Understanding the effects of dietary interventions on pancreatic ductal adenocarcinoma therapy cancer

了解饮食干预对胰腺导管腺癌治疗癌症的影响

• 批准号: 10680617
• 负责人: Evan Chen Lien
• 金额: $ 24.9万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680617
• 关键词: Affect; Anorexia; Antineoplastic Agents; Blood Circulation; Cachexia; Caloric Restriction; Cancer Biology; Cancer Model; Cancer Patient; Cell Death; Cell Signaling Process; Cells; Communication; Consumption; Dependence; Desire for food; Desmoplastic; Development; Development Plans; Diet; Diet and Nutrition; Diet therapy; Dietary Factors; Dietary Fats; Dietary Intervention; Dietary Practices; Digestion; Drug Combinations; Drug Targeting; Educational process of instructing; Environment; Epidemiology; Exocrine pancreatic insufficiency; Extracellular Matrix; Fatty acid glycerol esters; Food; Foundations; Genes; Goals; Growth; Impairment; Intercellular Fluid; Learning; Lipid Peroxidation; Lipids; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Mentors; Metabolic; Metabolic Pathway; Metabolism; Molecular; Mus; Nutrient; Pancreatic Ductal Adenocarcinoma; Pancreatic enzyme; Patient Care; Patients; Peripheral; Polyunsaturated Fatty Acids; Positioning Attribute; Quality of life; Recommendation; Reducing diet; Research; Research Personnel; Research Proposals; Science; Scientist; Shapes; Stromal Cells; Survival Rate; Technology; Testing; Therapeutic; Tissues; Training; Translations; Work; base; cancer cell; cancer therapy; career development; chemotherapy; dietary; enzyme replacement therapy; fatty acid metabolism; food restriction; improved; in vivo; inhibitor; lipid metabolism; lipidomics; metabolomics; mouse model; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; response; skills; stable isotope; standard of care; synergism; transcriptome sequencing; treatment response; tumor; tumor growth; tumor metabolism; tumor microenvironment; tumor progression; wasting

Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options that has a five-year survival rate of <10%. PDAC progression is associated with dysregulated tumor and whole- body metabolism that impacts therapy and quality of life, which has motivated research on how to best exploit metabolic dependencies in PDAC for better cancer treatment. Nutrient utilization by cancer cells is regulated in part by the availability of metabolites in the environment, and the PDAC tumor microenvironment in particular is highly desmoplastic, consisting of stromal cells, extracellular matrix, and nutrient-poor interstitial fluid. These microenvironmental factors can impact therapy response, suggesting that the efficacies of metabolism-targeted drugs can be improved by manipulating components of the PDAC tumor microenvironment. One determinant of metabolite levels in the tumor microenvironment is diet, and how diet affects cancer progression and treatment is an important question for many patients. Since dietary recommendations to patients must be made in the context of therapies being received, the value of any dietary intervention likely lies in its ability to enhance tumor responses to cancer therapies. Understanding the molecular mechanisms that drive synergistic interactions between diet and cancer therapies is critical for the translation of dietary recommendations into patient care. The main objective of this proposal is to identify dietary interventions that synergize with cancer therapies to impair PDAC progression. Mouse PDAC models will be used to examine how different diets enhance the efficacies of standard-of-care FOLFIRINOX chemotherapy (Aim 1), lipid metabolism inhibitors in development for cancer treatment (Aim 2), and inducers of ferroptosis, a non-apoptotic form of cell death being explored for PDAC treatment (Aim 3). Mass spectrometry-based metabolomics and lipidomics, stable isotope nutrient tracing, and RNA sequencing will be used to determine how diet-mediated changes to nutrient levels in the tumor microenvironment alter the metabolism of PDAC tumors to shape their responses to these therapies. Elucidating the metabolic mechanisms that underlie synergistic diet-drug combinations will provide scientific evidence that can benefit patients with guidance on how to best incorporate diet and nutrition into cancer therapy. The proposed training plan will help me transition into an independent academic position. A team of outstanding scientists will mentor me to help me achieve this goal: Dr. Tyler Jacks, a leader in mouse cancer models; Dr. Omer Yilmaz, a leader in dietary effects on cancer progression; Dr. Caroline Lewis, a leader in mass spectrometry-based metabolomics and lipidomics technologies; and Dr. Brian Wolpin, a leader in PDAC epidemiology. My training plan also outlines activities that will help me cultivate mentors, improve my scientific skillset, improve science communication skills, develop teaching and mentoring skills, build my network, and learn lab management skills. Together, the research proposal and career development plan will provide me with the expertise needed to become a successful independent investigator and educator in the cancer biology field.

项目总结/摘要 胰腺导管腺癌（PDAC）是一种高度侵袭性的癌症，治疗选择有限 五年存活率低于10%的肿瘤PDAC进展与失调的肿瘤和整体- 影响治疗和生活质量的身体代谢，这促使人们研究如何最好地利用 PDAC中的代谢依赖性，以更好地治疗癌症。癌细胞对营养物质的利用受到调节， 一部分是由于环境中代谢物的可用性，特别是PDAC肿瘤微环境， 高度促结缔组织增生，由基质细胞、细胞外基质和营养贫乏的间质液组成。这些 微环境因素可以影响治疗反应，这表明代谢靶向药物的疗效 药物可以通过操纵PDAC肿瘤微环境的组分来改善。的一个决定因素 肿瘤微环境中的代谢物水平是饮食，以及饮食如何影响癌症进展和治疗 这对许多患者来说是一个重要的问题。由于对患者的饮食建议必须在 在接受治疗的背景下，任何饮食干预的价值可能在于其增强肿瘤生长的能力。 对癌症治疗的反应。了解驱动协同作用的分子机制 饮食和癌症治疗之间的关系对于将饮食建议转化为患者护理至关重要。 这项建议的主要目的是确定与癌症治疗协同作用的饮食干预措施 阻碍PDAC进展小鼠PDAC模型将用于研究不同的饮食如何增强 开发中的标准治疗FOLFIRINOX化疗（目标1）、脂代谢抑制剂的疗效 用于癌症治疗（目标2），以及铁凋亡诱导剂，一种正在探索的非凋亡形式的细胞死亡， PDAC治疗（目标3）。基于质谱的代谢组学和脂质组学，稳定同位素营养追踪， RNA测序将用于确定饮食介导的肿瘤营养水平变化 微环境改变PDAC肿瘤的代谢，以塑造它们对这些疗法的反应。阐明 协同饮食-药物组合的代谢机制将提供科学证据， 可以通过指导患者如何将饮食和营养最好地结合到癌症治疗中来使患者受益。 建议的培训计划将帮助我过渡到一个独立的学术职位。一队 一位杰出的科学家将指导我，帮助我实现这一目标：泰勒杰克斯博士，小鼠癌症的领导者 奥默耶尔马兹博士，饮食对癌症进展的影响的领导者;卡罗琳刘易斯博士，质量的领导者 基于光谱的代谢组学和脂质组学技术;以及PDAC的领导者Brian Wolpin博士 流行病学我的培训计划还列出了一些活动，这些活动将帮助我培养导师，提高我的科学水平， 技能，提高科学沟通技能，发展教学和指导技能，建立我的网络， 学习实验室管理技能。研究计划和职业发展计划将为我提供 成为癌症生物学领域成功的独立研究者和教育者所需的专业知识。