Abstract 2484: Hyperpolarized magnetic resonance spectroscopy assessment of the metabolic effects of glutaminase inhibitor therapy in an ovarian cancer model
Authors: Glassman Deanna , Kim Mark S. , Dutta Prasanta , Kingsley Charles V. , Bayraktar Emine , Wu Yutuan , Stur Elaine , Mangala Lingegowda S. , Foster Katherine , Lee Sanghoon , Yap Timothy A. , Westin Shannon N. , Bhattacharya Pratip , Sood Anil K. 
Published: June 2022

Abstract
Introduction: Ovarian cancer accounts for more deaths than any other cancer of the female reproductive system despite advances in targeted drugs such as anti-VEGF antibody (AVA). Additionally, resistance to AVA therapy is nearly ubiquitous given the occurrence of metabolic adaptations such as a dependence on glutamine metabolism via the enzyme glutaminase.
Objectives: To examine the metabolic vulnerability of AVA-resistant cancer with glutaminase inhibitor (GLSi) therapy and to test the utility of hyperpolarized magnetic resonance spectroscopy (HP-MRS) for assessing changes in lactate metabolism associated with GLSi treatment following injection of hyperpolarized [1-13C] pyruvate.
Methods: We used a well-characterized SKOV3ip1 orthotopic mouse model of high-grade serous ovarian cancer with adaptive resistance to AVA (bevacizumab) treatment. Following three weeks of GLSi and bevacizumab treatment, we performed HP-MRS imaging to directly and non-invasively compare metabolic changes between the treatment groups of bevacizumab monotherapy versus a combined treatment of bevacizumab plus GLSi therapy. Upon injection of hyperpolarized [1-13C] pyruvate, we quantitatively assessed a normalized lactate ratio (nLac), defined as the 13C resonance signal of lactate divided by the sum of the pyruvate and lactate signals, sixty seconds after injection. GLSi treatment effect was subsequently compared between GLSi monotherapy, bevacizumab monotherapy and control mice receiving no therapy. This was performed via gross necropsy to assess disease burden and quantification of tumor weight and nodule number.
Results: Significance analysis microarrays (SAM) of bevacizumab treated tumors from the mouse models revealed greater glutamine and glutamate abundance in all tissues suggestive of a glutamine dependence in AVA resistant tumors that could be susceptible to glutaminase inhibition. The in vivo HP-MRS provided a direct and non-invasive investigation of pyruvate metabolism of tumors in situ. Our analysis indicated that the pyruvate-to-lactate conversion was significantly reduced in vivo by GLSi treatment (0.337 vs 0.178, p=0.0002), suggestive of therapeutic efficacy of GLSi in the setting of AVA-resistant tumors. Consistent with this, we observed a statistically significant reduction in tumor weight (0.05g vs 0.62g and 0.64g, p&lt;0.01) and tumor nodule number (n=3.3 vs n=12.8 and n=13.9, p&lt;0.05) in mice treated with a combination of bevacizumab and GLSi compared to the control group, or GLSi monotherapy, respectively.
Conclusions: Using HP-MRS in vivo, we directly monitored metabolic changes occurring after GLSi treatment. These findings are consistent with the notion of glutamine dependence being an important resistance mechanism to AVA therapy and imply potential future use of HP-MRS in monitoring therapeutic efficacy in a clinical realm.
Citation Format: Deanna Glassman, Mark S. Kim, Prasanta Dutta, Charles V. Kingsley, Emine Bayraktar, Yutuan Wu, Elaine Stur, Lingegowda S. Mangala, Katherine Foster, Sanghoon Lee, Timothy A. Yap, Shannon N. Westin, Pratip Bhattacharya, Anil K. Sood. Hyperpolarized magnetic resonance spectroscopy assessment of the metabolic effects of glutaminase inhibitor therapy in an ovarian cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2484.