^
Contact us  to learn more about
our Premium Content:  News alerts, weekly reports and conference planners
DRUG CLASS:

DKK1 protein inhibitor

14d
Targeted Agents in Esophagogastric Cancer Beyond Human Epidermal Growth Factor Receptor-2. (PubMed, Hematol Oncol Clin North Am)
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.
Review • Journal
|
HER-2 (Human epidermal growth factor receptor 2) • CLDN18 (Claudin 18)
|
sirexatamab (DKN-01) • bemarituzumab (AMG 552)
2ms
A Phase 1/2 multicenter trial of DKN-01 as monotherapy or in combination with docetaxel for the treatment of metastatic castration-resistant prostate cancer (mCRPC). (PubMed, Prostate Cancer Prostatic Dis)
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.
P1/2 data • Journal • Combination therapy • Metastases
|
DKK1 (dickkopf WNT signaling pathway inhibitor 1)
|
AR expression • AR underexpression
|
docetaxel • sirexatamab (DKN-01)
2ms
Current and Future Biomarkers in Esophagogastric Adenocarcinoma. (PubMed, J Gastrointest Cancer)
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.
Review • Journal • PD(L)-1 Biomarker • IO biomarker
|
HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • CLDN18 (Claudin 18)
|
sirexatamab (DKN-01) • Vyloy (zolbetuximab)
2ms
Enrollment closed • Combination therapy • Metastases
|
PD-L1 (Programmed death ligand 1) • DKK1 (dickkopf WNT signaling pathway inhibitor 1)
|
5-fluorouracil • Tevimbra (tislelizumab) • capecitabine • oxaliplatin • leucovorin calcium • sirexatamab (DKN-01)
3ms
Phase classification • Combination therapy • Metastases
|
docetaxel • sirexatamab (DKN-01)
4ms
WaKING: Wnt and checKpoint INhibition in Gastric Cancer (clinicaltrials.gov)
P1/2, N=52, Recruiting, Royal Marsden NHS Foundation Trust | Phase classification: P2 --> P1/2
Phase classification
|
HER-2 positive
|
Tecentriq (atezolizumab) • sirexatamab (DKN-01)
4ms
DKN-01 plus bevacizumab and chemotherapy as second-line (2L) investigational therapy in advanced microsatellite stable (MSS) colorectal adenocarcinoma (CRC): DeFianCe trial. (ASCO-GI 2024)
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.
Clinical • Metastases
|
KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • DKK1 (dickkopf WNT signaling pathway inhibitor 1)
|
KRAS mutation • NRAS mutation • RAS mutation
|
Avastin (bevacizumab) • 5-fluorouracil • oxaliplatin • irinotecan • leucovorin calcium • sirexatamab (DKN-01)
4ms
A Phase Ib/II Study Of JS015 Combination Therapy in Advanced Solid Tumors (clinicaltrials.gov)
P1/2, N=186, Not yet recruiting, Shanghai Junshi Bioscience Co., Ltd.
New P1/2 trial • Combination therapy • Metastases
|
Avastin (bevacizumab) • gemcitabine • 5-fluorouracil • Loqtorzi (toripalimab-tpzi) • capecitabine • albumin-bound paclitaxel • oxaliplatin • irinotecan • leucovorin calcium
7ms
Enrollment open • Metastases
|
CTNNB1 (Catenin (cadherin-associated protein), beta 1) • AXIN1 (Axin 1) • RSPO2 (R-Spondin 2) • ZNRF3 (Zinc And Ring Finger 3)
|
CTNNB1 mutation
|
Keytruda (pembrolizumab) • sirexatamab (DKN-01)
9ms
Combination therapy of DKK1 inhibition and NKG2D chimeric antigen receptor T cells for the treatment of gastric cancer. (PubMed, Cancer Sci)
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.
