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

肥胖对化疗引起的细胞毒性的影响：免疫细胞和骨骼肌

• 批准号: 10572695
• 负责人: Brandon VanderVeen
• 金额: $ 13万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-02 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572695
• 关键词: Acute; Address; Anorexia; Antineoplastic Agents; Body Surface Area; Body Weight; Body mass index; Breast; Cachexia; Cancer Patient; Cancer Survivor; Cancer Survivorship; Catabolism; Cells; Circulation; Clustered Regularly Interspaced Short Palindromic Repeats; Colon; Colorectal; Colorectal Cancer; Complement; Complex; Cytotoxic Chemotherapy; Data; Development; Diet; Dietary Intervention; Dihydropyrimidine Dehydrogenase; Disparity; Dose; Drug Kinetics; Drug toxicity; Enzymes; Epidemiology; Excretory function; Fatigue; Fluorouracil; Foundations; Funding; Genetic Variation; Genotype; Goals; Immune; Infection; Inflammation; Inflammatory; Intervention; Investigation; Link; Literature; Liver; Liver Dysfunction; Macronutrients Nutrition; Malignant Neoplasms; Messenger RNA; Metabolism; Mitochondria; Monitor; Mucositis; Mus; Muscle; Obese Mice; Obesity; PTPRC gene; Pathology; Pathway interactions; Patients; Pharmacodynamics; Pharmacogenetics; Pharmacology; Phase; Phenotype; Physical Function; Physiology; Plasmids; Positioning Attribute; Predisposition; Preparation; Prevalence; Prognosis; Proteins; Proteome; Quality of life; Recommendation; Regimen; Research; Risk; Role; Safety; Skeletal Muscle; Support System; Testing; Therapeutic Index; Thinness; Toxic effect; Training; Treatment Efficacy; Treatment-related toxicity; Urine; Weight; anti-cancer; anticancer treatment; cancer risk; cancer therapy; career; chemotherapy; colon cancer treatment; cytopenia; cytotoxicity; dietary; dietary manipulation; drug metabolism; enzyme activity; functional disability; gene environment interaction; improved; liver function; malignant breast neoplasm; muscle form; non-alcoholic fatty liver disease; obese patients; obese person; obesity treatment; primary outcome; targeted treatment; transcriptome; treatment effect; tumor

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.

项目摘要/摘要 癌症患者和癌症幸存者的数量继续增加，而肥胖的流行也 在美国继续增加。肥胖与40%的癌症的发生风险有关， 四种最常见的癌症中有两种（即乳腺癌和结肠癌）与肥胖症密切相关。5氟尿嘧啶 (5FU)仍然是结肠癌的第一线治疗，尽管5 FU具有公认的毒性-血细胞减少， 粘膜炎、厌食、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，并导致使人衰弱的功能损伤， 病人，还有病人的支持系统。考虑到美国肥胖症的流行率上升， 需要接受抗癌治疗的人肥胖的可能性越来越大。虽然通常 实践应用剂量上限，目前治疗肥胖癌症患者的建议是， 给予全身表面积给药方案，尽管一些证据表明肥胖患者 加重药物毒性并降低存活率。这种证据并不像某些调查那样普遍存在 强调随着BMI的增加，预后和生存率更好。我发现肥胖的老鼠 以维持2-3个周期的5 FU。我将此归因于二氢嘧啶脱氢酶（DPD）的减少， 负责在肝脏中分解代谢5 FU的酶。这突出了机械式调查的必要性 肥胖对5 FU毒性的影响;我的K99/R 00提案解决了这一未满足的需求， 作为一个平台来开始我在这个领域的独立职业生涯。我建议的K99/R 00的总体目标是： 1)了解肥胖对5 FU抗癌疗效和5 FU脱靶效应的影响，以及2）提供 关键的训练来帮助我过渡到独立。我的中心假设是肥胖导致非- 酒精性脂肪性肝病（NAFLD）通过以下途径导致5 FU催化剂中断和毒性增加： DPD降低，导致功能性生活质量和生存率降低。我提出了一个机械的目标（1）， 探索性目标（2）和治疗/干预目标（3）来验证这一假设：在目标1中，我将研究 DPD在肥胖症患者（K99）5 FU代谢和毒性中的作用;在目标2中，我将探讨 5 FU对肥胖症患者骨骼肌和免疫细胞组学的影响（R 00）;在目标3中，我将研究 操纵饮食宏量营养素对肥胖症的5 FU疗效和脱靶毒性（R 00）。我的研究 我的四个训练目标补充了这些目标：1）肥胖表型和专门饮食形成，2） 3）药物代谢（5 FU代谢物分析）， （4）专业发展和实验室管理。我希望我的发现能提供一个范例 改变肥胖患者应该如何给药和监测以限制化疗脱靶的证据 方面的影响.此外，这些研究的结果将成为独立之路的基础 继续研究癌症患者生活质量和生存率的影响因素。