University of Alabama at Birmingham, Birmingham, AL, USA.
University of Alabama at Birmingham, Birmingham, AL, USA.
Gynecol Oncol. 2023 May;172:82-91. doi: 10.1016/j.ygyno.2023.03.013. Epub 2023 Mar 29.
Dickkopf-1 (DKK1) is a Wnt signaling modulator promoting tumor growth, metastasis, angiogenesis, and immunosuppression by regulating innate immunity. DKK1 is over-expressed in gynecologic cancers and is associated with shortened survival. DKN-01 is a humanized monoclonal antibody with DKK1 neutralizing activity that may provide clinical benefit to patients whose tumors have overexpression of DKK1 or Wnt genetic alterations.
We conducted an open-label, Phase 2 basket study with 2-stage design in patients with endometrial carcinoma (EC) and platinum-resistant/refractory epithelial ovarian cancer. DKN-01 was administered either as monotherapy or in combination with weekly paclitaxel at investigator's discretion. All patients underwent NGS testing prior to enrollment; tumor tissue was also tested for DKK1 expression by RNAscope pre-treatment and after cycle 1 if available. At least 50% of patients were required to have a Wnt signaling alteration either directly or tangentially. This publication reports results from the EC population overall and by DKK1-expression.
DKN-01 monotherapy and in combination with paclitaxel was more effective in patients with high DKK1-expressing tumors compared to low-expressing tumors. DKN-01 monotherapy demonstrated an objective response rate [ORR] of 25.0% vs. 0%; disease control rate [DCR] of 62.5% vs. 6.7%; median progression-free survival [PFS] was 4.3 vs. 1.8 months, and overall survival [OS] was 11.0 vs. 8.2 months in DKK1-high vs DKK1-low patients. Similarly, DKN-01 in combination with paclitaxel demonstrated greater clinical activity in patients with DKK1-high tumors compared to DKK1-low tumors: DCR was 55% vs. 44%; median PFS was 5.4 vs. 1.8 months; and OS was 19.1 vs. 10.1 months. Wnt activating mutations correlated with higher DKK1 expression. DKN-01 was well tolerated as a monotherapy and in combination with paclitaxel.
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.
Dickkopf-1（DKK1）是一种 Wnt 信号调节剂，通过调节先天免疫促进肿瘤生长、转移、血管生成和免疫抑制。DKK1 在妇科癌症中过度表达，并与生存时间缩短有关。DKN-01 是一种具有 DKK1 中和活性的人源化单克隆抗体，可能为肿瘤过度表达 DKK1 或 Wnt 遗传改变的患者提供临床获益。
我们进行了一项开放标签、2 期篮式研究，入组患者为子宫内膜癌（EC）和铂耐药/难治性上皮性卵巢癌患者。DKN-01 可作为单药或联合每周紫杉醇使用，具体由研究者决定。所有患者在入组前均接受 NGS 检测；如果有条件，在第 1 周期后也通过 RNAscope 检测肿瘤组织中 DKK1 的表达。至少 50%的患者需要直接或间接存在 Wnt 信号改变。本出版物报告了 EC 人群的总体结果和 DKK1 表达结果。
与低表达肿瘤相比，高 DKK1 表达肿瘤患者接受 DKN-01 单药或联合紫杉醇治疗更有效。DKN-01 单药治疗的客观缓解率（ORR）为 25.0% vs. 0%；疾病控制率（DCR）为 62.5% vs. 6.7%；中位无进展生存期（PFS）为 4.3 个月 vs. 1.8 个月，总生存期（OS）为 11.0 个月 vs. 8.2 个月，高 DKK1 组 vs. 低 DKK1 组。同样，与低 DKK1 组相比，高 DKK1 肿瘤患者接受 DKN-01 联合紫杉醇治疗的临床获益更大：DCR 为 55% vs. 44%；中位 PFS 为 5.4 个月 vs. 1.8 个月；OS 为 19.1 个月 vs. 10.1 个月。Wnt 激活突变与更高的 DKK1 表达相关。DKN-01 单药和联合紫杉醇治疗均具有良好的耐受性。
总之，数据表明，在高 tumoral DKK1 表达的 EC 患者中，一种耐受性良好的药物 DKN-01 具有有前景的临床活性，这通常与 Wnt 激活突变的存在相关。未来的研究将侧重于在 DKK1 高 EC 患者中使用 DKN-01 联合免疫治疗。
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