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Endometrial cancer
2022-RA-1315-ESGO Anti-LSR monoclonal antibody exerts an antitumor activity associated with apoptosis in endometrial cancer
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  1. Yoshikazu Nagase1,2,
  2. Kosuke Hiramatsu2,
  3. Mamoru Kakuda2,
  4. Satoshi Nakagawa2,
  5. Eiji Kobayashi2,
  6. Toshihiro Kimura2,
  7. Satoshi Serada3,
  8. Yutaka Ueda2,
  9. Tetsuji Naka3 and
  10. Tadashi Kimura2
  1. 1Department of Obstetrics and Gynecology, Kaizuka City Hospital, Kaizuka, Osaka, Japan
  2. 2Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
  3. 3Institute for Biomedical Sciences Molecular Pathophysiology, Iwate Medical University, Iwate, Japan

Abstract

Introduction/Background Advanced endometrial cancer (EC) remains a disease with a poor prognosis. Since the efficacy of current chemotherapy is limited, new therapeutic agents are need to be investigated. We focused on lipolysis-stimulated lipoprotein receptor (LSR), a membrane protein highly expressed in EC cells, and developed a novel chimeric chicken-mouse anti-LSR monoclonal antibody (mAb). The aim of this study was to investigate the function of LSR and the antitumor activity of anti-LSR mAb in EC.

Methodology The relationship between LSR expression level and clinical outcomes was investigated using immunohistochemistry in 230 clinical samples of EC. To clarify the function of LSR, we conducted in vitro assays using LSR-knockdown EC cell lines (HEC1 and HEC116) generated by transfected with siRNA. We investigated the antitumor activity of anti-LSR mAb in EC cell xenograft mouse model.

Results Patients were divided into two groups based on LSR expression level; High-LSR (n=153) and Low-LSR (n=75) groups. The 5-year overall survival rate in High-LSR group was significantly lower than that in Low-LSR group (hazard ratio: 3.53, 95% confidence interval: 1.35–9.24, p=0.01). In addition, High-LSR expression was associated with deep myometrial invasion and distant metastasis in EC (p < 0.05, respectively). In vitro analysis demonstrated that LSR-knockdown suppressed the activation of MEK/ERK signaling and subsequent matrix metalloproteinases (MT1-MMP and MMP2), which downregulated cell proliferation, invasion, and migration. Our anti-LSR mAb significantly inhibited the tumor growth in EC cell xenograft mouse model (p = 0.019). Anti-LSR mAb suppressed the activation of ERK1/2 and increased the expression of cleaved caspase-3 in vivo. Moreover, anti-LSR mAb also suppressed the activation of MEK/ERK signaling in vitro.

Conclusion LSR is associated with tumor growth, invasion, metastasis, and poor prognosis through MAPK signaling in EC. Anti-LSR mAb is a potential therapeutic agent which induces apoptosis and shows a significant antitumor effect in EC.

https://doi.org/10.1136/ijgc-2022-ESGO.305

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