Year of Publication

2015

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department

Behavioral Science

First Advisor

Dr. Tianyan Gao

Second Advisor

Dr. Mark Evers

Abstract

Metformin is an oral biguanide that is prescribed to over 120 million people worldwide for the treatment of conditions including type II diabetes mellitus, polycystic ovarian syndrome, and gestational diabetes. This hypoglycemic agent is rapidly emerging as a potential cost-effective anti-oncogenic agent. Over the past decade multiple epidemiologic studies have consistently associated metformin with decreased cancer incidence and cancer-related mortality. More recently numerous preclinical and clinical studies have demonstrated anti-cancer effects of metformin, leading to the proposal of numerous clinical trials to better understand this drug and its mechanism of action.

Previously experts believed metformin primarily targeted AMP-activated protein kinase (AMPK), a crucial cellular energy sensor, but more recent data suggest the impact of metformin has a multi-faceted impact on various metabolic pathways. Current understanding of the potential anti-cancer effects of metformin raises the intriguing possibility of a duality of action, suggesting that metformin has the ability to act directly on a tumor while also indirectly lowering insulin levels in the host. This complexity creates challenges in determining the true impact of this drug in the clinical and translational setting.

Despite an increase in investment, only one in every 10 new molecular therapeutic agents that enters clinical development receives approval from the Food and Drug Administration. This warrants a demand for better designed clinical trials with more elegant and robust analyses of relevant primary endpoints to determine which targeted therapies are cost-effective, and more importantly which agents will provide the best care for our patients. Stable isotope resolved metabolomics (SIRM) is a powerful tool capable of robust analyses that can address these questions. Using these capabilities we have determined that metformin does significantly impact cellular metabolism by shifting colon cancer cells into glycolytic overdrive, ultimately leading to decreased proliferation and protein synthesis in cancer cells. This study contributes to the literature and implores that we continue to elucidate the full potential of this drug, especially in the setting of personalized medicine where select patients may receive maximal benefit from this agent.

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