P2, N=37, Not yet recruiting, Shanghai East Hospital; Shanghai East Hospital

DKN-01 can be safely combined with frontline fluoropyrimidine/oxaliplatin and tislelizumab and demonstrates encouraging activity independent of PD-L1 expression levels. A randomized phase II trial is ongoing (ClinicalTrials.gov identifier: NCT04363801).

Malignant cell states co-varied with distinct immune cell states, revealing diverse mechanisms of myeloid and T-cell mediated immune suppression, including M2 myeloid and terminally exhausted T cell programs that were induced by DKN-01/nivolumab. Here, we provide the first systematic classification of functionally annotated cell states in biliary tract cancer and provide new insight into resistance mechanisms to an immunotherapy combination that can inform the next generation of trials.

Moreover, DKN-01 activated the cGAS/STING pathway, while the inactivation of cGAS-STING pathway using RU.521 reversed the inhibition of tumor growth in vivo and macrophage M2 polarization caused by DKN-01. This study reveals that DKN-01 suppresses GC tumor growth through activating cGAS-STING pathway to block macrophage M2 polarization.

P2, N=189, Active, not recruiting, Leap Therapeutics, Inc. | Recruiting --> Active, not recruiting

Andrographolide can enhance anti-tumor activity of TMZ against glioma by inhibiting DKK1 expression.

Additionally, combination of Hv1Lt1 and other chemotherapy drugs exhibited stronger effects compared with monotherapy. These results suggest that Hv1Lt1 represents a promising anti-cancer therapy.

P1/2, N=52, Active, not recruiting, Royal Marsden NHS Foundation Trust | Recruiting --> Active, not recruiting | Trial primary completion date: May 2024 --> Dec 2024

P2, N=200, Recruiting, Leap Therapeutics, Inc. | N=150 --> 200

P2, N=150, Recruiting, Leap Therapeutics, Inc. | Trial completion date: Aug 2024 --> Dec 2025 | Trial primary completion date: Mar 2024 --> Dec 2025

P2, N=15, Terminated, Massachusetts General Hospital | N=30 --> 15 | Recruiting --> Terminated; Based on a Simon 2-stage design, this study did not meet response criteria to proceed to stage 2.

Other targeted agents, such as bemarituzumab and DKN-01, are under active investigation. As new agents are incorporated into the treatment continuum, the questions of biomarker overlap, tumor heterogeneity, and toxicity management will need to be addressed.

DKN-01 600 mg was well tolerated. DKK1 blockade has modest anti-tumor activity as a monotherapy for mCRPC. Anti-tumor activity was observed in the combination cohorts, but the response duration was limited. DKK1 expression in the majority of mCRPC is low and did not clearly correlate with anti-tumor activity of DKN-01 plus docetaxel.

Ongoing efforts to identify novel biomarkers in EGA have led to enhanced subclassification of upper GI cancers. These advances, coupled with the strategic application of targeted therapies and immunotherapy when appropriate, hold promise to further improve patients outcomes.

P2, N=232, Active, not recruiting, Leap Therapeutics, Inc. | Recruiting --> Active, not recruiting

P1/2, N=18, Terminated, NYU Langone Health | Phase classification: P1b/2a --> P1/2

P1/2, N=52, Recruiting, Royal Marsden NHS Foundation Trust | Phase classification: P2 --> P1/2

Elevated DKK1 expression has been shown to correlate with fluorouracil (5FU) resistance in CRC tumors... DeFianCe (NCT05480306) is a Phase 2 randomized, open-label, two-part, multicenter study to evaluate efficacy and safety of DKN-01 plus FOLFIRI/FOLFOX and bevacizumab versus standard of care (SOC) [FOLFIRI/FOLFOX and bevacizumab] as 2L treatment of advanced MSS CRC patients (pts)...All patients had received prior 5FU-based therapies, 30 pts (91%) with oxaliplatin in combination and 17 pts (52%) had prior bevacizumab... DKN-01 in combination with SOC was well tolerated with promising preliminary activity (ORR 30% and DCR 93%) in the single arm Part A. PFS has not been reached and survival follow up is ongoing. Part B randomized expansion phase has begun and is enrolling an additional 130 pts. Tumoral DKK1 expression and correlation with clinical outcomes will be evaluated as an exploratory efficacy endpoint.

P1/2, N=186, Not yet recruiting, Shanghai Junshi Bioscience Co., Ltd.

P2, N=60, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

In sum, our study reveals the role of DKK1 in remodeling GC TIME and regulating the expression levels of NKG2DLs in GC. We also provide a promising treatment strategy of combining DKK1 inhibition with NKG2D-CAR-T cell therapy, which could bring new breakthroughs for GC immunotherapy.

