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

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 MangalaSanghoon Lee, Timothy A. Yap, Shannon N. Westin, Livia S. Eberlin, Deepak Nagrath, Anil K. Sood

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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.

Original language	English (US)
Article number	106020
Journal	iScience
Volume	26
Issue number	2
DOIs	https://doi.org/10.1016/j.isci.2023.106020
State	Published - Feb 17 2023

Keywords

Cancer
Cellular physiology
Oncology

ASJC Scopus subject areas

General

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10.1016/j.isci.2023.106020

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Glassman, D., Kim, M. S., Spradlin, M., Badal, S., Taki, M., Bhattacharya, P., Dutta, P., Kingsley, C. V., Foster, K. I., Animasahun, O., Jeon, J. H., Achreja, A., Jayaraman, A., Kumar, P., Nenwani, M., Wuchu, F., Bayraktar, E., Wu, Y., Stur, E., ... Sood, A. K. (2023). Exploiting metabolic vulnerabilities after anti-VEGF antibody therapy in ovarian cancer. iScience, 26(2), Article 106020. https://doi.org/10.1016/j.isci.2023.106020

Glassman, D, Kim, MS, Spradlin, M, Badal, S, Taki, M, Bhattacharya, P , Dutta, P, Kingsley, CV, Foster, KI, Animasahun, O, Jeon, JH, Achreja, A, Jayaraman, A, Kumar, P, Nenwani, M, Wuchu, F, Bayraktar, E, Wu, Y, Stur, E, Mangala, L , Lee, S , Yap, TA , Westin, SN, Eberlin, LS, Nagrath, D & Sood, AK 2023, 'Exploiting metabolic vulnerabilities after anti-VEGF antibody therapy in ovarian cancer', iScience, vol. 26, no. 2, 106020. https://doi.org/10.1016/j.isci.2023.106020

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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.",

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AU - Glassman, Deanna

AU - Kim, Mark S.

AU - Spradlin, Meredith

AU - Badal, Sunil

AU - Taki, Mana

AU - Bhattacharya, Pratip

AU - Dutta, Prasanta

AU - Kingsley, Charles V.

AU - Foster, Katherine I.

AU - Animasahun, Olamide

AU - Jeon, Jin Heon

AU - Achreja, Abhinav

AU - Jayaraman, Anusha

AU - Kumar, Praveen

AU - Nenwani, Minal

AU - Wuchu, Fulei

AU - Bayraktar, Emine

AU - Wu, Yutuan

AU - Stur, Elaine

AU - Mangala, Lingegowda

AU - Lee, Sanghoon

AU - Yap, Timothy A.

AU - Westin, Shannon N.

AU - Eberlin, Livia S.

AU - Nagrath, Deepak

AU - Sood, Anil K.

PY - 2023/2/17

Y1 - 2023/2/17

N2 - 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.

AB - 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.

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

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