DKK1 is a predictive biomarker for response to DKN-01: Results of a phase 2 basket study in women with recurrent endometrial carcinoma

Arend, Rebecca C.; Dholakia, Jhalak; Castro, C. de; Matulonis, Ursula A.; Hamilton, Erika; Jackson, Camille Gunderson; LyBarger, Kristopher; Goodman, Howard M.; Duska, Linda R.; Mahdi, Haider; ElNaggar, Adam C.; Kagey, Michael H.; Liu, Amy; Piper, Diane; Barroilhet, Lisa; Bradley, William E.; Sachdev, Jasgit C.; Sirard, Cynthia A.; O’Malley, David M.; Birrer, Michael J.

doi:10.1016/j.ygyno.2023.03.013

Cited by 11 publications

(5 citation statements)

References 40 publications

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“…45 46 Another mAb, DKN-01, produced promising results in phase II study. [47][48][49] DKN-01 is an anti-DKK1 mAb that has demonstrated antitumor activity in patients with advanced gastroesophageal adenocarcinoma with low tumor programmed death-ligand 1 (PD-L1) expression, a subset of patients with limited therapeutic options. DKN-01 has immunomodulatory activity, stimulates a pro-inflammatory tumor microenvironment, and upregulates PD-L1 expression.…”

Section: Discussionmentioning

confidence: 99%

Development of therapeutic monoclonal antibodies against DKK1 peptide-HLA-A2 complex to treat human cancers

Qian,

Wang,

Xiao

et al. 2024

J Immunother Cancer

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BackgroundTargeted immunotherapy with monoclonal antibodies (mAbs) is an effective and safe method for the treatment of malignancies. Development of mAbs with improved cytotoxicity, targeting new and known tumor-associated antigens, therefore continues to be an active research area. We reported that Dickkopf-1 (DKK1) is a good target for immunotherapy of human cancers based on its wide expression in different cancers but not in normal tissues. As DKK1 is a secreted protein, mAbs binding directly to DKK1 have limited effects on cancer cells in vivo.MethodsThe specificity and antibody-binding capacity of DKK1-A2 mAbs were determined using indirect ELISA, confocal imaging, QIFIKIT antibody-binding capacity and cell surface binding assays. The affinity of mAbs was determined using a surface plasmon resonance biosensor. A flow cytometry-based cell death was performed to detect tumor cell apoptosis. Antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) assays were used to evaluate the ability of DKK1-A2 mAbs to mediate ADCC and CDC activities against tumor cells in vitro. Flow cytometry data were collected with an FACSymphony A3 cell analyzer and analyzed with FlowJo V.10.1 software. Human cancer xenograft mouse models were used to determine the in vivo therapeutic efficacy and the potential safety and toxicity of DKK1-A2 mAbs. In situ TUNEL assay was performed to detect apoptosis in tumors and mouse organs.ResultsWe generated novel DKK1-A2 mAbs that recognize the DKK1 P20 peptide presented by human HLA-A*0201 (HLA-A2) molecules (DKK1-A2 complexes) that are naturally expressed by HLA-A2+DKK1+cancer cells. These mAbs directly induced apoptosis in HLA-A2+DKK1+hematologic and solid cancer cells by activating the caspase-9 cascade, effectively lysed the cancer cells in vitro by mediating CDC and ADCC and were therapeutic against established cancers in their xenograft mouse models. As DKK1 is not detected in most human tissues, DKK1-A2 mAbs neither bound to or killed HLA-A2+blood cells in vitro nor caused tissue damage in tumor-free or tumor-bearing HLA-A2-transgenic mice.ConclusionOur study suggests that DKK1-A2 mAbs may be a promising therapeutic agent to treat human cancers.

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Section: Discussionmentioning

confidence: 99%

Development of therapeutic monoclonal antibodies against DKK1 peptide-HLA-A2 complex to treat human cancers

Qian,

Wang,

Xiao

et al. 2024

J Immunother Cancer

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“…The NCT02013154 study documented by the U.S. National Library of Medicine (NLM) has verified the safety and clinical utility of DKN‐01 (a novel DKK1‐neutralizing antibody) combined with pembrolizumab in patients with advanced esophagogastric cancers 14 . The clinical trial of NCT03395080 has been completed and confirmed the promising clinical activity of DKN‐01 in endometrial carcinoma patients with high tumoral DKK1 expression 15 . Besides, the clinical trial of NCT01457417 displaying treatment effect of DKN‐01 on multiple myeloma and non‐small‐cell lung cancer has also been completed as indicated by the NLM records on the official website of http://clinicaltrials.gov 16 .…”

