1384P DKN-01 in combination with tislelizumab and chemotherapy as a first-line therapy in unselected patients with advanced gastroesophageal adenocarcinoma (GEA): DisTinGuish trial

Klempner, Samuel J.; Sirard, Cynthia A.; Chao, Jung; Chiu, Vi K.; Mahalingam, Devalingam; Uronis, Hope E.; Kagey, Michael H.; Baum, Joanna; Dayyani, Farshid; Song, Jin Ho; Wang, J.; Iqbal, Sameer; Tejani, Mohamed; Sonbol, Mohamad Bassam; Scott, Aaron J.; Wainberg, Zev A.; Ajani, Jaffer A.

doi:10.1016/j.annonc.2021.08.1493

Cited by 5 publications

(4 citation statements)

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“…Whether or not ongoing approaches directed at IL2, Toll-like receptors 7 and 8, CCL2/CCR2, and Wnt and MDSC modulation (DKN-01) will help to recapitulate a more favorable TME seen in our data remains to be seen. Interestingly, in a small phase II trial, the addition of DKN-01 to 5-FU/oxaliplatin and PD-1 blockade appeared to enhance activity in both PD-L1–negative and particularly DKK1-high gastroesophageal adenocarcinomas perhaps reflecting modulation of unfavorable TME features ( 56 ). Ongoing studies earlier in the disease paradigm (nonmetastatic patients) when tumor–immune interactions are earlier in evolution will also be important orthogonal data.…”

Section: Discussionmentioning

confidence: 99%

Early Tumor–Immune Microenvironmental Remodeling and Response to First-Line Fluoropyrimidine and Platinum Chemotherapy in Advanced Gastric Cancer

Kim

Lee

et al. 2021

Cancer Discovery

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Chemotherapy is ubiquitous in first-line treatment of advanced gastric cancer, yet responses are heterogeneous, and little is known about mediators of chemotherapy response. To move forward, an understanding of the effects of standard chemotherapy on the tumor–immune microenvironment (TME) is needed. Coupling whole-exome sequencing, bulk RNA and single-cell transcriptomics from paired pretreatment and on-treatment samples in treatment-naïve patients with HER2-positive and HER2-negative gastric cancer, we define features associated with response to platinum-based chemotherapy. Response was associated with on-treatment TME remodeling including natural killer (NK) cell recruitment, decreased tumor-associated macrophages, M1-macrophage repolarization, and increased effector T-cell infiltration. Among chemotherapy nonresponders, we observed low/absent PD-L1 expression or modulation, on-treatment increases in Wnt signaling, B-cell infiltration, and LAG3-expressing T cells coupled to an exodus of dendritic cells. We did not observe significant genomic changes in early on-treatment sampling. We provide a map of on-treatment TME modulation with standard chemotherapy and nominate candidate future approaches. Significance: Using paired pretreatment and on-treatment samples during standard first-line chemotherapy, we identify chemotherapy-induced NK-cell infiltration, macrophage repolarization, and increased antigen presentation among responders. Increased LAG3 expression and decreased dendritic cell abundance were seen in nonresponders, emphasizing remodeling of the TME during chemotherapy response and resistance. This article is highlighted in the In This Issue feature, p. 873

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Section: Discussionmentioning

confidence: 99%

Early Tumor–Immune Microenvironmental Remodeling and Response to First-Line Fluoropyrimidine and Platinum Chemotherapy in Advanced Gastric Cancer

Kim

Lee

et al. 2021

Cancer Discovery

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“…Clinical trials have been conducted combining DKN‐01, an antibody to DKK1, with tislelizumab and chemotherapy as first‐line treatments for patients with GC and gastroesophageal junction cancer, with a preliminary objective response rate (ORR) of 68% and disease control rate of 100%. In particular, patients with high DKK1 expression achieved an ORR of 100% 42 . However, the efficacy of anti‐DKK1 treatment in AFPGC requires further validation.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, patients with high DKK1 expression achieved an ORR of 100%. 42 However, the efficacy of anti‐DKK1 treatment in AFPGC requires further validation. In conclusion, we analyzed and characterized the molecular characteristics of AFPGC at the single‐cell level.…”

