Notably, Wnt/β-catenin activation with LiCl significantly enhanced the proliferation and epithelial-mesenchymal transformation (EMT) inhibition effect of silencing FNDC1, whereas Wnt/β-catenin inhibition with XAV-939 significantly weakened the proliferation and EMT promotion effect of FNDC1...These data suggested that FNDC1 exerts its oncogene function through modulating Wnt/β-catenin signaling pathway. In conclusion, FNDC1 promotes cell proliferation, migration, invasion, and EMT through modulating Wnt/β-catenin signaling pathway in breast cancer, providing a new idea for the development of breast cancer therapeutic targets.

"Allarity Therapeutics, Inc...announced that the European Patent Office (EPO) has issued a formal notice of its intention to grant a patent for Allarity’s Drug Response Predictor (DRP) companion diagnostic specific to stenoparib, the Company’s dual-targeted PARP/Tankyrase inhibitor. This patent represents a significant step forward in securing Allarity’s market position for stenoparib and the Stenoparib DRP companion diagnostic, which identifies patients most likely to derive clinical benefit from stenoparib treatment....Patent applications for the Stenoparib DRP companion diagnostic are also pending in the United States, Japan, China, Australia, and India."

Moreover, XAV-939, a β-catenin inhibitor, was capable of suppressing the malignant phenotypes in TARDBP-overexpressed T-ALL cells...In aggregate, we explored a promising biomarker, TARDBP, for T-ALL treatment. The underlying mechanisms might involve the interaction with MDM2 mRNA and the regulation of the β-catenin pathway.

P2 | N=60 | PREDICT 2X-121 (NCT03878849) | Sponsor: Allarity Therapeutics | "Allarity Therapeutics, Inc...announced that two patients enrolled in its Phase 2 clinical trial of stenoparib for advanced, recurrent ovarian cancer have now exceeded one year on therapy....This remarkably lengthy treatment period highlights the potential of stenoparib to provide durable clinical benefit, even in heavily pre-treated ovarian cancer patients who have limited treatment options. The trial continues to evaluate stenoparib’s safety and efficacy, showing a confirmed, complete response as well as long term disease stability for multiple patients."

Additionally, Wnt pathway inhibitors like XAV-939 have demonstrated preclinical efficacy, underscoring their therapeutic potential. This review comprehensively analyzes the lncRNA/Wnt axis, highlighting its impact on cell proliferation, motility, and chemoresistance. By elucidating the complex molecular mechanisms of the lncRNA/Wnt axis, we aim to identify potential therapeutic targets for digestive system tumors to pave the way for the development of targeted treatment strategies.

P1, N=24, Recruiting, Onconic Therapeutics Inc. | Not yet recruiting --> Recruiting | Trial completion date: Aug 2023 --> Dec 2024 | Trial primary completion date: Aug 2023 --> Dec 2024

P2, N=58, Active, not recruiting, Onconic Therapeutics Inc. | Not yet recruiting --> Active, not recruiting

Taken together, the present data elucidated that reduced RASAL1 through its promoter hypermethylation regulated by TET2 promoted the tumorigenicity and chemoresistance of CC via modulating β-catenin both in vitro and in vivo.

Finally, drug sensitivity analysis revealed that ALDOB increased the sensitivity of gastric cancer cells to most antitumor drugs, especially talazoparib, XAV939, and FTI-277. And ALDOB significantly inhibited proliferation and migration, delayed glycolysis in GC cells. Consequently, our study suggests that ALDOB may be a potential target for the clinical treatment of gastric cancer.

This work exposed a new mechanistic framework by linking PARylation to respiration and metabolism, thereby broadening the current understanding that underlies these vital processes. XAV-939 poses an immediate and straightforward strategy to improve aerobic activities, and metabolism, in (immature) cell cultures.

It was also found that the upregulation of β-catenin protein in NG2-glia in the hippocampus of 16-week-old db/db mice was significantly alleviated by treatment with XAV-939. The results indicate that NG2-glia can lead to structural and functional disruption of the diabetic BBB by activating Wnt/β-catenin signaling, upregulating MMP-9, and degrading tight junction proteins.

APC and TP53 mutations were more frequent in the low LINC01550 expression group, while the high LINC01550 expression group was significantly more sensitive to 5-fluorouracil, irinotecan, trametinib, gemcitabine, rapamycin, and XAV939. LINC01550 exerted these effects by inhibiting Wnt/β-catenin signaling. Our results suggest LINC01550 as a diagnostic and prognostic predictor in CRC that acts as a tumor suppressor and a potential therapeutic target.

P2, N=92, Not yet recruiting, Yonsei University

Moreover, SKL2001, a Wnt/β-catenin activator, partially abrogated the effects of TROAP silencing on EC cell proliferation and apoptosis, while the signaling inhibitor XAV-939 had the opposite effect. In conclusion, TROAP knockout retarded proliferation and elicited apoptosis in EC cells by blocking the Wnt/β-catenin pathway.

