2. Academic Validation
  3. Preclinical efficacy of CBR-5884 against epithelial ovarian cancer cells by targeting the serine synthesis pathway

Preclinical efficacy of CBR-5884 against epithelial ovarian cancer cells by targeting the serine synthesis pathway

  • Discov Oncol. 2024 May 11;15(1):154. doi: 10.1007/s12672-024-01013-0.
Kunxiang Gong # 1 2,  Yinger Huang # 3,  Yanqin Zheng 2,  Yinfu Zhu 4,  Wenbo Hao 5,  Kun Shi 6 7
Affiliations

Affiliations

  • 1 Institute of Reproductive Health and Perinatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China.
  • 2 Department of Gynecology and Obstetrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China.
  • 3 School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China.
  • 4 Institute of Antibody Engineering, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, Guangdong, China.
  • 5 Institute of Antibody Engineering, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, Guangdong, China. haowa@126.com.
  • 6 Institute of Reproductive Health and Perinatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China. shikun28@hotmail.com.
  • 7 Department of Gynecology and Obstetrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China. shikun28@hotmail.com.
  • # Contributed equally.
PMID: 38733440 DOI: 10.1007/s12672-024-01013-0
Abstract

Reprogramming of the serine synthesis pathway (SSP) is intricately linked to the progression of epithelial ovarian Cancer (EOC). CBR-5884, a selective small-molecule inhibitor targeting phosphoglycerate dehydrogenase (PHGDH), effectively impedes the de novo synthesis of serine within Cancer cells. This study aimed to evaluate the inhibitory effect of CBR-5884 on EOC cells and delineate its specific mechanism, thereby proposing a novel therapeutic approach for treating EOC. The suppression of serine biosynthesis after CBR-5884 treatment was evaluated using RNA sequencing and a serine assay kit, and the results showed that CBR-5884 effectively downregulated serine biosynthesis in EOC cells, particularly those expressing high levels of PHGDH. In vitro studies revealed that CBR-5884 demonstrated significant antitumor effects and suppressed migration and invasion of EOC cells through down-regulation of the Integrin subunit beta 4 (ITGB4)/extracellular signal-regulated kinase (ERK)/epithelial-mesenchymal transition signal axis. Additionally, CBR-5884 mitigated the stemness of EOC cells and heightened their sensitivity to chemotherapy. Moreover, in vivo studies revealed that CBR-5884 significantly delayed tumor growth, with histological analysis indicating the safety profile of CBR-5884. Finally, the patient-derived organoid (PDO) models were utilized to explore the preclinical efficacy of CBR-5884 against EOC cells, and the results unveiled that CBR-5884 impeded proliferation and downregulated the expression of ITGB4 in EOC PDO models. Our findings supports the Anticancer properties of CBR-5884 in EOC cells exhibiting high PHGDH expression, manifesting through the suppression of proliferation, migration, and invasion, while enhancing chemotherapy sensitivity, suggesting that CBR-5884 holds promise as an efficacious strategy for the treatment of EOC.

Keywords

CBR-5884; Epithelial ovarian cancer; PHGDH; Patient-derived organoid model; Serine biosynthesis.

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