2. Academic Validation
  3. Antitumor Activity of a Mitochondrial-Targeted HSP90 Inhibitor in Gliomas

Antitumor Activity of a Mitochondrial-Targeted HSP90 Inhibitor in Gliomas

  • Clin Cancer Res. 2022 May 13;28(10):2180-2195. doi: 10.1158/1078-0432.CCR-21-0833.
Shiyou Wei  # 1 2 3,  Delong Yin  # 2 3 4,  Shengnan Yu  # 2 3 5,  Xiang Lin 6,  Milan R Savani 7,  Kuang Du 6,  Yin Ku 1,  Di Wu 1,  Shasha Li 1,  Hao Liu 8,  Meng Tian 8 9,  Yaohui Chen 1,  Michelle Bowie 2 3,  Seethalakshmi Hariharan 2 3,  Matthew Waitkus 2 3,  Stephen T Keir 2 3,  Eric T Sugarman 10,  Rebecca A Deek 11,  Marilyne Labrie 12,  Mustafa Khasraw 2 3,  Yiling Lu 13,  Gordon B Mills 12,  Meenhard Herlyn 14,  Kongming Wu 15,  Lunxu Liu 1,  Zhi Wei 6,  Keith T Flaherty 16,  Kalil Abdullah 7,  Gao Zhang 2 3 17,  David M Ashley 2 3
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 2 The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.
  • 3 Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina.
  • 4 Department of Orthopedics, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
  • 5 Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 6 Department of Computer Science, Ying Wu College of Computing, New Jersey Institute of Technology, Newark, New Jersey.
  • 7 Department of Neurosurgery, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas.
  • 8 Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 9 Neurosurgery Research Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 10 Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania.
  • 11 Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 12 Knight Cancer Institute, Oregon Health Sciences University, Portland, Oregon.
  • 13 Division of Cancer Medicine, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 14 The Wistar Institute, Philadelphia, Pennsylvania.
  • 15 Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 16 Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
  • 17 Department of Pathology, Duke University School of Medicine, Durham, North Carolina.
  • # Contributed equally.
PMID: 35247901 DOI: 10.1158/1078-0432.CCR-21-0833
Abstract

Purpose: To investigate the antitumor activity of a mitochondrial-localized HSP90 Inhibitor, Gamitrinib, in multiple glioma models, and to elucidate the antitumor mechanisms of Gamitrinib in gliomas.

Experimental design: A broad panel of primary and temozolomide (TMZ)-resistant human glioma cell lines were screened by cell viability assays, flow cytometry, and crystal violet assays to investigate the therapeutic efficacy of Gamitrinib. Seahorse assays were used to measure the mitochondrial respiration of glioma cells. Integrated analyses of RNA Sequencing (RNAseq) and reverse phase protein array (RPPA) data were performed to reveal the potential antitumor mechanisms of Gamitrinib. Neurospheres, patient-derived organoids (PDO), cell line-derived xenografts (CDX), and patient-derived xenografts (PDX) models were generated to further evaluate the therapeutic efficacy of Gamitrinib.

Results: Gamitrinib inhibited cell proliferation and induced cell Apoptosis and death in 17 primary glioma cell lines, 6 TMZ-resistant glioma cell lines, 4 neurospheres, and 3 PDOs. Importantly, Gamitrinib significantly delayed the tumor growth and improved survival of mice in both CDX and PDX models in which tumors were either subcutaneously or intracranially implanted. Integrated computational analyses of RNAseq and RPPA data revealed that Gamitrinib exhibited its antitumor activity via (i) suppressing mitochondrial biogenesis, OXPHOS, and cell-cycle progression and (ii) activating the energy-sensing AMP-activated kinase, DNA damage, and stress response.

Conclusions: These preclinical findings established the therapeutic role of Gamitrinib in gliomas and revealed the inhibition of mitochondrial biogenesis and tumor bioenergetics as the primary antitumor mechanisms in gliomas.

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