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

项目摘要/摘要 癌症患者和癌症幸存者的数量继续增加，同时肥胖症的流行也在增加 在美国继续增加。肥胖与罹患40%癌症的风险更高有关， 四种最常见的癌症中有两种(即乳腺癌和结肠癌)与肥胖密切相关。5-氟尿嘧啶 (5FU)仍然是治疗结肠癌的一线药物，尽管5FU的毒性已经确定--细胞减少， 粘膜炎、食欲不振、虚弱和疲劳。这些毒性有助于降低相对剂量强度， 增加患者对感染的易感性，并导致衰弱的功能障碍，不仅是负担 病人，还有病人的支持系统。鉴于肥胖症在美国的流行程度不断上升， 那些需要接受抗癌治疗的人越来越有可能肥胖。虽然这很常见 在实践中应用剂量上限，目前治疗肥胖癌症患者的建议是 尽管有证据表明肥胖患者有 加剧了药物中毒，降低了存活率。这种证据并不像某些调查那样无处不在。 随着BMI的增加，患者的预后和存活率也随之提高。我发现肥胖的老鼠不能 维持2-3个周期的5FU。我把这归因于二氢嘧啶脱氢酶(DPD)的减少， 负责分解肝脏中5FU的酶。这凸显了机械式调查的必要性。 肥胖对5FU毒性的影响；我的K99/R00建议解决了这一未得到满足的需求，并将 作为一个平台，开始我在这个领域的独立职业生涯。我提议的K99/R00的总体目标是： 1)了解肥胖对5FU抗癌效果的影响和5FU的非靶向作用；2)提供 关键的训练，帮助我过渡到独立。我的中心假设是肥胖导致的非 酒精性脂肪性肝病(NAFLD)通过以下途径导致5FU分解代谢紊乱和毒性增加 DPD降低导致功能生活质量和生存质量下降。我提出了一个机械论的目标(1)， 检验这一假设的探索性目标(2)和治疗/干预目标(3)：在目标1中，我将调查 DPD在肥胖5FU(K99)代谢和毒性中的作用；在目标2，我将探讨 5FU对骨骼肌和免疫细胞的影响-肥胖的组学(R00)；在目标3中，我将研究 控制饮食中的大量营养素对5FU的疗效和肥胖的非靶向毒性(R00)。我的研究 我的四个培训目标与我的目标相辅相成：1)肥胖表型和专门的饮食形成，2) 质粒制备，CRISPR/CAS9利用，组学，3)药物代谢(5FU代谢产物分析)， 4)专业发展和实验室管理。我希望我的发现将提供范例 关于肥胖患者应该如何服药和监测以限制化疗偏离目标的证据不断变化 效果。此外，这些研究的结果将作为独立道路的基础 继续研究癌症患者生活质量和生存的影响因素。

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.