Journal • Combination therapy • CAR T-Cell Therapy • IO biomarker
|
DKK1 (dickkopf WNT signaling pathway inhibitor 1) • NKG2D (killer cell lectin like receptor K1)
|
KD-025 CAR T-cells
10ms
DKK1 is a predictive biomarker for response to DKN-01: Results of a phase 2 basket study in women with recurrent endometrial carcinoma. (PubMed, Gynecol Oncol)
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 data • Clinical Trial,Phase II • Journal • IO biomarker • Pan tumor
|
DKK1 (dickkopf WNT signaling pathway inhibitor 1)
|
DKK1 overexpression
|
paclitaxel • sirexatamab (DKN-01)
1year
New P2 trial • Metastases
|
CTNNB1 (Catenin (cadherin-associated protein), beta 1) • AXIN1 (Axin 1) • RSPO2 (R-Spondin 2)
|
CTNNB1 mutation
|
Keytruda (pembrolizumab) • sirexatamab (DKN-01)
1year
DisTinGuish: A Study of DKN-01 in Combination With Tislelizumab ± Chemotherapy in Patients With Gastric or Gastroesophageal Cancer (clinicaltrials.gov)
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
Phase classification • Enrollment change • Trial completion date • Trial primary completion date • Combination therapy • Metastases
|
PD-L1 (Programmed death ligand 1) • DKK1 (dickkopf WNT signaling pathway inhibitor 1)
|
5-fluorouracil • Tevimbra (tislelizumab) • capecitabine • oxaliplatin • leucovorin calcium • sirexatamab (DKN-01)
over1year
Dickkopf-1 drives tumor immune evasion by inducing PD-L1 expression in hepatocellular carcinoma. (PubMed, Biochem Pharmacol)
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.
Journal • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • CD8 (cluster of differentiation 8) • DKK1 (dickkopf WNT signaling pathway inhibitor 1) • CKAP4 (Cytoskeleton Associated Protein 4)
|
PD-L1 expression • DKK1 overexpression
over1year
A new risk model for CSTA, FAM83A, and MYCT1 predicts poor prognosis and is related to immune infiltration in lung squamous cell carcinoma. (PubMed, Am J Transl Res)
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.
Journal
|
DKK4 (Dickkopf WNT Signaling Pathway Inhibitor 4) • MYCT1 (MYC Target 1)
over1year
DKK1 promotes NUAK1 transcriptional expression through the activation Akt in hepatocellular carcinoma. (PubMed, Cell Biol Int)
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.
Journal
|
DKK1 (dickkopf WNT signaling pathway inhibitor 1)
over1year
DKN-01 and tislelizumab as a second-line (2L) investigational therapy in advanced DKK1 high gastroesophageal adenocarcinoma (GEA): DisTinGuish Trial (SITC 2022)
<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.
Clinical • MSi-H Biomarker • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • MSI (Microsatellite instability) • DKK1 (dickkopf WNT signaling pathway inhibitor 1)
|
MSI-H/dMMR
|
Tevimbra (tislelizumab) • sirexatamab (DKN-01)
over1year
miR-1290 contributes to oncogenesis and angiogenesis via targeting of THBS1, DKK3 and, SCAI. (PubMed, Bioimpacts)
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.
Journal
|
DKK3 (Dickkopf WNT Signaling Pathway Inhibitor 3) • MIR1290 (MicroRNA 1290)
over1year
Apogossypolone Inhibits Cell Proliferation and Epithelial-Mesenchymal Transition in Cervical Cancer via Activating DKK3. (PubMed, Front Oncol)
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.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • CDH1 (Cadherin 1) • CASP3 (Caspase 3) • VIM (Vimentin) • CDH2 (Cadherin 2) • DKK3 (Dickkopf WNT Signaling Pathway Inhibitor 3)
|
DKK3 overexpression
|
R-(-)-gossypol (AT 101)
over1year
DKK1 drives immune suppressive phenotypes in intrahepatic cholangiocarcinoma and can be targeted with anti-DKK1 therapeutic DKN-01. (PubMed, Liver Int)
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.
Journal
|
DKK1 (dickkopf WNT signaling pathway inhibitor 1) • FOXP3 (Forkhead Box P3)
|
DKK1 overexpression
|
sirexatamab (DKN-01)
over1year
Molecular networks of hepatoblastoma predisposition and oncogenesis in Beckwith-Wiedemann syndrome. (PubMed, Hepatol Commun)
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.
Journal
|
FBXW7 (F-Box And WD Repeat Domain Containing 7) • DKK1 (dickkopf WNT signaling pathway inhibitor 1) • FOXO3 (Forkhead box O3) • HDAC1 (Histone Deacetylase 1)
over1year
Safety and efficacy of Wnt inhibition with a DKK1 inhibitor, DKN-01, in combination with atezolizumab in patients with advanced oesophagogastric adenocarcinoma: Phase IIa results of the WAKING trial (ESMO 2022)
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.
