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

项目摘要/摘要 摘要胰腺导管腺癌是一种高度侵袭性的癌症，治疗方法有限。 其五年存活率为10%。PDAC进展与调节失调的肿瘤和整个- 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中的新陈代谢依赖于更好的癌症治疗。癌细胞对营养物质的利用受 部分是由于环境中代谢产物的可用性，特别是PDAC肿瘤微环境是 高度促结缔组织，由基质细胞、细胞外基质和营养不良的间质液体组成。这些 微环境因素可以影响治疗反应，这表明新陈代谢靶向治疗的疗效 药物可以通过操纵PDAC肿瘤微环境的成分来改进。决定因素之一 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的进展和治疗 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是将饮食建议转化为患者护理的关键。 这项建议的主要目标是确定与癌症治疗相协同的饮食干预措施。 以阻碍PDAC的进展。小鼠PDAC模型将被用来研究不同的饮食如何增强 开发中的脂代谢抑制剂标准FolFirinOX化疗(AIM 1)的疗效 用于癌症治疗(目标2)，以及铁下垂的诱导剂，一种正在探索的非凋亡性细胞死亡形式 PDAC治疗(目标3)。基于质谱学的代谢组学和类脂组学，稳定同位素营养示踪， RNA测序将被用来确定饮食介导的肿瘤营养水平的变化 微环境改变PDAC肿瘤的新陈代谢，以形成它们对这些治疗的反应。澄清 协同饮食-药物组合的代谢机制将提供科学证据 可以使患者受益，指导如何最好地将饮食和营养纳入癌症治疗。 拟议的培训计划将帮助我过渡到一个独立的学术职位。一支由 杰出的科学家将指导我实现这一目标：老鼠癌症的领军人物泰勒·杰克斯博士 模特；奥梅尔·耶尔马兹博士，饮食影响癌症进展的领导者；卡罗琳·刘易斯博士，大众领袖 以光谱为基础的代谢组学和脂质组学技术；以及PDAC领域的领导者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，提高我的科学能力 技能集，提高科学交流技能，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。总之，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调查者和教育者所需的专业知识。

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.