Senescence-Associated Secretory Phenotype (SASP) modulation of the tumor microenvironment as a therapeutic strategy for KRAS-driven tumors

肿瘤微环境的衰老相关分泌表型 (SASP) 调节作为 KRAS 驱动肿瘤的治疗策略

• 批准号: 10474386
• 负责人: Marcus A. Ruscetti
• 金额: $ 24.9万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474386
• 关键词: Ablation; Academia; Advisory Committees; Antigen Presentation; Antigens; Award; Biological; Biology; Bypass; CDK4 gene; CTLA4 gene; Cancer Biology; Cancer Etiology; Cell Aging; Cell Communication; Cell Cycle Arrest; Cells; Cessation of life; Characteristics; Clinic; Cytotoxic Chemotherapy; Disease; Effectiveness; Endothelial Cells; Engineering; Environment; Faculty; Fibroblasts; Functional disorder; Funding Mechanisms; Genetic; Genetic Transcription; Genetically Engineered Mouse; Goals; Human; Immune; Immune system; Immunity; Immunocompetent; Immunologic Surveillance; Immunooncology; Immunosuppression; In Vitro; Individual; Infiltration; International; Intervention; Interview; K-ras mouse model; KRAS2 gene; Label; Lung Neoplasms; MEKs; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mediating; Memorial Sloan-Kettering Cancer Center; Mentors; Methods; Modeling; Molecular; Molecular Target; Monitor; NK Cell Activation; Natural Killer Cells; Organ; Pathway interactions; Patients; Pharmacology; Phenotype; Positioning Attribute; Predisposition; Premalignant Cell; Process; Production; Reporter; Research; Research Proposals; Resources; Role; Signal Transduction; Solid Neoplasm; Stromal Neoplasm; T cell response; TP53 gene; The Sun; Therapeutic; Time; Tissues; Training Programs; Tumor Antigens; Tumor Suppressor Proteins; United States; Vascular remodeling; Vascularization; Visualization; Work; cancer cell; cancer therapy; career; career development; clinically relevant; disorder control; effective therapy; flexibility; immune checkpoint blockade; immunoregulation; improved; in vivo; inhibitor; intravital microscopy; molecular targeted therapies; mouse model; mutant; neoplastic cell; novel therapeutic intervention; pancreatic cancer cells; pancreatic neoplasm; patient derived xenograft model; patient subsets; pleiotropism; programmed cell death protein 1; programs; recruit; response; restoration; screening; senescence; standard of care; targeted agent; therapy outcome; treatment response; tumor; tumor initiation; tumor microenvironment; tumorigenesis

PROJECT SUMMARY/ABSTRACT This proposal describes a training program to advance my academic career in the study of the tumor suppressive barriers that are bypassed during progression to malignancy and how they can be restored for therapeutic benefit in established tumors. Cellular senescence, a tumor suppressive process involving durable cell cycle arrest and activation of a senescence-associated secretory phenotype (SASP), can recruit immune cells to target and clear tumors. During my postdoctoral work, I identified molecularly targeted agents that can reestablish senescence, SASP, and a unique form of Natural Killer (NK) immune surveillance that drives tumor regressions and long-term survival in KRAS mutant lung cancer. This research proposal aims to characterize and exploit the SASP to sustain immune and stromal control of RAS-driven solid tumors, with the goal of identifying new or potentiating existing therapies for these deadly diseases. My expertise in mouse modeling, target discovery, and the biology of senescence and immune surveillance that I have acquired during my postdoctoral studies puts me in a unique position to significantly contribute to elucidating the role of senescence in cancer therapy and identifying new therapeutic strategies for KRAS mutant tumors. To accomplish the research outlined in this application, I will leverage modular and immune competent mouse models of KRAS mutant lung and pancreas cancer, as well as methods to reestablish senescence, SASP, and NK cell immune surveillance that I have already developed in the Lowe lab. In Aim 1, with the hypothesis that methods to overcome NK cell dysfunction are needed to establish disease control, I will explore mechanisms and strategies to further potentiate NK cell responses in KRAS mutant lung cancer through transcriptional and immune profiling and functional screening. In Aim 2, the organ-specific and pleiotropic effects of the SASP on tumor-stromal interactions in pancreas tumors will be interrogated to determine SASP factors necessary for productive tumor control and how they impact the efficacy of standard-of-care therapies. Together, these approaches will unveil new ways by which the SASP can be used to control KRAS-driven tumors. To achieve the goals of this award, I will be mentored by Dr. Scott Lowe and guided by an exceptional advisory committee I have established at MSKCC. Dr. Lowe is an internationally recognized expert in cancer biology, and is focused on understanding tumor suppressor networks through the use of sophisticated mouse models. The advisory committee, constituted by Dr. Lowe, Dr. Sun, Dr. Rosen, Dr. Iacobuzio-Donahue, and Dr. Rudin will monitor and support my transition to independence. Moreover, they will provide invaluable guidance during the process of applying and interviewing for faculty positions. MSKCC will provide me institutional support, including resources for experimental work and career development, as well as an engaging scientific environment. My objective is to obtain a faculty position to develop an impactful research program, where the K99/R00 funding mechanism will serve as an essential step in my transition to independence in academia. ! ! !