Clinical • P2a data • Combination therapy • PD(L)-1 Biomarker • IO biomarker
|
DKK1 (dickkopf WNT signaling pathway inhibitor 1)
|
Tecentriq (atezolizumab) • sirexatamab (DKN-01)
over1year
A Parallel Arm Phase 1b/2a Study of DKN-01 as Monotherapy or in Combination With Docetaxel for the Treatment of Advanced Prostate Cancer With Elevated DKK1 (clinicaltrials.gov)
P1b/2a, N=18, Active, not recruiting, NYU Langone Health | Recruiting --> Active, not recruiting | N=97 --> 18 | Trial completion date: Dec 2022 --> Aug 2023
Enrollment closed • Enrollment change • Trial completion date • Combination therapy
|
DKK1 (dickkopf WNT signaling pathway inhibitor 1)
|
docetaxel • sirexatamab (DKN-01)
almost2years
lncRNAs UC.145 and PRKG1-AS1 Determine the Functional Output of DKK1 in Regulating the Wnt Signaling Pathway in Gastric Cancer. (PubMed, Cancers (Basel))
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.
Journal
|
DKK1 (dickkopf WNT signaling pathway inhibitor 1)
almost2years
DOC2B is a Negative Regulator of Wnt/β-catenin Signaling Pathway in Cervical Cancer. (PubMed, Pharmacol Res)
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.
Journal
|
DKK1 (dickkopf WNT signaling pathway inhibitor 1)
almost2years
The Apoptotic Resistance of BRCA1-Deficient Ovarian Cancer Cells is Mediated by cAMP. (PubMed, Front Cell Dev Biol)
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.
Journal • BRCA Biomarker
|
BRCA1 (Breast cancer 1, early onset) • HRD (Homologous Recombination Deficiency) • DKK1 (dickkopf WNT signaling pathway inhibitor 1)
|
BRCA1 mutation
almost2years
DisTinGuish: A Study of DKN-01 in Combination With Tislelizumab ± Chemotherapy in Patients With Gastric or Gastroesophageal Cancer (clinicaltrials.gov)
P2a, N=72, Recruiting, Leap Therapeutics, Inc. | Trial completion date: May 2022 --> Jun 2023 | Trial primary completion date: Dec 2021 --> Dec 2022
Trial completion date • Trial primary completion date • Combination therapy
|
DKK1 (dickkopf WNT signaling pathway inhibitor 1)
|
Tevimbra (tislelizumab) • capecitabine • oxaliplatin • sirexatamab (DKN-01)
almost2years
Cancer stem cell regulated phenotypic plasticity protects metastasized cancer cells from ferroptosis. (PubMed, Nat Commun)
Combined treatment with a ferroptosis inducer and a DKK1 inhibitor exhibits synergistic effects in diminishing metastasis. Hence, this study deciphers the contribution of CSC-regulated phenotypic plasticity in metastatic colonization and provides therapeutic approaches to limit metastatic outgrowth.
Journal
|
DKK1 (dickkopf WNT signaling pathway inhibitor 1) • SLC7A11 (Solute Carrier Family 7 Member 11)
|
SLC7A11 expression
2years
Dormant mammary tumors resist antigen-specific killing and regulate systemic immunity in association with PTN and DKK3 (AACR 2022)
Taken together, these data indicate that dormant tumors can resist antigen-specific killing by CD8 T cells despite high T cell infiltration, and possibly suppress antigen-specific immunity in distant tumor sites. Moreover, both PTN and DKK3 emerge as potential mediators of dormancy-induced immune evasion.
IO biomarker
|
CD8 (cluster of differentiation 8) • CD44 (CD44 Molecule) • DKK3 (Dickkopf WNT Signaling Pathway Inhibitor 3)
2years
A Parallel Arm Phase 1b/2a Study of DKN-01 as Monotherapy or in Combination With Docetaxel for the Treatment of Advanced Prostate Cancer With Elevated DKK1 (clinicaltrials.gov)
P1b/2a, N=97, Recruiting, NYU Langone Health | Trial completion date: Mar 2021 --> Dec 2022 | Trial primary completion date: Mar 2021 --> Dec 2022
Trial completion date • Trial primary completion date • Combination therapy
|
DKK1 (dickkopf WNT signaling pathway inhibitor 1)
|
docetaxel • sirexatamab (DKN-01)
2years
Sequential modulation of the Wnt/β-catenin signaling pathway enhances tumor-intrinsic MHC I expression and tumor clearance. (PubMed, Gynecol Oncol)
Wnt/β-catenin pathway modulation increases MHC I expression and promotes tumor leukocytic infiltration, facilitating a pro-immune TME associated with decreased tumor burden. This intervention overcomes common tumor immune-evasion mechanisms and may render ovarian tumors susceptible to immunotherapy.
Journal • IO biomarker
|
CXCL10 (Chemokine (C-X-C motif) ligand 10) • DKK1 (dickkopf WNT signaling pathway inhibitor 1)
|
sirexatamab (DKN-01) • CGX1321
2years
Dickkopf-1 Inhibition Reactivates Wnt/β-Catenin Signaling in Rhabdomyosarcoma, Induces Myogenic Markers In Vitro and Impairs Tumor Cell Survival In Vivo. (PubMed, Int J Mol Sci)
In addition, WAY-262611 was able to impair survival of tumor cells in vivo. Therefore, DKK-1 could constitute a molecular target, which could lead to novel therapeutic strategies in RMS, especially in those patients with high DKK-1 expression.