Section: Discussionmentioning

confidence: 99%

Single‐cell characteristics and malignancy regulation of alpha‐fetoprotein‐producing gastric cancer

Mei

Wen

et al. 2023

Cancer Medicine

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Alpha-fetoprotein-producing gastric cancer (AFPGC) is a rare but highly malignant subtype of gastric cancer (GC) characterized by elevated serum alpha-fetoprotein (AFP) levels (>20 ng/mL). AFPGC accounts for 1.3%-15% of all GCs. 1 Patients with AFPGC have an aggressive clinical course, early occurrence of multiple organ metastases, primary multidrug resistance, and a poor prognosis. The 5-year survival rate of patients with stage IV AFPGC is 4.4%. 2 The pathogenesis of AFPGC is still not fully understood and effective therapeutic targets are lacking.In recent years, whole-exome sequencing (WES) has been used to study the genetic mutation profiles of AFPGC. In our previous study, we performed whole-exome sequencing of 29 cases of AFP-producing gastrointestinal cancer (AFPGI),

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“…Another humanized DKK1-neutralizing antibody, DKN-01, demonstrated tolerability and clinical activity in phase I studies with advanced biliary cancer, non-small cell lung cancer, esophageal cancer, and gastroesophageal junction tumors [32][33][34]. In a phase II study, DKN-01 combined with tislelizumab and chemotherapy improved overall survival in advanced gastroesophageal adenocarcinoma patients [35]. Furthermore, anti-CKAP4 monoclonal antibodies effectively blocked the DKK1/CKAP4 interaction, reducing AKT activation, pancreatic cancer cell proliferation, and tumor growth in mouse models [36].…”

Section: Introductionmentioning

confidence: 99%

DKK1 as a chemoresistant protein modulates oxaliplatin responses in colorectal cancer

Shen,

Hsieh,

et al. 2024

Preprint

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Oxaliplatin is effective against colorectal cancer (CRC), but resistance hampers treatment. We found upregulated Dickkopf-1 (DKK1, a secreted protein) in oxaliplatin-resistant (OR) CRC cell lines and DKK1 levels increased by more than 2-fold in approximately 50% of oxaliplatin-resistant CRC tumors. DKK1 activates AKT via cytoskeleton-associated protein 4 (CKAP4, a DKK1 receptor), modulating oxaliplatin responses in vitro and in vivo. The leucine zipper (LZ) domain of CKAP4 and cysteine-rich domain 1 (CRD1) of secreted DKK1 are crucial for their interaction and AKT signaling. By utilizing the LZ protein, we disrupted DKK1 signaling, enhancing oxaliplatin sensitivity in OR CRC cells and xenograft tumors. This suggests that DKK1 as a chemoresistant factor in CRC via AKT activation. Targeting DKK1 with the LZ protein offers a promising therapeutic strategy for oxaliplatin-resistant CRC with high DKK1 levels. This study sheds light on oxaliplatin resistance mechanisms and proposes an innovative intervention for managing this challenge.

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1384P DKN-01 in combination with tislelizumab and chemotherapy as a first-line therapy in unselected patients with advanced gastroesophageal adenocarcinoma (GEA): DisTinGuish trial

Cited by 5 publications

References 0 publications

Early Tumor–Immune Microenvironmental Remodeling and Response to First-Line Fluoropyrimidine and Platinum Chemotherapy in Advanced Gastric Cancer

Early Tumor–Immune Microenvironmental Remodeling and Response to First-Line Fluoropyrimidine and Platinum Chemotherapy in Advanced Gastric Cancer

Single‐cell characteristics and malignancy regulation of alpha‐fetoprotein‐producing gastric cancer

DKK1 as a chemoresistant protein modulates oxaliplatin responses in colorectal cancer

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