Stabilizing WNT-targeted scaffold protein Axin2 by XAV939 during embryonic development causes overproduction of cortical neurons and leads to autistic-like behaviors in mice...The results suggest that the WNT signaling pathway is crucial for optic nerve development. This study provides experimental evidence that conditions interfering with brain development may also lead to visual problems, which in turn might exaggerate the autistic features in humans.

This combined effect was also observed in H2170, an HER2-amplified lung cancer cell line. These results suggest that the proposed 3D co-culture system may help in evaluating the efficacy of T-DXd and may recapitulate the tumor microenvironment.

P2, N=30, Active, not recruiting, Allarity Therapeutics | Trial completion date: May 2024 --> Aug 2024

P2, N=60, Active, not recruiting, Allarity Therapeutics | Recruiting --> Active, not recruiting | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Sep 2023 --> Sep 2024

Functionally, CRTC2 contributed to HCC malignant phenotypes through the activated Wnt/β-catenin pathway, which could be abrogated by the small-molecular inhibitor XAV-939...In immunocompetent mice models of HCC, targeting Crtc2 in combination with anti-PD-1 therapy prominently suppressed tumor growth by synergistically enhancing responsiveness to immunotherapy. Collectively, targeting CRTC2 might be a promising therapeutic strategy to sensitize immunotherapy in HCC.

The hypoxia-EMT-β-catenin axis functions as an important regulator for the proportion of CSCs in NSCLC and could potentially be explored as therapeutic targets in the future.

XAV939 or Axin1 overexpression was co-treated with UBE2N overexpression to detect the involvement of the Wnt/β-catenin signaling and Axin1 in the UBE2N function...Wnt/β-catenin inhibition and Axin1 overexpression reversed the promoting viability and glycolysis function of UBE2N. UBE2N promoted Axin1 ubiquitination and decreased Axin1 protein level.

It was confirmed that HPOE had a certain inhibitory effect on the activation of the Wnt signaling pathway caused by the activator Licl and could enhance the inhibitory effect of the inhibitor XAV939. Our findings provide a basis for developing functional foods or dietary supplements, especially positioning HPOE as a functional food raw material for adjuvant treatment of CRC, given its ability to inhibit metastasis through the Wnt/β-catenin pathway.

Our finding demonstrate that single knockdown of Dsg2 or Dsc2 could promote proliferation, motility and invasion in triple-negative MDA-MB-231 and luminal MCF-7 cells. Nevertheless, the underlying mechanisms were cellular context-specific and distinct.

Furthermore we found that continued exposure to XAV, further addition of neither liraglutide nor insulin-like growth factor-1 counteracted XAV-mediated inhibition of IK(erg). Overall the suppression of IK(erg) by XAV may serve as a significant ionic mechanism that contribute to the functional properties of MA-10 cells. However, it is important to note that this effect cannot be attributed solely to the inhibition of tankyrase.

"Allarity Therapeutics, Inc....announced a strategic pivot aimed at advancing its clinical-stage candidate stenoparib, a novel PARP/Tankyrase dual inhibitor, toward registration in advanced recurrent ovarian cancer, leveraging its DRP platform to identify and enroll only the patients most likely to derive clinical benefit....This decisive shift in priorities is driven by the compelling initial data from the Phase 2 monotherapy trial evaluating stenoparib in advanced, recurrent ovarian cancer patients, as announced on December 5, 2023....As part of this strategic shift, the Company will deprioritize the other clinical trials for dovitinib and IXEMPRA."

The tankyrase inhibitor XAV939, effectively prevents RNF166-dependent destabilization of angiomotins and subsequent activation of YAP...Importantly, the C-terminus of RNF66, particularly the Di19-ZF domain, is the crucial region responsible for recognizing ADP-ribosylated angiomotins. Together, this work not only sheds light on the regulation of the Hippo pathway in colorectal cancer but also uncovers a novel poly(ADP-ribose)-binding domain, which may serve as a potential therapeutic target for intervention.

In this study, novel reprogrammed pluripotent stem cells (rPSCs) were induced from mouse EpiSCs using a chemically defined medium containing mouse LIF, BMP4, CHIR99021, XAV939, and SB203580...Conversely, overexpression of pri-miR-290 reversed these changes. In addition, Map2k6 was identified as a direct target gene of miR-291b-3p, indicating that the miR-290 family maintains pluripotency and self-renewal in rPSCs by regulating the MAPK signaling pathway.

XAV-939, Fulvestrant, and SR16157 may have potential value in the clinical use of LUAD. We revealed the potential linkage between PRGs and LUAD prognosis, and the application of these prognostic factors in risk stratification and prognosis prediction of LUAD patients may be of great significance.

