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: 10449570
• 负责人: Evan Chen Lien
• 金额: $ 14.72万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449570
• 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.

项目概要/摘要 胰腺导管腺癌 (PDAC) 是一种高度侵袭性癌症，治疗选择有限 五年生存率<10%。 PDAC 进展与肿瘤失调和整体相关 影响治疗和生活质量的身体新陈代谢，这促使人们研究如何最好地利用 PDAC 中的代谢依赖性可实现更好的癌症治疗。癌细胞的营养利用受到调节 部分取决于环境中代谢物的可用性，尤其是 PDAC 肿瘤微环境 高度促纤维化，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 可以通过操纵 PDAC 肿瘤微环境的成分来改善药物。决定因素之一 肿瘤微环境中的代谢水平是饮食，以及饮食如何影响癌症进展和治疗 是很多患者的一个重要问题。由于必须向患者提出饮食建议 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的能力 对癌症治疗的反应。了解驱动协同相互作用的分子机制 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。 该提案的主要目标是确定与癌症治疗具有协同作用的饮食干预措施 损害 PDAC 进展。小鼠 PDAC 模型将用于研究不同饮食如何增强 标准护理 FOLFIRINOX 化疗（目标 1）的疗效，正在开发的脂质代谢抑制剂 用于癌症治疗（目标 2），以及铁死亡诱导剂，铁死亡是一种正在探索的细胞死亡的非凋亡形式 PDAC 治疗（目标 3）。基于质谱的代谢组学和脂质组学、稳定同位素营养示踪、 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，从而塑造它们对这些疗法的反应。阐明 协同饮食-药物组合背后的代谢机制将提供科学证据： 可以为患者提供如何最好地将饮食和营养纳入癌症治疗的指导。 拟议的培训计划将帮助我过渡到独立的学术职位。一个团队 杰出的科学家将指导我帮助我实现这一目标：小鼠癌症领域的领军人物 Tyler Jacks 博士 模型； Omer Yilmaz 博士，饮食对癌症进展影响领域的领军人物；卡罗琳·刘易斯博士，大众领域的领导者 基于光谱分析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。我的培训计划还概述了一些活动，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，以及 学习实验室管理技能。研究计划和职业发展计划共同将为我提供 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。