Collectively, data demonstrates promising clinical activity of a well-tolerated drug, DKN-01, in EC patients with high tumoral DKK1 expression which frequently corresponded to the presence of a Wnt activating mutation. Future development will focus on using DKN-01 in DKK1-high EC patients in combination with immunotherapy.

P2, N=60, Not yet recruiting, M.D. Anderson Cancer Center

P2, N=232, Recruiting, Leap Therapeutics, Inc. | Phase classification: P2a --> P2 | N=72 --> 232 | Trial completion date: Jun 2023 --> Dec 2025 | Trial primary completion date: Dec 2022 --> Jun 2025

Correlation analysis of human HCC tumor specimens further revealed that DKK1 and PD-L1 expression were positively correlated with p-β-catenin expression. Together, our findings revealed that DKK1 promotes PD-L1 expression through the activation of Akt/β-catenin signaling, providing a potential strategy to enhance the clinical efficacy of PD-1/PD-L1 blockade therapy in HCC patients.

The expression levels of CSTA, FAM83A, and MYCT1 are related to the diagnosis and prognosis of LUSC and may have potential as therapeutic targets in LUSC. A risk model and nomogram based on CSTA, FAM83A, and MYCT1 can predict the prognosis of LUSC.

Furthermore, immunohistochemical analysis of 20 HCC clinical samples showed that the expression level of NUAK1 was positively correlated with DKK1 and p-Akt. Taken together, we provide the first evidence that DKK1 promotes NUAK1 transcriptional expression via the activation Akt in HCC.

<1 n=13 (27%); 1-<10 n=22 (45%); ≥10 n=14 (29%). 38 pts with genomic profiling: Wnt activating mutations in 12 pts, no MSI-H. 4 pts were IO experienced.

We demonstrated that miR-1290 enhanced proliferation, migration, and angiogenesis partially through suppression of THBS1, DKK3, and SCAI in CRC. These results suggest a novel function of miR-1290 which may contribute to tumorigenesis and angiogenesis in CRC.

In addition, ApoG2 treatment inhibited CC xenograft tumor growth and upregulated the protein levels of DKK3, cleaved caspase-3 and E-cadherin. In conclusions, these findings suggested that ApoG2 could effectively inhibit the growth and invasion of CC cells at least partly by activating DKK3.

DKK1 promotes tumour immune evasion in iCCA through the recruitment of immune suppressive macrophages. Targeting DKK1 with a neutralizing antibody is effective at reducing tumour growth in vivo. As such, DKK1 targeted and immune modulatory therapies may be an effective strategy in iCCA patients with high DKK1 tumour expression or tolerogenic immune phenotypes.

Furthermore, we found oncogenic factors such as dickkopf WNT signaling pathway inhibitor 1 and 4, WNT16, forkhead box O3 (FOXO3), and MAPK10 are differentially expressed in 11p15-altered HB in both the BWS and non-syndromic backgrounds. These genes warrant further investigation as diagnostic or therapeutic targets.

Conclusions DKN-01 plus atezolizumab has a manageable safety profile with no new safety signals in pts with advanced OGA. DKN-01 600mg plus atezolizumab 840mg q2W was the RP2D taken through to the ongoing expansion phase to confirm efficacy.

P1b/2a, N=18, Active, not recruiting, NYU Langone Health | Recruiting --> Active, not recruiting | N=97 --> 18 | Trial completion date: Dec 2022 --> Aug 2023

Inactivation of UC.145 induced apoptosis and inhibited the growth and migratory, invasive, and colony-forming abilities of gastric cancer cells. The study findings provide insights into Wnt signaling in gastric cancer and support UC.145 as a potential novel predictive biomarker for the disease.

We have provided evidence for DOC2B-DKK1-senescence-Wnt/β-catenin-EMT signaling crosstalk to have tumor growth regulatory functions in CC. Thus, targeting DOC2B-DKK1-senescence-Wnt/β-catenin-EMT signaling crosstalk via activation of DOC2B may offer a novel approach to restraint malignant behaviors in CC.

Inhibition of ADRB1 effectively killed cancer cells by abolishing the apoptotic resistance. These findings uncover a novel mechanism of apoptotic resistance in BRCA1-deficient ovarian cancer cells and point to a potentially new strategy for treating BRCA1-mutated tumors.

P2a, N=72, Recruiting, Leap Therapeutics, Inc. | Trial completion date: May 2022 --> Jun 2023 | Trial primary completion date: Dec 2021 --> Dec 2022