWP232291 is a peptidomimetic targeting Sam68, an RNA-binding protein, and is currently profiled on acute myeloid leukaemia in phase 1/2.…”

Section: Introductionmentioning

confidence: 99%

Wnt-pathway inhibitors with selective activity against triple-negative breast cancer: From thienopyrimidine to quinazoline inhibitors

Boudou

Mattio²,

Koval³

et al. 2022

Front. Pharmacol.

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The Wnt-pathway has a critical role in development and tissue homeostasis and has attracted increased attention to develop anticancer drugs due to its aberrant activation in many cancers. In this study, we identified a novel small molecule series with a thienopyrimidine scaffold acting as a downstream inhibitor of the β-catenin-dependent Wnt-pathway. This novel chemotype was investigated using Wnt-dependent triple-negative breast cancer (TNBC) cell lines. Structure activity relationship (SAR) exploration led to identification of low micromolar compounds such as 5a, 5d, 5e and a novel series with quinazoline scaffold such as 9d. Further investigation showed translation of activity to inhibit cancer survival of HCC1395 and MDA-MB-468 TNBC cell lines without affecting a non-cancerous breast epithelial cell line MCF10a. This anti-proliferative effect was synergistic to docetaxel treatment. Collectively, we identified novel chemotypes acting as a downstream inhibitor of β-catenin-dependent Wnt-pathway that could expand therapeutic options to manage TNBC.

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Section: Introductionmentioning

confidence: 99%

Wnt-pathway inhibitors with selective activity against triple-negative breast cancer: From thienopyrimidine to quinazoline inhibitors

Boudou

Mattio²,

Koval³

et al. 2022

Front. Pharmacol.

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“…Porcupine is an O-acetyltransferase that is part of the Wnt pathway, and could be postulated as a possible therapy in this type of Wnt-induced tumors [59][60][61]. To date, five porcupine inhibitors have entered phase I/II clinical trials in patients with advanced solid tumors and showed promising preliminary clinical data [62,63]. Porcupine inhibitors were well-tolerated, also when they were used in combination with anti-PD-1 therapy [64] In tumors of the metabolic molecular group, a high expression of genes that play an essential role in cancer-specific metabolic reprogramming, such as PHGDH, has been observed [65].…”

Section: Discussionmentioning

confidence: 99%

A novel molecular analysis approach in colorectal cancer suggests new treatment opportunities

López-Camacho

Prado-Vázquez

Martínez-Pérez

et al. 2023

Preprint

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Colorectal cancer (CRC) is a molecular and clinically heterogeneous disease. In 2015, the Colorectal Cancer Subtyping Consortium classified CRC into four consensus molecular subtypes (CMS), but these CMS have had little impact on the clinical practice. The purpose of this study is to deepen into the molecular characterization of CRC. A novel approach, based on probabilistic graphical models (PGM) and sparse k-means-Consensus Cluster layer analyses was applied in order to functionally characterize CRC tumors. First, PGM was used to functionally characterize CRC, and then, sparse k-means-Consensus cluster was used to explore layers of biological information and establish classifications. To this aim, gene expression and clinical data of 805 CRC samples from three databases were analyzed. Tree different layers based on biological features were identified: adhesion, immune and molecular. The adhesion layer divided patients into high and low adhesion groups, with prognostic value. The immune layer divided patients into immune-high and immune-low groups, according to the expression of immune-related genes. The molecular layer established four molecular groups related to stem cells, metabolism, Wnt signalling pathway and extracellular functions. Immune-high patients, with a higher expression of immune-related genes and genes involved in viral mimicry response may be benefit for immunotherapy and viral mimicry-related therapies. Additionally, several possible therapeutic targets have been identified in each molecular group. Therefore, this improved CRC classification could be useful for searching new therapeutic targets and specific therapeutic strategies in CRC disease.

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“…Dysregulation of canonical and noncanonical Wnt pathways plays a pivotal role in many gastrointestinal cancers (26). To date, attempts to target these pathways clinically have been limited to biological approaches, including the anti-Frizzled-7 antibody vantictumab and the decoy Frizzled receptor ipafricept, or small-molecule compounds with poorly defined mechanisms of action.…”

Section: Discussionmentioning

confidence: 99%

The Wnt Pathway Inhibitor RXC004 Blocks Tumor Growth and Reverses Immune Evasion in Wnt Ligand–dependent Cancer Models

Phillips

Bhamra

Eagle

et al. 2022

Cancer Research Communications

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Wnt signalling is implicated in the etiology of gastrointestinal tract cancers. Targeting Wnt signalling is challenging due to on-target toxicity concerns and lack of druggable pathway components. We describe the discovery and characterization of RXC004, a potent and selective inhibitor of the membrane-bound-o-acyl-transferase Porcupine, essential for Wnt-ligand secretion. Absorption, distribution, metabolism and excretion (ADME) and safety pharmacology studies were conducted with RXC004 in-vitro, and pharmacokinetic (PK) exposure assessed in-vivo. RXC004 effects on proliferation and tumor metabolism were explored in genetically-defined colorectal and pancreatic cancer models in-vitro and in-vivo. RXC004 effects on immune evasion were assessed in B16F10 immune "cold" and CT26 immune "hot" murine syngeneic models, and in human cell co-cultures. RXC004 showed a promising PK profile, inhibited Wnt-ligand palmitoylation, secretion and pathway activation, and demonstrated potent anti-proliferative effects in Wnt-ligand-dependent (RNF43-mutant or RSPO3-fusion) colorectal and pancreatic cell lines. Reduced tumor growth, and increased cancer cell differentiation were observed in SNU-1411 (RSPO3-fusion), AsPC1 and HPAF-II (both RNF43-mutant) xenograft models, with a therapeutic window versus Wnt homeostatic functions. Additional effects of RXC004 on tumor cell metabolism were confirmed in-vitro and in-vivo by glucose uptake and 18fluorodeoxyglucose-positron emission tomography (18FDG-PET) respectively. RXC004 stimulated host tumor immunity; reducing resident myeloid-derived suppressor cells (MDSCs) within B16F10 tumors and synergizing with anti-programmed cell death protein-1 (PD-1) to increase CD8+/regulatory T-cell ratios within CT26 tumors. Moreover, RXC004 reversed the immuno-suppressive effects of HPAF-II cells co-cultured with human peripheral-blood-mononuclear cells (PBMCs), confirming the multiple anti-cancer mechanisms of this compound, which has progressed into phase 2 clinical trials.

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Targeting ligand-dependent wnt pathway dysregulation in gastrointestinal cancers through porcupine inhibition

Cited by 15 publications

References 172 publications

Wnt-pathway inhibitors with selective activity against triple-negative breast cancer: From thienopyrimidine to quinazoline inhibitors

Wnt-pathway inhibitors with selective activity against triple-negative breast cancer: From thienopyrimidine to quinazoline inhibitors

A novel molecular analysis approach in colorectal cancer suggests new treatment opportunities

The Wnt Pathway Inhibitor RXC004 Blocks Tumor Growth and Reverses Immune Evasion in Wnt Ligand–dependent Cancer Models

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