项目摘要/摘要 这项建议描述了一个培训计划，以促进我在肿瘤研究方面的学术生涯 在癌变过程中被绕过的抑制性障碍以及如何修复它们 对已确定的肿瘤的治疗益处。细胞衰老，一种持久的肿瘤抑制过程 细胞周期停滞和激活的一种衰老相关的分泌表型(SASP)，可以招募免疫 细胞来靶向和清除肿瘤。在我的博士后工作中，我发现了可以 重建衰老、SASP和独特形式的自然杀手(NK)免疫监控，推动 KRAS突变肺癌的肿瘤消退和长期生存。这项研究提案旨在 表征和开发SASP以维持RAS驱动的实体肿瘤的免疫和间质控制， 确定这些致命疾病的新疗法或加强现有疗法的目标。我在鼠标方面的专业知识 建模，目标发现，衰老生物学和免疫监视 在我的博士后研究期间，我处于一个独特的位置，可以对阐明 癌症治疗中的衰老和寻找KRAS突变肿瘤的新治疗策略。 为了完成本应用程序中概述的研究，我将利用模块化和免疫能力强的小鼠 KRAS突变肺癌和胰腺癌模型，以及重建衰老、SASP和 我在洛威实验室已经开发出的NK细胞免疫监测。在目标1中，假设 克服NK细胞功能障碍的方法是建立疾病控制所必需的，我将探讨其机制 以及进一步增强KRAS突变肺癌中NK细胞反应的策略 免疫分析和功能筛查。在目标2中，SASP的器官特异性和多效性效应对 胰腺肿瘤中肿瘤-间质的相互作用将被询问以确定必要的SASP因子 有效的肿瘤控制以及它们如何影响标准护理疗法的疗效。加在一起，这些 方法将揭示SASP可用于控制KRAS驱动的肿瘤的新方法。 为了实现这个奖项的目标，我将得到斯科特·洛博士的指导，并得到一位特殊的顾问的指导 我在MSKCC成立的委员会。洛博士是国际公认的癌症生物学专家， 并专注于通过使用复杂的小鼠模型来了解肿瘤抑制因子网络。 咨询委员会由洛博士、孙博士、罗森博士、亚科布齐奥-多纳休博士和鲁丁博士组成 将监督并支持我向独立的过渡。此外，它们将提供宝贵的指导，在 申请和面试教师职位的过程。MSKCC将为我提供机构支持， 包括实验工作和职业发展的资源，以及一个引人入胜的科学 环境。我的目标是获得一个教职员工的职位，以开发一个有影响力的研究计划，其中 K99/R00资助机制将是我向学术界独立过渡的重要一步。 好了！ 好了！ 好了！

项目成果

Senescence and the tumor-immune landscape: Implications for cancer immunotherapy.

• DOI: 10.1016/j.semcancer.2022.02.005
• 发表时间: 2022-11
• 期刊: SEMINARS IN CANCER BIOLOGY
• 影响因子: 14.5
• 作者: Chibaya, Loretah;Snyder, Jarin;Ruscetti, Marcus
• 通讯作者: Ruscetti, Marcus

Nanoparticle delivery of innate immune agonists combines with senescence-inducing agents to mediate T cell control of pancreatic cancer.

先天免疫激动剂的纳米粒子递送与衰老诱导剂相结合，介导 T 细胞对胰腺癌的控制。

• DOI: 10.1101/2023.09.18.558307
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Chibaya,Loretah;Lusi,ChristinaF;DeMarco,KellyD;Kane,GriffinI;Brassil,MeghanL;Parikh,ChaitanyaN;Murphy,KatherineC;Li,Junhui;Naylor,TianaE;Cerrutti,Julia;Peura,Jessica;Pitarresi,JasonR;Zhu,LihuaJulie;Fitzgerald,Katherine
• 通讯作者: Fitzgerald,Katherine

Senescent macrophages: A new "old" player in lung cancer development.

• DOI: 10.1016/j.ccell.2023.05.008
• 发表时间: 2023-07-10
• 期刊: CANCER CELL
• 影响因子: 50.3
• 作者: Zhou, Lin;Ruscetti, Marcus
• 通讯作者: Ruscetti, Marcus