Impact of Obesity on Chemotherapy-Induced Cytotoxicity: Immune Cells and Skeletal Muscle

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PROJECT SUMMARY / ABSTRACT The number of cancer patients and cancer survivors continues to increase while the prevalence of obesity also continues to increase in the US. Obesity is associated with a greater risk for developing 40% of cancers and two of the four most prevalent cancers (i.e. breast and colon), are tightly linked with obesity. 5 fluorouracil (5FU) remains the first line of treatment for colon cancer despite 5FU’s well established toxicities - cytopenia, mucositis, anorexia, weakness, and fatigue. These toxicities contribute to reduction in relative dose intensity, increase patient susceptibility to infection, and lead to debilitating functional impairments that not only burden the patient, but also the patient’s support system. Given the increased prevalence of obesity in the US, it is increasingly more likely that those needing to undergo anti-cancer treatment will be obese. While it is common practice to apply a dosing cap, the current recommendations for the treatment of obese cancer patients are to give full body surface area dosing regimens, despite some evidence suggesting obese patients have exacerbated drug toxicities and reduced survival. This evidence is not ubiquitous as certain investigations have highlighted better prognosis and survival with increasing BMIs. I have discovered that obese mice are unable to sustain 2-3 cycles of 5FU. This I have attributed to a reduction in dihydropyrimidine dehydrogenase (DPD), the enzyme responsible for catabolizing 5FU in the liver. This has highlighted the need for mechanistic inquiry into the impact of obesity on 5FU’s toxicities; my K99/R00 proposal addresses this unmet need and will serve as a platform to launch my independent career in this domain. The overall goal of my proposed K99/R00 is to: 1) to understand the impact of obesity on 5FU’s anti-cancer efficacy and 5FU’s off-target effects and 2) provide critical training to facilitate my transition to independence. My central hypothesis is that obesity induced non- alcoholic fatty liver disease (NAFLD) contributes to disrupted 5FU catabolism and increased toxicity through reduced DPD resulting in reduced functional quality of life and survival. I am proposing a mechanistic aim (1), an exploratory aim (2), and a treatment/intervention aim (3) to test this hypothesis: in aim 1, I will investigate the role of DPD in the metabolism and toxicity of 5FU with obesity (K99); in aim 2, I will explore the impact of 5FU on skeletal muscle and immune cell -omics with obesity (R00); and in aim 3, I will examine the utility of manipulating dietary macronutrients on 5FU’s efficacy and off-target toxicities with obesity (R00). My research aims are complemented by my four training aims: 1) Obesity Phenotyping and Specialized Diet Formation, 2) Plasmid Preparation, CRISPR/Cas 9 Utilization, and –omics, 3) Drug Metabolism (5FU metabolite analysis), and 4) Professional Development and Lab Management. I expect that my findings will provide paradigm shifting evidence for how obese patients should be dosed and monitored to limit chemotherapy’s off-target effects. Additionally, the results from these studies will serve as the foundation for a pathway to independence to continue examining the contributing factors underlying cancer patient life quality and survival.