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 癌症患者和癌症存活的数量继续增加，而肥胖症的患病率也在 在美国继续增加。肥胖与出现40％癌症的风险更大，并且 四种最普遍的癌症（即乳腺癌和结肠）中的两个与肥胖密切相关。 5氟尿嘧啶 （5FU）仍然是结肠癌目的地5FU良好毒性的第一道治疗 - 细胞质， 粘膜炎，厌食，无力和疲劳。这些毒性有助于降低相对剂量强度， 增加患者对感染的敏感性，并导致功能障碍，不仅伯恩（Burnen） 患者，也是患者的支持系统。考虑到美国肥胖的患病率增加，这是 越来越有可能需要接受抗癌治疗的人越来越有可能肥胖。虽然很常见 实践要应用给药上限，目前有关肥胖癌症患者治疗的建议是 给出全身表面积的给药方案，dospite一些证据表明肥胖患者有 加剧药物毒性并降低生存率。这些证据并不普遍，因为某些调查已经 随着BMI的增加，强调了更好的预后和生存。我发现肥胖的老鼠无法 维持5FU的2-3个周期。我归因于二氢嘧啶脱氢酶（DPD）的减少， 负责在肝脏中分解5FU的酶。这突出了需要机械查询的需求 肥胖对5FU的毒性的影响；我的K99/R00提案解决了这种未满足的需求，并将服务 作为我在这个领域开展独立职业的平台。我建议的K99/R00的总体目标是： 1）了解肥胖对5FU的抗癌效率和5FU的脱靶效果的影响，2） 批判性培训以促进我向独立过渡。我的中心假设是肥胖引起的非 - 酒精性脂肪肝病（NAFLD）有助于5FU分解代谢，并通过 DPD降低，导致生活质量降低和生存。我提出了一个机械目标（1）， 探索目的（2）和治疗/干预目的（3）来检验以下假设：在AIM 1中，我将调查 DPD在肥胖症5FU的代谢和毒性中的作用（K99）；在AIM 2中，我将探讨 5FU在骨骼肌和肥胖症的免疫细胞 - 瘤中（R00）；在AIM 3中，我将研究 在5FU的效率和肥胖的脱靶毒性上操纵饮食大营养素（R00）。我的研究 目的是由我的四个培训目标完成的：1）肥胖表型和专业饮食形成，2） 质粒制备，CRISPR/CAS 9利用和 - 组，3）药物代谢（5FU代谢物分析）， 4）专业发展和实验室管理。我希望我的发现将提供范式 转移证据表明应如何对肥胖患者进行涂抹和监测以限制化学疗法的脱靶 效果。此外，这些研究的结果将成为实现独立途径的基础 继续研究癌症患者生活质量和生存的基本因素。