Systematic interrogation of the pancreatic cancer microenvironment in patient-derived specimens

系统研究患者来源标本中的胰腺癌微环境

基本信息

  • 批准号:
    10242454
  • 负责人:
  • 金额:
    $ 61.16万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-09-30 至 2022-08-31
  • 项目状态:
    已结题

项目摘要

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a 5-year survival rate of only 8%. Despite success in other cancer types, immunotherapy approaches in PDAC have not shown efficacy. PDAC demonstrates a heterogeneous and immunosuppressive tumor microenvironment (TME) that is poorly understood and serves as a barrier to effective immunotherapy strategies in this disease. We propose that an improved understanding of the TME and novel approaches that target key tumor-stroma interactions will enable remodeling of the immunosuppressive TME to enhance the efficacy of current and future immunotherapy strategies. In particular, we believe that successful combination immunotherapy approaches in PDAC will include strategies that alter myeloid cells to relieve immunosuppression, cytotoxic therapies that target tumor cells to improve immune response, and agents that augment anti-tumor T cell activity. In this project, we will perform a comprehensive characterization of the PDAC TME in both primary and metastatic PDAC in the baseline untreated context as well as across multiple different clinical therapies. In Aim 1, we will utilize single-cell transcriptomic and proteomic technologies to provide a cellular atlas of the PDAC TME at unprecedented resolution. In Aim 2, we will examine how the PDAC TME changes with chemotherapy, radiation therapy and a novel CCR2 inhibitor that modulates macrophage recruitment in the TME. For these studies, we will utilize human samples derived from both resectable and metastatic patients on clinical trials at Dana-Farber Cancer Institute. We will employ a novel ex vivo co-culture approach to enable rapid functional evaluation of tumor-stroma interactions and how they may impact immunotherapy responses. Lastly, in Aim 3 we will employ faithful immune competent PDAC mouse models and a novel cytokine delivery platform to investigate how targeted cytokine delivery to the TME may alter myeloid cell recruitment and function and improve immune responses. We have assembled a multi-disciplinary collaborative team including experts in PDAC biology and genetics, immunologists and translational oncologists to comprehensively study PDAC TME and identify novel opportunities to develop combination immunotherapy approaches in this devastating disease.
摘要 胰腺导管腺癌(PDAC)是一种致命的疾病,5年生存率仅为8%。尽管 尽管免疫疗法在其他癌症类型中取得了成功,但PDAC中的免疫疗法方法尚未显示出功效。PDAC 显示了异质性和免疫抑制性肿瘤微环境(TME), 理解并作为有效的免疫治疗策略在这种疾病的障碍。我们建议, 提高对TME的理解和针对关键肿瘤-间质相互作用的新方法将 能够重塑免疫抑制性TME,以增强当前和未来的疗效, 免疫治疗策略。特别是,我们认为,成功的联合免疫治疗方法, PDAC将包括改变骨髓细胞以缓解免疫抑制的策略, 靶向肿瘤细胞以改善免疫应答,以及增强抗肿瘤T细胞活性的药剂。在这 项目,我们将在原发性和转移性PDAC TME中进行全面表征。 基线未治疗背景下以及多种不同临床治疗中的PDAC。在目标1中,我们 利用单细胞转录组学和蛋白质组学技术提供PDAC TME的细胞图谱, 前所未有的决心。在目标2中,我们将研究PDAC TME如何随着化疗而变化, 放射治疗和一种新的CCR 2抑制剂,调节TME中的巨噬细胞募集。为这些 研究中,我们将利用来自可切除和转移患者的人体样本进行临床试验, 丹娜-法伯癌症研究所。我们将采用一种新的离体共培养方法,使快速功能性 评估肿瘤-间质相互作用以及它们如何影响免疫治疗反应。在Aim 3中 我们将采用可靠的免疫活性PDAC小鼠模型和一种新的细胞因子递送平台, 研究靶向细胞因子递送至TME如何改变骨髓细胞募集和功能, 提高免疫反应。我们已经组建了一个多学科的合作团队,包括专家, PDAC生物学和遗传学,免疫学家和转化肿瘤学家全面研究PDAC TME 并确定新的机会,开发联合免疫治疗方法,在这一破坏性的 疾病