Section: Introductionmentioning

confidence: 86%

“…14 The clinical trial of NCT03395080 has been completed and confirmed the promising clinical activity of DKN-01 in endometrial carcinoma patients with high tumoral DKK1 expression. 15 Besides, the clinical trial of NCT01457417 displaying treatment effect of DKN-01 on multiple myeloma and non-small-cell lung cancer has also been completed as indicated by the NLM records on the official website of Clini calTr ials.gov. 16 Additionally, DKK1 also regulates lipid metabolism.…”

Section: Introductionmentioning

confidence: 99%

Dickkopf‐1 promotes vascular smooth muscle cell foam cell formation and atherosclerosis development through CYP4A11/SREBP2/ABCA1

Li,

Zheng,

Zhang

et al. 2023

The FASEB Journal

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Vascular smooth muscle cells (VSMCs) are considered to be a crucial source of foam cells in atherosclerosis due to their low expression level of cholesterol exporter ATP‐binding cassette transporter A1 (ABCA1) intrinsically. While the definite regulatory mechanisms are complicated and have not yet been fully elucidated, we previously reported that Dickkopf‐1 (DKK1) mediates endothelial cell (EC) dysfunction, thereby aggravating atherosclerosis. However, the role of smooth muscle cell (SMC) DKK1 in atherosclerosis and foam cell formation remains unknown. In this study, we established SMC‐specific DKK1‐knockout (DKK1SMKO) mice by crossbreeding DKK1flox/flox mice with TAGLN‐Cre mice. Then, DKK1SMKO mice were crossed with APOE−/− mice to generate DKK1SMKO/APOE−/− mice, which exhibited milder atherosclerotic burden and fewer SMC foam cells. In vitro loss‐ and gain‐of‐function studies of DKK1 in primary human aortic smooth muscle cells (HASMCs) have proven that DKK1 prevented oxidized lipid‐induced ABCA1 upregulation and cholesterol efflux and promoted SMC foam cell formation. Mechanistically, RNA‐sequencing (RNA‐seq) analysis of HASMCs as well as chromatin immunoprecipitation (ChIP) experiments showed that DKK1 mediates the binding of transcription factor CCAAT/enhancer‐binding protein delta (C/EBPδ) to the promoter of cytochrome P450 epoxygenase 4A11 (CYP4A11) to regulate its expression. In addition, CYP4A11 as well as its metabolite 20‐HETE‐promoted activation of transcription factor sterol regulatory element‐binding protein 2 (SREBP2) mediated the DKK1 regulation of ABCA1 in SMC. Furthermore, HET0016, the antagonist of CYP4A11, has also shown an alleviating effect on atherosclerosis. In conclusion, our results demonstrate that DKK1 promotes SMC foam cell formation during atherosclerosis via a reduction in CYP4A11‐20‐HETE/SREBP2‐mediated ABCA1 expression.

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“… 213 The feasibility and efficacy of DKN-01 is also demonstrated in several other tumors. 214 , 215 In a phase I study, 47 BTC patients receive DKN-01 plus GemCis. This therapy is well tolerated by participants and is consistent with the toxicity profile of GemCis.…”

Section: Ici Combination Trialsmentioning

confidence: 99%

Focusing on the Immune Cells: Recent Advances in Immunotherapy for Biliary Tract Cancer

Ni,

Xu,

et al. 2024

CMAR

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Biliary tract cancer (BTC) represents a challenging malignancy characterized by aggressive behavior, high relapse rates, and poor prognosis. In recent years, immunotherapy has revolutionized the treatment landscape for various cancers, but its efficacy in BTC remains limited. This article provides a comprehensive overview of the advances in preclinical and clinical studies of immunotherapy for BTC. We explore the potential of immune checkpoint inhibitors in reshaping the management of BTC. Despite disappointing results thus far, ongoing clinical trials are investigating the combination of immunotherapy with other treatment modalities. Furthermore, research on the tumor microenvironment has unveiled novel targets for immunotherapeutic interventions. By understanding the current state of immunotherapy in BTC and highlighting future directions, this article aims to fuel further exploration and ultimately improve patient outcomes in this challenging disease.

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DKK1 is a predictive biomarker for response to DKN-01: Results of a phase 2 basket study in women with recurrent endometrial carcinoma

Cited by 11 publications

References 40 publications

Development of therapeutic monoclonal antibodies against DKK1 peptide-HLA-A2 complex to treat human cancers

Development of therapeutic monoclonal antibodies against DKK1 peptide-HLA-A2 complex to treat human cancers

Dickkopf‐1 promotes vascular smooth muscle cell foam cell formation and atherosclerosis development through CYP4A11/SREBP2/ABCA1

Focusing on the Immune Cells: Recent Advances in Immunotherapy for Biliary Tract Cancer

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