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.

项目摘要/摘要 胰腺导管腺癌（PDAC）是一种高度侵略性的癌症，治疗方案有限 五年生存率<10％。 PDAC进展与肿瘤失调和全肿瘤有关 影响治疗和生活质量的身体代谢，这激发了如何最好地利用的研究 PDAC中的代谢依赖性用于更好的癌症治疗。癌细胞的营养利用受到调节 部分由环境中的代谢物以及PDAC肿瘤微环境的可用性为 高度塑性塑料，由基质细胞，细胞外基质和营养贫困的间质液组成。这些 微环境因素会影响治疗反应，表明以代谢为目标的效力 可以通过操纵PDAC肿瘤微环境的成分来改善药物。一个决定因素 肿瘤微环境中的代谢物水平是饮食，饮食如何影响癌症的进展和治疗 对于许多患者而言，这是一个重要的问题。由于必须向患者提出饮食建议 接受疗法的背景，任何饮食干预的价值都可能在于其增强肿瘤的能力 对癌症疗法的反应。了解驱动协同相互作用的分子机制 饮食和癌症疗法之间对于将饮食建议转化为患者护理至关重要。 该提案的主要目的是确定与癌症疗法协同作用的饮食干预措施 损害PDAC的进展。小鼠PDAC模型将用于检查不同的饮食如何增强 护理标准Folfirinox化学疗法的疗效（AIM 1），发育中的脂质代谢抑制剂 对于癌症治疗（AIM 2）和铁凋亡的诱导者，正在探索一种细胞死亡的一种非凋亡形式 PDAC治疗（AIM 3）。基于质谱的代谢组学和脂质组学，稳定的同位素营养追踪， RNA测序将用于确定饮食介导的肿瘤中养分水平的变化 微环境改变了PDAC肿瘤的代谢，以塑造其对这些疗法的反应。阐明 协同饮食 - 药物组合的基础的代谢机制将提供科学证据表明 可以通过指导如何最好地将饮食和营养纳入癌症治疗中的指导。 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：泰勒·杰克斯（Tyler Jacks）博士，老鼠癌的领导者 模型；饮食对癌症进展影响的领导者Omer Yilmaz博士；马萨诸塞州领导者卡罗琳·刘易斯博士 基于光谱法的代谢组学和脂肪组学技术； PDAC的领导者Brian Wolpin博士 流行病学。我的培训计划还概述了可以帮助我培养导师，改善我的科学的活动 技能，提高科学沟通技巧，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。研究建议和职业发展计划将为我提供 该专业知识需要成为癌症生物学领域的成功独立研究者和教育者。