iScience (Feb 2023)
Exploiting metabolic vulnerabilities after anti-VEGF antibody therapy in ovarian cancer
- Deanna Glassman,
- Mark S. Kim,
- Meredith Spradlin,
- Sunil Badal,
- Mana Taki,
- Pratip Bhattacharya,
- Prasanta Dutta,
- Charles V. Kingsley,
- Katherine I. Foster,
- Olamide Animasahun,
- Jin Heon Jeon,
- Abhinav Achreja,
- Anusha Jayaraman,
- Praveen Kumar,
- Minal Nenwani,
- Fulei Wuchu,
- Emine Bayraktar,
- Yutuan Wu,
- Elaine Stur,
- Lingegowda Mangala,
- Sanghoon Lee,
- Timothy A. Yap,
- Shannon N. Westin,
- Livia S. Eberlin,
- Deepak Nagrath,
- Anil K. Sood
Affiliations
- Deanna Glassman
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Unit 1362, 1515 Holcombe Blvd, Houston, TX 77030, USA
- Mark S. Kim
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Unit 1362, 1515 Holcombe Blvd, Houston, TX 77030, USA
- Meredith Spradlin
- Department of Chemistry, The University of Texas at Austin, Austin, TX, USA; Department of Surgery, Baylor College of Medicine, Houston, TX, USA
- Sunil Badal
- Department of Chemistry, The University of Texas at Austin, Austin, TX, USA
- Mana Taki
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Unit 1362, 1515 Holcombe Blvd, Houston, TX 77030, USA
- Pratip Bhattacharya
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Prasanta Dutta
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Charles V. Kingsley
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Katherine I. Foster
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Unit 1362, 1515 Holcombe Blvd, Houston, TX 77030, USA
- Olamide Animasahun
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA; Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA
- Jin Heon Jeon
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
- Abhinav Achreja
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
- Anusha Jayaraman
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
- Praveen Kumar
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
- Minal Nenwani
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
- Fulei Wuchu
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
- Emine Bayraktar
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Unit 1362, 1515 Holcombe Blvd, Houston, TX 77030, USA
- Yutuan Wu
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Unit 1362, 1515 Holcombe Blvd, Houston, TX 77030, USA
- Elaine Stur
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Unit 1362, 1515 Holcombe Blvd, Houston, TX 77030, USA
- Lingegowda Mangala
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Unit 1362, 1515 Holcombe Blvd, Houston, TX 77030, USA
- Sanghoon Lee
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Unit 1362, 1515 Holcombe Blvd, Houston, TX 77030, USA; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Timothy A. Yap
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Shannon N. Westin
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Unit 1362, 1515 Holcombe Blvd, Houston, TX 77030, USA
- Livia S. Eberlin
- Department of Chemistry, The University of Texas at Austin, Austin, TX, USA; Department of Surgery, Baylor College of Medicine, Houston, TX, USA
- Deepak Nagrath
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
- Anil K. Sood
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Unit 1362, 1515 Holcombe Blvd, Houston, TX 77030, USA; Corresponding author
- Journal volume & issue
-
Vol. 26,
no. 2
p. 106020
Abstract
Summary: Despite modest clinical improvement with anti-vascular endothelial growth factor antibody (AVA) therapy in ovarian cancer, adaptive resistance is ubiquitous and additional options are limited. A dependence on glutamine metabolism, via the enzyme glutaminase (GLS), is a known mechanism of adaptive resistance and we aimed to investigate the utility of a GLS inhibitor (GLSi). Our in vitro findings demonstrated increased glutamine abundance and a significant cytotoxic effect in AVA-resistant tumors when GLSi was administered in combination with bevacizumab. In vivo, GLSi led to a reduction in tumor growth as monotherapy and when combined with AVA. Furthermore, GLSi initiated after the emergence of resistance to AVA therapy resulted in a decreased metabolic conversion of pyruvate to lactate as assessed by hyperpolarized magnetic resonance spectroscopy and demonstrated robust antitumor effects with a survival advantage. Given the increasing population of patients receiving AVA therapy, these findings justify further development of GLSi in AVA resistance.
