Regulation and targeting of tumor cell states and plasticity in pancreatic cancer

胰腺癌肿瘤细胞状态和可塑性的调节和靶向

• 批准号: 10449418
• 负责人: Srivatsan Raghavan
• 金额: $ 26.02万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449418
• 关键词: Address; Adopted; Advisory Committees; Area; Award; Basal Cell; Basal Cell Cancer; Biological Markers; Biomedical Engineering; Biopsy; CRISPR screen; Cancer Biology; Cells; Chemoresistance; Cholangiocarcinoma; Chronic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Committee Members; Dana-Farber Cancer Institute; Disease; Drug resistance; Environment; Evolution; Exhibits; Faculty; Genetic; Genetic Screening; Genetic Transcription; Goals; Heterogeneity; Immune; Infrastructure; Inpatients; Institutes; Knock-out; Laboratories; Libraries; Ligands; MADH2 gene; MADH4 gene; MAP Kinase Gene; MAP3K7 gene; MAPK8 gene; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of pancreas; Mediating; Medical Oncologist; Mentors; Mentorship; Metastatic to; Modeling; Molecular; Oncology; Organoids; Outcome; Outpatients; Pancreatic Ductal Adenocarcinoma; Patient Care; Patients; Pharmacology; Phenotype; Physicians; Prognosis; Regulation; Research; Research Personnel; Research Proposals; Resistance; Role; Sampling; Scientist; Selection for Treatments; Signal Pathway; Signal Transduction; Specific qualifier value; TGF Beta Signaling Pathway; Techniques; Testing; Therapeutic; Time; Training; Transforming Growth Factor beta; Variant; Work; base; career development; chemotherapeutic agent; chemotherapy; drug sensitivity; effective therapy; in vivo; insight; medical schools; member; neoplastic cell; non-genetic; overexpression; p38 Mitogen Activated Protein Kinase; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; predict clinical outcome; receptor; research and development; resistance mechanism; single-cell RNA sequencing; skills; targeted agent; therapeutic development; therapy resistant; treatment response; tumor; tumor microenvironment

Project Summary/Abstract: Metastatic pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal malignancy with few therapeutic options. Tumor transcriptional states are strongly correlated with therapeutic responses and clinical outcomes in PDAC. However, the mechanisms that regulate PDAC cell states and their roles in tumor evolution and therapeutic resistance are not well understood. In this proposal, I will investigate mechanisms regulating PDAC cell state specification, characterize tumor cell plasticity as a potential mechanism of therapeutic resistance, and identify cell state-specific therapeutic vulnerabilities using genetic and pharmacologic approaches. In Aim 1, I will investigate how TGF-β signaling specifies the basal cell state in organoid models. In Aim 2, I will examine whether TGF-β-mediated cellular plasticity drives chemo-resistance in organoid models and serially collected metastatic biopsies analyzed with single-cell RNA-sequencing. In Aim 3, I will perform compound testing and CRISPR screening in isogenic organoid models induced to adopt either basal or classical states to identify state-specific therapeutic vulnerabilities. Together, these aims will establish a rigorous framework for the analysis and modeling of PDAC evolution and will advance our mechanistic understanding of how microenvironmental factors such as TGF-β regulate PDAC cell states, plasticity, and drug resistance, thereby uncovering new avenues for therapeutic development. I am a medical oncologist with a clinical focus in gastrointestinal cancers and a research background in cancer biology and biomedical engineering. I am applying for the K08 award with the long-term goal of becoming an independent laboratory-based investigator with a translational focus in pancreatic and biliary cancers. During my K08 training, I will perform mentored research in the laboratory of Dr. William Hahn at the Dana-Farber Cancer Institute (DFCI). Dr. Brian Wolpin will serve as a co-mentor for the translational aspects of my research and will also act as my clinical mentor. I plan to spend 90% of my time performing research and 10% of my time on patient care, initially as an inpatient oncology attending but eventually transitioning to the outpatient setting where I will see patients with gastrointestinal cancers. I have organized an outstanding advisory committee consisting of faculty from DFCI, Harvard Medical School, the Broad Institute, and MIT to help guide my research and career development. In addition to Drs. Hahn and Wolpin, my committee members - Drs. Ramesh Shivdasani, Stuart Schreiber, Alex Shalek, and Stephanie Dougan - are scientific experts in specific areas of my proposed research, and their insights will prove invaluable to the successful completion of this proposal. The research environments at DFCI and the Broad Institute are unparalleled and offer numerous opportunities for scientific advancement and career development. The K08 award along with the aid of my mentors and a focused training plan will enable me to achieve my goal of becoming an independent physician-scientist.

项目摘要/摘要：转移性胰腺导管腺癌 (PDAC) 是一种侵袭性和致命性的癌症 几乎没有治疗选择的恶性肿瘤的转录状态与治疗密切相关。 PDAC 的反应和临床结果然而，调节 PDAC 细胞状态的机制及其。 在肿瘤进化和治疗耐药中的作用尚不清楚，在本提案中，我将进行研究。 调节 PDAC 细胞状态规范的机制，将肿瘤细胞可塑性描述为潜在机制 治疗耐药性，并使用遗传和识别细胞状态特异性治疗脆弱性 在目标 1 中，我将研究 TGF-β 信号传导如何指定基底细胞状态。 在目标 2 中，我将研究 TGF-β 介导的细胞可塑性是否会驱动化疗耐药性。 在目标 3 中，通过单细胞 RNA 测序分析类器官模型和连续收集的转移性活检。 我将在诱导采用任一基因的类器官模型中进行化合物测试和 CRISPR 筛选 基础或经典状态，以确定特定状态的治疗漏洞，这些目标将共同建立。 一个用于 PDAC 进化分析和建模的严格框架，并将推进我们的机制 了解 TGF-β 等微环境因素如何调节 PDAC 细胞状态、可塑性和药物 耐药性，从而揭示治疗发展的新途径。 我是一名肿瘤内科医生，临床重点是胃肠道癌症，并具有以下方面的研究背景： 我正在申请 K08 奖，长期目标是成为癌症生物学和生物医学工程专业。 一位独立的实验室研究者，专注于胰腺癌和胆管癌的转化研究。 在我的 K08 培训中，我将在丹娜—法伯癌症研究所的 William Hahn 博士实验室进行指导性研究 癌症研究所 (DFCI) 的 Brian Wolpin 博士将担任我的研究转化方面的联合导师。 我也将担任我的临床导师，我计划用 90% 的时间进行研究，用 10% 的时间进行研究。 患者护理，最初作为住院肿瘤科主治，但最终过渡到门诊环境 我在那里组织了一个出色的咨询委员会来诊治胃肠道癌症患者。 由来自 DFCI、哈佛医学院、布罗德研究所和麻省理工学院的教员组成，帮助指导我的研究 除了哈恩博士和沃尔平博士之外，我的委员会成员 - 拉梅什博士。 Shivdasani、Stuart Schreiber、Alex Shalek 和 Stephanie Dougan - 是我的特定领域的科学专家 拟议的研究以及他们的见解对于成功完成该提案将具有无价的价值。 DFCI 和布罗德研究所的研究环境是无与伦比的，为 K08 奖是在我的导师的帮助和重点关注下获得的。 培训计划将使我能够实现成为一名独立医师科学家的目标。