2. Academic Validation
  3. Effect of the mRNA decapping enzyme scavenger (DCPS) inhibitor RG3039 on glioblastoma

Effect of the mRNA decapping enzyme scavenger (DCPS) inhibitor RG3039 on glioblastoma

  • J Transl Med. 2024 Sep 30;22(1):880. doi: 10.1186/s12967-024-05658-x.
Hao Duan # 1,  Yuan Xie # 1,  Suwen Wu # 2,  Guangyin Zhao # 3,  Zhen Zeng 4,  Hongrong Hu 1,  Yanjiao Yu 1,  Wanming Hu 5,  Yuanzhong Yang 5,  Yukun Chen 6,  Haoqun Xie 1,  Zexin Chen 7,  Gao Zhang 8,  Keith T Flaherty 9,  Shanshan Hu 10,  Haineng Xu 11,  Wenjuan Ma 12,  Yonggao Mou 13
Affiliations

Affiliations

  • 1 Department of Neurosurgery/Neuro-Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 2 Department of Thoracic Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 3 Experimental Animal Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 4 Department of Thoracic Surgery, Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 5 Department of Pathology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 6 Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 7 Guangdong Research Center of Organoid Engineering and Technology, Guangzhou, China.
  • 8 Faculty of Dentistry, University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
  • 9 Department of Medicine, Massachusetts General Hospital, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • 10 Department of Statistics, Rutgers University, New Brunswick, NJ, USA.
  • 11 Ovarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. haineng@pennmedicine.UPenn.edu.
  • 12 Intensive Care Unit, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China. mawenj@sysucc.org.cn.
  • 13 Department of Neurosurgery/Neuro-Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China. mouyg@sysucc.org.cn.
  • # Contributed equally.
PMID: 39350123 DOI: 10.1186/s12967-024-05658-x
Abstract

Background: Patients with glioblastoma (GBM) have a poor prognosis and limited treatment options. The mRNA decapping Enzyme scavenger (DCPS) is a cap-hydrolyzing Enzyme. The DCPS inhibitor RG3039 exhibited excellent central nervous system bioavailability in vivo and was safe and well tolerated in healthy volunteers in a phase 1 clinical trial. In this study, we investigated the expression of DCPS in GBM and the anti-tumor activity of RG3039 in various preclinical models of GBM.

Methods: DCPS expression was examined in human GBM and paired peritumoral tissues. Its prognostic role was evaluated together with clinicopathological characteristics of patients. The anti-GBM effect of RG3039 was determined using GBM cell lines, patient-derived organoids, and orthotopic mouse models. The therapeutic mechanisms of DCPS inhibition were explored.

Results: DCPS is overexpressed in GBM and is associated with poor survival of patients with GBM. The DCPS inhibitor RG3039 exhibited robust anti-GBM activities in GBM cell lines, patient-derived organoids and orthotopic mouse models, with drug exposure achievable in humans. Mechanistically, RG3039 downregulated STAT5B expression, thereby suppressing proliferation, survival and colony formation of GBM cells.

Conclusions: DCPS is a promising target for GBM. Inhibition of DCPS with RG3039 at doses achievable in humans downregulates STAT5B expression and reduces proliferation, survival and colony formation of GBM cells. Given the excellent anti-cancer activity and central nervous system bioavailability in vivo and good tolerance in humans, RG3039 warrants further study as a potential GBM therapy.

Keywords

DCPS; Glioblastoma; RG3039; STAT5B.

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