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

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 re...

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Published in:iScience 2023-02, Vol.26 (2), p.106020-106020, Article 106020
Main Authors: Glassman, Deanna, Kim, Mark S., Spradlin, Meredith, Badal, Sunil, Taki, Mana, Bhattacharya, Pratip, Dutta, Prasanta, Kingsley, Charles V., Foster, Katherine I., Animasahun, Olamide, Jeon, Jin Heon, Achreja, Abhinav, Jayaraman, Anusha, Kumar, Praveen, Nenwani, Minal, Wuchu, Fulei, Bayraktar, Emine, Wu, Yutuan, Stur, Elaine, Mangala, Lingegowda, Lee, Sanghoon, Yap, Timothy A., Westin, Shannon N., Eberlin, Livia S., Nagrath, Deepak, Sood, Anil K.
Format: Article
Language:English
Subjects:
Cancer
Cellular physiology
Oncology
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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. [Display omitted] •Resistance to anti-vascular endothelial growth factor antibody (AVA) is common•We examine a small molecule inhibitor of glutaminase (GLSi) to combat resistance•GLSi enhanced the efficacy of AVA in vitro and in vivo, even in AVA-resistant tumors•This work supports further development of GLSi in AVA-resistant ovarian cancer Oncology; Cellular physiology; Cancer.
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2023.106020