Delta-like 1 homolog (DLK1) as a possible therapeutic target and its application to radioimmunotherapy using 125I-labelled anti-DLK1 antibody in lung cancer models (HOT1801 and FIGHT004)

Hironori Takagi, Songji Zhao, Satoshi Muto, Hiroshi Yokouchi, Hiroshi Nishihara, Toshiyuki Harada, Hikaru Yamaguchi, Hayato Mine, Masayuki Watanabe, Yuki Ozaki, Takuya Inoue, Takumi Yamaura, Mitsuro Fukuhara, Naoyuki Okabe, Yuki Matsumura, Takeo Hasegawa, Jun Osugi, Mika Hoshino, Mitsunori Higuchi, Yutaka ShioRyuzo Kanno, Miho Aoki, Chengbo Tan, Saki Shimoyama, Shigeo Yamazaki, Hajime Kikuchi, Jun Sakakibara-Konishi, Satoshi Oizumi, Masao Harada, Kenji Akie, Fumiko Sugaya, Yuka Fujita, Kei Takamura, Tetsuya Kojima, Osamu Honjo, Yoshinori Minami, Masaharu Nishimura, Hirotoshi Dosaka-Akita, Koji Nakamura, Akihiro Inano, Hiroshi Isobe, Hiroyuki Suzuki

Research output: Contribution to journalArticlepeer-review

Abstract

Objectives: Delta-like 1 homolog (DLK1) is a non-canonical Notch ligand known to be expressed in several cancers but whose role in lung cancer is not yet fully understood. We sought to confirm DLK1 expression in small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), and to examine DLK1's clinical significance. Furthermore, we examined the possible utility of DLK1 as a novel target in radioimmunotherapy (RIT). Methods: We retrospectively assessed the correlation between clinical features and DLK1 expression by immunohistochemistry in resected specimens from 112 patients with SCLC and 101 patients with NSCLC. Moreover, we performed cell and animal experiments, and examined the possibility of RIT targeting DLK1 in SCLC using iodine-125 (125I) -labeled anti-DLK1 antibody, knowing that 125I can be replaced with the alpha-particle-emitter astatine-211 (211At). Results: In SCLC and NSCLC, 20.5 % (23/112) and 16.8 % (17/101) of patients (respectively) had DLK1-positive tumors. In NSCLC, DLK1 expression was associated with recurrence-free survival (P < 0.01) but not with overall survival. In SCLC, there was no association between DLK1 expression and survival. In addition, 125I-labeled anti-DLK1 antibody specifically targeted DLK1 on human SCLC tumor cell lines. Furthermore, 125I-labeled anti-DLK1 antibody was incorporated into tumor tissue in a mouse model. Conclusion: A proportion of SCLC and NSCLC exhibits DLK1 expression. As a clinical feature, DLK1 expression could be a promising prognostic factor for recurrence in patients with resected NSCLC. In addition, DLK1 could serve as a new therapeutic target, including RIT, as suggested by our pilot study using a radiolabeled anti-DLK1 antibody in SCLC.

Original languageEnglish
Pages (from-to)134-142
Number of pages9
JournalLung Cancer
Volume153
DOIs
Publication statusPublished - 2021 Mar

Keywords

  • Astatine
  • DLK1
  • Lung cancer
  • Notch ligand
  • Radioimmunotherapy

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

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