Abstract 4410: LSR promotes ovarian cancer cell growth following the activation of β-oxidation and its antibody inhibits lipid catabolism
Authors: Hiramatsu Kosuke , Serada Satoshi , Enomoto Takayuki , Yokoyama Takuhei , Takahashi Yusuke , Fujimoto Minoru , Yoshino Kiyoshi , Kimura Tadashi , Naka Tetsuji 
Published: July 2017

Ovarian cancer is the most lethal gynecologic malignancy; thus developing new treatment options is urgently required. Molecular targeted therapies for cancers, which are generally more tolerable than widely used cytotoxic agents, have shown highly specific inhibition of target molecules. In this study, we aimed to identify a new ovarian cancer antigen and to develop a novel monoclonal antibody (mAb). Furthermore we evaluated its preclinical efficacy and analyzed the function of its antigen in ovarian cancer.To identify a new ovarian cancer antigen, cell surface membrane proteins of normal ovarian epithelial and ovarian cancer cell lines were analyzed by iTRAQ-based proteomic technology. We identified lipolysis-stimulated lipoprotein receptor (LSR) as the new therapeutic target for ovarian cancer. By the immunohistochemical analysis, significant poor prognosis was observed in high-LSR expression patients with ovarian cancer compared to patients with low-LSR expression by survival assay (p &lt; 0.05). Our newly developed anti-LSR mAb showed significant inhibition of tumor growth in vivo against xenograft model of LSR-positive ovarian cancer cell line and patient derived LSR-positive ovarian cancer tissue (p &lt; 0.05). In LSR-positive ovarian cancer cells, high number and large lipid droplets were observed compared to LSR-negative cells and anti-LSR mAb decreased these droplets. Moreover addition of VLDL to LSR-positive ovarian cancer cells significantly promoted the cell proliferation (p &lt; 0.05) and anti-LSR mAb inhibited that in vitro (p &lt; 0.05). Supporting these data, addition of VLDL to LSR-positive ovarian cancer cells significantly promoted β-oxidation-mediated lipid catabolism (p &lt; 0.05) and anti-LSR mAb also inhibited that (p &lt; 0.05). In addition, this anti-LSR mAb which cross-reacted with mouse LSR did not show any cytotoxicity on normal organs and lipid metabolism in mice. In summary, high expression of LSR in ovarian cancer was the poor prognostic factor. Our newly developed anti-LSR mAb showed significant tumor growth inhibition against not only LSR-positive ovarian cancer cell line but also patient derived LSR-positive ovarian cancer tissue. In LSR-positive ovarian cancer cells, high number and large lipid droplets were observed and LSR promoted cell proliferation following β-oxidation-mediated lipid catabolism. Anti-LSR mAb inhibited these processes. Our preclinical data demonstrated that targeting LSR by mAb is a promising therapy for patients with LSR-positive ovarian cancer.

Citation Format: Kosuke Hiramatsu, Satoshi Serada, Takayuki Enomoto, Takuhei Yokoyama, Yusuke Takahashi, Minoru Fujimoto, Kiyoshi Yoshino, Tadashi Kimura, Tetsuji Naka. LSR promotes ovarian cancer cell growth following the activation of β-oxidation and its antibody inhibits lipid catabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4410. doi:10.1158/1538-7445.AM2017-4410