Targeting Metabolic Adaptations to Anti-Angiogenic Therapy In Ovarian Cancer

<h3><strong>ABSTRACT</strong><strong></strong></h3> <p><strong>Background: </strong>Ovarian cancer is the most lethal gynecologic malignancy. Despite modest clinical improvements with anti-VEGF antibody (AVA) therapy, adaptive resistance is nearly ubiquitous and additional therapeutic options are limited. A dependence on glutamine metabolism, <em>via </em>the enzyme glutaminase (GLS), is a known mechanism of adaptive resistance.</p> <p><strong>Purpose: </strong>To assess the efficacy of a glutaminase inhibitor as a means of exploiting the metabolic vulnerability of glutamine dependence that develops as a result of adaptive resistance to AVA therapy.</p> <p><strong>Experimental Design: </strong>We used a glutaminase inhibitor (GLSi) synthesized at MD Anderson Cancer Center for all <em>in vitro </em>and <em>in vivo</em> experiments. We first assessed the <em>in vitro</em> effect of culturing ovarian cancer cell lines under hypoxic conditions and subsequently evaluated the metabolic adaptations that occurred as a result of this metabolic stress. Following this, we analyzed the effects of GLSi treatment on these cells. We then performed a series of <em>in vivo </em>experiments to determine the efficacy of GLSi therapy and the downstream metabolic impact of treatment. Statistical analysis of all experiments was performed using Student <em>t</em> test or Mann-Whitney test, as applicable, with a p value < 0.05 considered significant. </p> <p><strong>Results: </strong>Eight ovarian cancer cell lines were screened for glutaminase (GLS) expression with the SKOV3 cell line demonstrating the greatest expression and therefore it was utilized for all <em>in vivo</em> experiments. We demonstrated a significant sensitivity of these GLS-expressing cells to GLSi treatment <em>in vitro. </em>AVA treatment <em>in vivo </em>was associated with an increased abundance of glutamine in tumor tissue. Treatment with a GLSi in this setting led to a reduction in tumor growth and decreased metabolic conversion of pyruvate to lactate as assessed by hyperpolarized magnetic resonance spectroscopy. Furthermore, GLSi therapy initiated after the emergence of AVA resistance restored sensitivity to AVA therapy as evidenced by a reduction in tumor volume and a prolongation of survival of the orthotopic mouse model.</p> <p><strong>Conclusions: </strong>Our analyses indicate that alterations in glutamine metabolism occur in adaptive resistance to AVA therapy and that this can be targeted by GLSi therapy. The combination of AVA and GLSi <em>in vivo</em> led to robust anti-tumor responses supporting the inclusion of this combination of therapy in future clinical trials in the setting of AVA resistance. </p>

Name thesis:degree_name

Masters of Science (MS)

Level thesis:degree_level

Thesis (MS)

Year dc:date.available

2022

Authors dc:creator

• Glassman, Deanna M
• Glassman, Deanna
• <p><strong>0000-0003-4591-8272</strong></p>

Contributors dc:contributor

• Anil K. Sood
• Menashe Bar Eli
• Pratip Bhattachayra

• glutaminase
• metabolism
• ovarian cancer
• hypoxia
• VEGF
• bevacizumab
• resistance
• Biochemical Phenomena, Metabolism, and Nutrition
• Medicine and Health Sciences
• Obstetrics and Gynecology
• Therapeutics

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1156

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2224