Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours

Rodón, Jordi; Argilés, Guillem; Connolly, Roisín M.; Vaishampayan, Ulka N.; Jonge, Maja de; Garralda, Elena; Giannakis, Marios; Smith, David C.; Dobson, Jason R.; McLaughlin, Margaret E.; Seroutou, Abdelkader; Ji, Yan; Morawiak, Jennifer; Moody, Susan E.; Janků, Filip

doi:10.1038/s41416-021-01389-8

Cited by 91 publications

(90 citation statements)

References 29 publications

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“…ZNRF3 loss has also been suggested as a potential predictive biomarker for sensitivity to porcupine inhibitors 58 , which are in clinical trials for WNT- and NOTCH-driven cancers (e.g. NCT01351103) 59 . Thus, while the precise clinical impact of assessing ZNRF3 loss is unclear, its presence in ~10% of localized disease could make it a valuable endpoint to routinely assess.…”

Section: Discussionmentioning

confidence: 99%

Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse

et al. 2021

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Driver gene mutations that are more prevalent in metastatic, castration-resistant prostate cancer (mCRPC) than localized disease represent candidate prognostic biomarkers. We analyze 1,844 localized (1,289) or mCRPC (555) tumors and quantify the prevalence of 113 somatic driver single nucleotide variants (SNVs), copy number aberrations (CNAs), and structural variants (SVs) in each state. One-third are significantly more prevalent in mCRPC than expected while a quarter are less prevalent. Mutations in AR and its enhancer are more prevalent in mCRPC, as are those in TP53, MYC, ZNRF3 and PRKDC. ZNRF3 loss is associated with decreased ZNRF3 mRNA abundance, WNT, cell cycle & PRC1/2 activity, and genomic instability. ZNRF3 loss, RNA downregulation and hypermethylation are prognostic of metastasis and overall survival, independent of clinical and pathologic indices. These data demonstrate a strategy for identifying biomarkers of localized cancer aggression, with ZNRF3 loss as a predictor of metastasis in prostate cancer.

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Section: Discussionmentioning

confidence: 99%

Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse

et al. 2021

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“…In addition, inhibitors against porcupine, an enzyme involved in the processing of Wnt signaling proteins, have been developed to target Wnt-driven cancers, most notably with WNT974, which has shown safety but limited efficacy in advanced solid tumors. 18 However, issues remain surrounding the efficacy of targeting upstream targets, in regard to resistance in tumors with more downstream mutations, such as CTNNB1 - or APC -mutated cancers. 19 Currently, direct inhibition of beta-catenin or APC remains a pharmacologic challenge limited to preclinical testing 19 , 20 and significant concerns for off-target effects remain, such as toxicity to normal intestinal tissues.…”

Section: Discussionmentioning

confidence: 99%

Sporadic adamantinomatous craniopharyngioma with double-hit somatic APC mutations

Hong

Omuro

et al. 2021

Neuro-Oncology Advances

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“…WNT974 (LGK974) is a first-in-class PORCN inhibitor that was shown to be potent and efficacious in multiple tumor models [109]. In an ongoing clinical study, biomarker analyses show that WNT974 inhibit WNT pathway activity in tumors [110]. In a recent 2020 AACR conference, a phase I clinical trial of WNT974 demonstrated that combination therapy using WNT974 and the monoclonal PD-1 antibody spartalizumab, was well tolerated in cancer patients with advanced solid tumors in a variety of cancers.…”

Section: Canonical Wnt Pathway Inhibitors In Clinical Trialsmentioning

confidence: 99%

“…ETC-159 is an orally administered and potent porcupine inhibitor that has shown preclinical efficacy in combinations with phosphoinositide 3-kinase (PI-3K) inhibitors and poly (ADP-ribose) polymerase (PARP) inhibitors [110,111]. ETC-159 was shown to inhibit WNT signaling at doses that were well tolerated in the clinical study [111][112][113].…”

Section: Canonical Wnt Pathway Inhibitors In Clinical Trialsmentioning

confidence: 99%

WNT Signaling as a Therapeutic Target for Glioblastoma

Latour

Her

Kesari

et al. 2021

IJMS

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The WNT (Wingless/Integrated) signaling pathway is implicated in various stages of glioblastoma, which is an aggressive brain tumor for which therapeutic options are limited. WNT has been recognized as a hallmark of therapeutic challenge due to its context-dependent role and critical function in healthy tissue homeostasis. In this review, we deeply scrutinize the WNT signaling pathway and its involvement in the genesis of glioblastoma as well as its acquired therapy resistance. We also provide an analysis of the WNT pathway in terms of its therapeutic importance in addition to an overview of the current targeted therapies under clinical investigation.

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Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours

Cited by 91 publications

References 29 publications

Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse

Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse

Sporadic adamantinomatous craniopharyngioma with double-hit somatic APC mutations

WNT Signaling as a Therapeutic Target for Glioblastoma

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