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

doi:10.1016/j.isci.2023.106020

Exploiting metabolic vulnerabilities after anti-VEGF antibody therapy in ovarian cancer

iScience. 2023 Jan 19;26(2):106020. doi: 10.1016/j.isci.2023.106020. eCollection 2023 Feb 17.

Authors

Deanna Glassman¹, Mark S Kim¹, Meredith Spradlin^{2

3}, Sunil Badal², Mana Taki¹, Pratip Bhattacharya⁴, Prasanta Dutta⁴, Charles V Kingsley⁴, Katherine I Foster¹, Olamide Animasahun^{5

6}, Jin Heon Jeon⁵, Abhinav Achreja⁵, Anusha Jayaraman⁵, Praveen Kumar⁵, Minal Nenwani⁵, Fulei Wuchu⁵, Emine Bayraktar¹, Yutuan Wu¹, Elaine Stur¹, Lingegowda Mangala¹, Sanghoon Lee^{1

7}, Timothy A Yap^{8

9}, Shannon N Westin¹, Livia S Eberlin^{2

3}, Deepak Nagrath⁵, Anil K Sood¹

Affiliations

¹ Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Unit 1362, 1515 Holcombe Blvd, Houston, TX 77030, USA.
² Department of Chemistry, The University of Texas at Austin, Austin, TX, USA.
³ Department of Surgery, Baylor College of Medicine, Houston, TX, USA.
⁴ Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁵ Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
⁶ Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.
⁷ Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸ Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁹ The Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Abstract

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.

Keywords: Cancer; Cellular physiology; Oncology.

Abstract

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