Preclinical • Journal
|
DKK1 (dickkopf WNT signaling pathway inhibitor 1)
2years
Combination of Wnt/β-Catenin Targets S100A4 and DKK1 Improves Prognosis of Human Colorectal Cancer. (PubMed, Cancers (Basel))
The newly discovered transcriptional cross-regulation of Wnt target S100A4 and Wnt antagonist DKK1 is predominated by an S100A4-induced Wnt signaling feedback loop, increasing cell motility and metastasis risk. S100A4 and DKK1 combination improves the identification of CRC patients at high risk.
Journal
|
CTNNB1 (Catenin (cadherin-associated protein), beta 1) • DKK1 (dickkopf WNT signaling pathway inhibitor 1) • S100A4 (S100 calcium binding protein A4)
|
DKK1 overexpression
2years
Lactobacillus fermentum ZS09 Mediates Epithelial-Mesenchymal Transition (EMT) by Regulating the Transcriptional Activity of the Wnt/β-Catenin Signalling Pathway to Inhibit Colon Cancer Activity. (PubMed, J Inflamm Res)
The levels of related proteins (β-catenin, N-cadherin, and VEGF) were downregulated, and the levels of p-β-catenin and E-cadherin were upregulated. The results indicate that L. fermentum ZS09 could inhibit EMT and angiogenesis pathways by inhibiting the Wnt/β-catenin signalling pathway, which could inhibit tumour metastasis.
Journal
|
MYC (V-myc avian myelocytomatosis viral oncogene homolog) • CCND1 (Cyclin D1) • KDR (Kinase insert domain receptor) • TNFA (Tumor Necrosis Factor-Alpha) • CDH1 (Cadherin 1) • DKK1 (dickkopf WNT signaling pathway inhibitor 1) • IL6R (Interleukin 6 receptor) • MMP9 (Matrix metallopeptidase 9) • AXIN1 (Axin 1)
|
CCND1 expression • KDR expression • CDH1 expression
2years
NK4 Regulates Laryngeal Squamous Cell Carcinoma Cell Properties and Inhibits Tumorigenicity by Modulating the DKK1/Wnt/β-Catenin Axis. (PubMed, Front Oncol)
NK4 gene inhibit cell proliferation and migration, while promote cell apoptosis, and induce cell cycle arrest in S phase of laryngeal carcinoma AMC-HN-8 cells. NK4 overexpression inhibit the tumorigenesis ability of AMC-HN-8 cells, which may be related to the regulation of DKK1/Wnt1/β-Catenin signal axis.
Journal
|
CTNNB1 (Catenin (cadherin-associated protein), beta 1) • DKK1 (dickkopf WNT signaling pathway inhibitor 1)
2years
Journal
|
DKK1 (dickkopf WNT signaling pathway inhibitor 1)
over2years
RYR2 mutation in non-small cell lung cancer prolongs survival via down-regulation of DKK1 and up-regulation of GS1-115G20.1: A weighted gene Co-expression network analysis and risk prognostic models. (PubMed, IET Syst Biol)
Several target miRNAs interacting with GS1-115G20.1 were observed to show the relationship with the phenotype, treatment, and survival of NSCLC. NSCLC patients with RYR2 mutation may obtain better prognosis by down-regulating DKK1 and up-regulating GS1-115G20.1.
Journal
|
TP53 (Tumor protein P53) • mTOR (Mechanistic target of rapamycin kinase) • DKK1 (dickkopf WNT signaling pathway inhibitor 1)
|
TP53 expression • VEGFA expression
over2years
Derivation of a Novel CIHI in Patients with Lung Adenocarcinoma for Estimating Tumor Microenvironment and Clinical Prognosis. (PubMed, Dis Markers)
We also discussed the evaluation value in the immune microenvironment and clinical application of CIHI. In conclusion, this study developed and validated a hypoxia-immune formula that can guide hypoxia modifier treatment and immunotherapy in LUAD.
Clinical • Journal • IO biomarker
|
LDHA (Lactate dehydrogenase A) • BTK (Bruton Tyrosine Kinase) • DKK1 (dickkopf WNT signaling pathway inhibitor 1) • VEGFC (Vascular Endothelial Growth Factor C) • GAPDH (Glyceraldehyde-3-Phosphate Dehydrogenase)