Meanwhile, further studies showed that in SW48 cells, overexpressing SLC26A9 was cocultured with the β-catenin inhibitor XAV-939, β-catenin was downregulated, and EMT was reversed. Our study demonstrated SLC26A9 may be responsible for alterations in the proliferative ability and aggressive potential of CRC by regulating the Wnt/β-catenin signaling pathway.

"Allarity Therapeutics, Inc...is pleased to announce that it has been invited to present at Biomarkers 2024. Thomas Jensen, CEO and co-founder of Allarity, will present the company's novel work in developing the drug-specific Drug Response Predictor (DRP) companion diagnostics (CDx) platform. This work spans from cancer cell line research to the validation of concepts through retrospective clinical data analysis and into the area of prospective clinical trials, notably an ongoing trial for ovarian cancer. This trial investigates how a DRP created specifically for the Company’s lead clinical asset, the dual PARP/Tankyrase inhibitor stenoparib, can be used to pre-select advanced ovarian cancer patients who are predicted to have a significant likelihood of clinical benefit from treatment for enrollment in this phase 2 monotherapy study, NCT03878849."

BIRC6 was also upregulated in cancer stem-like cells of RCC and increased the drug resistance of RCC cells against sunitinib...Pharmacological administration of a Wnt/β-catenin inhibitor, XAV-939, or genetic knockdown of β-catenin inhibited cell growth, tumor sphere formation, colony formation, migration, and invasion of BIRC6-overexpressed cells...In conclusion, we propose that BIRC6 activates the β-catenin signaling pathway via mediating the ubiquitination and degradation of Axin, promoting the growth, stemness, and drug resistance of RCC cells. This project aims to elucidate the role of BIRC6 as a potential therapeutic target and provide new insights into the clinical treatment of RCC.

Consistent with this notion, β-catenin inhibition using XAV939 or ICG-001 partially prevented centrinone-induced death and rescued the growth two APC-mutant organoid lines tested. Our study reveals a novel role for canonical WNT signaling in regulating centrosome loss-induced growth defect/death in a subset of APC-mutant colorectal cancer independently of the classical p53 pathway.

P1, N=32, Completed, ST Pharm Co., Ltd. | Active, not recruiting --> Completed

Combination of tankyrase and BET inhibitors significantly suppress tumor growth in a mouse xenograft model. These observations suggest that the combination of tankyrase and BET inhibitors may be a useful therapeutic approach to overcome the resistance of a subset of CRCs to tankyrase inhibitors.

PRRX1 is upregulated in oesophageal cancer is closely correlated with cancer metastasis. Additionally, PRRX1 induces EMT in oesophageal cancer metastasis through activation of Wnt/β-catenin signalling.

The enhancing effects of FAM83F overexpression on CC cell proliferation and glycolysis could be impaired by the Wnt/β-catenin inhibitor XAV939...In summary, our study demonstrated that FAM83F promoted CC growth and glycolysis through regulating the Wnt/β-catenin pathway, suggesting that FAM83F may be a potential molecular target for CC treatment. Schematic summary of c-Myc-activated FAM83F transcription to promote cervical cancer growth and glycolysis by targeting the Wnt/β-catenin signal pathway.

P2 | N=60 | PREDICT 2X-121 (NCT03878849) | Sponsor: Allarity Therapeutics | "Allarity Therapeutics, Inc...today announced encouraging initial results from its ongoing Phase 2 clinical trial evaluating the efficacy of its PARP inhibitor, stenoparib, in women with advanced ovarian cancer (AOC). Of the five evaluable patients included in the initial data analysis, one patient experienced a complete response and the other four demonstrated stable disease...Of the 22 patients screened with the DRP^®-Stenoparib CDx, 17 DRP^® positive patients were identified...One patient experienced a complete response (CR) by scan (to be confirmed by second scan) and by decreased levels of CA125 (a biomarker of AOC)....Allarity anticipates an interim data readout in Q1 2024."

The Wnt/β-catenin pathway inhibitor, XAV939, prevents the adhesion and survival of POU5F1-expressing cells in vitro. Early administration of XAV939 also completely inhibits liver metastasis induced by POU5F1-positive cells.

These findings suggest that TBX3 may play an important role in the development of ADM. The expression of TBX3 in ADM was regulated by the Wnt3a/β-catenin pathway. The activation of the Wnt3a/β-catenin pathway in ADM promoted TBX3 expression and induced the occurrence of EMT, thus promoting cell proliferation and inhibiting apoptosis, ultimately accelerating the development of ADM. The study provides a reference for the diagnosis of ADM.

APC/PIK3CA mutations and β-catenin predict the sensitivity of APC-mutated CRC PDCs to tankyrase inhibitors. These observations may help inform the strategy of patient selection in future clinical trials of tankyrase inhibitors.

GOLPH3 promotes cell proliferation, migration and invasion in CC, possibly by regulating the Wnt/β-catenin signaling pathway, which may provide a new idea for the development of CC therapeutic targets.