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. ! ! !

项目概要/摘要 该提案描述了一项培训计划，以促进我在肿瘤研究方面的学术生涯 在恶性肿瘤进展过程中绕过的抑制屏障以及如何恢复它们 对已形成的肿瘤有治疗效果。细胞衰老，一种涉及持久性的肿瘤抑制过程 细胞周期停滞和衰老相关分泌表型（SASP）的激活，可以招募免疫系统 细胞靶向并清除肿瘤。在我的博士后工作期间，我发现了分子靶向药物可以 重建衰老、SASP 和一种独特形式的自然杀伤 (NK) 免疫监视，从而驱动 KRAS 突变肺癌的肿瘤消退和长期生存。本研究计划旨在 表征和利用 SASP 来维持 RAS 驱动的实体瘤的免疫和基质控制， 目标是确定针对这些致命疾病的新疗法或增强现有疗法。我对鼠标的专业知识 我所掌握的建模、目标发现以及衰老和免疫监视生物学 在我的博士后研究期间，我处于一个独特的位置，可以为阐明 癌症治疗中的衰老并确定 KRAS 突变肿瘤的新治疗策略。 为了完成本申请中概述的研究，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 我已经在 Lowe 实验室开发了 NK 细胞免疫监视。在目标 1 中，假设 需要克服 NK 细胞功能障碍的方法来建立疾病控制，我将探索机制 以及通过转录和转录进一步增强 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 对器官特异性和多效性的影响 将对胰腺肿瘤中的肿瘤-基质相互作用进行研究，以确定胰腺癌所需的 SASP 因子 有效的肿瘤控制以及它们如何影响标准治疗的疗效。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。 为了实现该奖项的目标，我将得到 Scott Lowe 博士的指导和杰出顾问的指导 我在 MSKCC 设立了委员会。 Lowe 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网络。 顾问委员会由 Lowe 博士、Sun 博士、Rosen 博士、Iacobuzio-Donahue 博士和 Rudin 博士组成 将监督并支持我向独立的过渡。此外，他们将在期间提供宝贵的指导。 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，以及引人入胜的科学 环境。我的目标是获得一个教职职位来开发一个有影响力的研究项目，其中 K99/R00资助机制将成为我向学术界独立过渡的重要一步。 ！ ！ ！

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