项目成果

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William C. Hahn其他文献

SV40 small T antigen and PP2A phosphatase in cell transformation
  • DOI:
    10.1007/s10555-008-9116-0
  • 发表时间:
    2008-01-23
  • 期刊:
  • 影响因子:
    8.700
  • 作者:
    Anna A. Sablina;William C. Hahn
  • 通讯作者:
    William C. Hahn
A compendium of Amplification-Related Gain Of Sensitivity genes in human cancer
人类癌症中与扩增相关的敏感性增益基因纲要
  • DOI:
    10.1038/s41467-025-56301-2
  • 发表时间:
    2025-01-27
  • 期刊:
  • 影响因子:
    15.700
  • 作者:
    Veronica Rendo;Michael Schubert;Nicholas Khuu;Maria F. Suarez Peredo Rodriguez;Declan Whyte;Xiao Ling;Anouk van den Brink;Kaimeng Huang;Michelle Swift;Yizhou He;Johanna Zerbib;Ross Smith;Jonne Raaijmakers;Pratiti Bandopadhayay;Lillian M. Guenther;Justin H. Hwang;Amanda Iniguez;Susan Moody;Ji-Heui Seo;Elizabeth H. Stover;Levi Garraway;William C. Hahn;Kimberly Stegmaier;René H. Medema;Dipanjan Chowdhury;Maria Colomé-Tatché;Uri Ben-David;Rameen Beroukhim;Floris Foijer
  • 通讯作者:
    Floris Foijer
The present and future of the Cancer Dependency Map
癌症依赖图谱的现在与未来
  • DOI:
    10.1038/s41568-024-00763-x
  • 发表时间:
    2024-10-28
  • 期刊:
  • 影响因子:
    66.800
  • 作者:
    Rand Arafeh;Tsukasa Shibue;Joshua M. Dempster;William C. Hahn;Francisca Vazquez
  • 通讯作者:
    Francisca Vazquez
Developing a library of authenticated Traditional Chinese Medicinal (TCM) plants for systematic biol
开发经过认证的中药 (TCM) 植物库,用于系统生物分析
  • DOI:
  • 发表时间:
    2011
  • 期刊:
  • 影响因子:
    0
  • 作者:
    David Eisenberg;Eric S. J. Harris;Bruce A. Littlefield;Shugeng Cao;Jane A. Craycroft;Robert Scholten;Peter E. Bayliss;Yanling Fu;Wenquan Wang;Yan;Zhongzhen Zhao;Hubiao Chen;Yong Liu;Ted J. Kaptchuk;William C. Hahn;Xiaoxin Wang;Thomas M. Roberts;C. Shamu;Jon Clardy
  • 通讯作者:
    Jon Clardy
CDK8 is a colorectal cancer oncogene that regulates β-catenin activity
CDK8 是一种调节β-连环蛋白活性的结直肠癌致癌基因
  • DOI:
    10.1038/nature07179
  • 发表时间:
    2008-09-14
  • 期刊:
  • 影响因子:
    48.500
  • 作者:
    Ron Firestein;Adam J. Bass;So Young Kim;Ian F. Dunn;Serena J. Silver;Isil Guney;Ellen Freed;Azra H. Ligon;Natalie Vena;Shuji Ogino;Milan G. Chheda;Pablo Tamayo;Stephen Finn;Yashaswi Shrestha;Jesse S. Boehm;Supriya Jain;Emeric Bojarski;Craig Mermel;Jordi Barretina;Jennifer A. Chan;Jose Baselga;Josep Tabernero;David E. Root;Charles S. Fuchs;Massimo Loda;Ramesh A. Shivdasani;Matthew Meyerson;William C. Hahn
  • 通讯作者:
    William C. Hahn

William C. Hahn的其他文献

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{{ truncateString('William C. Hahn', 18)}}的其他基金

Development of p300/CBP histone acetyltransferase inhibitors for oncogene-driven cancers
开发用于癌基因驱动癌症的 p300/CBP 组蛋白乙酰转移酶抑制剂
  • 批准号:
    10627744
  • 财政年份:
    2022
  • 资助金额:
    $ 61.16万
  • 项目类别:
Novel genetic dependencies in VRK2 methylated glioblastoma multiforme
VRK2甲基化多形性胶质母细胞瘤的新遗传依赖性
  • 批准号:
    10046375
  • 财政年份:
    2020
  • 资助金额:
    $ 61.16万
  • 项目类别:
Development and implementation of multiplex methods to understand the biology and heterogeneity of patient-derived cancer models
开发和实施多重方法来了解源自患者的癌症模型的生物学和异质性
  • 批准号:
    10004385
  • 财政年份:
    2020
  • 资助金额:
    $ 61.16万
  • 项目类别:
Systematic interrogation of the pancreatic cancer microenvironment in patient-derived specimens
系统研究患者来源标本中的胰腺癌微环境
  • 批准号:
    10250566
  • 财政年份:
    2017
  • 资助金额:
    $ 61.16万
  • 项目类别:
PROJECT 4: Interrogating PP2A Signaling in Human Cancers
项目 4:探究人类癌症中的 PP2A 信号传导
  • 批准号:
    9981674
  • 财政年份:
    2017
  • 资助金额:
    $ 61.16万
  • 项目类别:
Systematic identification of oncogenic KRAS synthetic lethal interactions
系统鉴定致癌 KRAS 合成致死相互作用
  • 批准号:
    9330127
  • 财政年份:
    2015
  • 资助金额:
    $ 61.16万
  • 项目类别:
Systematic identification of oncogenic KRAS synthetic lethal interactions
系统鉴定致癌 KRAS 合成致死相互作用
  • 批准号:
    9150537
  • 财政年份:
    2015
  • 资助金额:
    $ 61.16万
  • 项目类别:
The Dana-Farber Cancer Institute Cancer Target Discovery and Development Center
丹娜—法伯癌症研究所癌症靶标发现和开发中心
  • 批准号:
    9362809
  • 财政年份:
    2013
  • 资助金额:
    $ 61.16万
  • 项目类别:
The Dana-Farber Cancer Institute Cancer Target Discovery and Development Center
丹娜—法伯癌症研究所癌症靶标发现和开发中心
  • 批准号:
    9979771
  • 财政年份:
    2013
  • 资助金额:
    $ 61.16万
  • 项目类别:
Identification of TBK1 inhibitors in KRAS-dependent lung cancer
KRAS 依赖性肺癌中 TBK1 抑制剂的鉴定
  • 批准号:
    8237125
  • 财政年份:
    2012
  • 资助金额:
    $ 61.16万
  • 项目类别:

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