Role of Tumor Stroma in Therapeutic Response and Resistance

肿瘤基质在治疗反应和耐药中的作用

• 批准号: 8912396
• 负责人: KEITH T FLAHERTY
• 金额: $ 84.33万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8912396
• 关键词: Accounting; Address; Aftercare; Area; Automobile Driving; BAY 54-9085; BRAF gene; Basic Science; Biology; CTLA4 gene; Cells; Clinic; Clinical; Clinical Research; Clinical Trials; Communication; Computational Science; Data; Disease; Ensure; Future; Generations; Genetic; Genetically Engineered Mouse; Genomics; Human; Immune; Immunology; Immunosuppression; Immunotherapy; In Vitro; In complete remission; Instruction; Life; Malignant Neoplasms; Melanoma Cell; Metastatic Melanoma; Modeling; Mus; Mutation; Oncogenes; Pathogenesis; Pathway interactions; Patients; Phase; Play; Progression-Free Survivals; Proteomics; Regimen; Regulatory Pathway; Relapse; Research; Resistance; Resource Sharing; Role; Sampling; Stromal Neoplasm; Testing; Therapeutic; Time; Translational Research; Ursidae Family; advanced disease; cancer genomics; chemotherapy; clinical efficacy; cohort; epigenomics; in vivo; inhibitor/antagonist; melanoma; mouse model; mutant; neoplastic cell; resistance mechanism; response; targeted treatment; therapy resistant; transcriptomics; tumor; tumor microenvironment

DESCRIPTION (provided by applicant): The single agent efficacy of selective mutant BRAF inhibitors in patients with advanced melanoma is a transformative advance but the uniformly short-lived responses have now defined therapeutic resistance as the central paramount question in the field. While much of the field is focusing on somatic alterations in the melanoma cells that can drive resistance, we hypothesize that the tumor microenvironment plays an active contributory role in dictating the response to therapy initially and in facilitating emergence of resistance over time, hence modulating tumor-stromal alterations together with targeted therapy is a rational combination strategy to minimize emergence of resistance. To address this systematically, we have brought together this U54 team with diverse but complementary expertise in clinical, translational and basic research in areas of melanoma biology and genetics, immunology and cancer genomics to pursue the following two highly inter dependent and interrelated projects. Project 1: Identification of resistance-conferring stromal alterations i BRAF mutant melanoma. Here, global unbiased profiling on transcriptomic, epigenomic and proteomic levels in BRAF mutant human melanomas and derivative cells at baseline, post-treatment and upon relapse on selective BRAF inhibitor, compared with similar analyses in genetically engineered mouse models, will identify candidate stromal alterations associated with resistance that are dependent on tumor stromal interactions. Functional relevance of these candidates will be validated through genetic or pharmacological perturbation in vitro and in vivo while human relevance will be confirmed through analysis of larger cohort of human samples. Finally, mechanism of action will be explored to support possible strategy of modulating such stromal components to minimize resistance. Project 2: Roles of immune regulatory pathways in resistance to BRAF targeted therapy. Clinical efficacy of immune-inhibitory pathway blockade in human melanoma, supported by preliminary data in human and mouse, has pointed to an active role for immunosuppression in melanoma pathogenesis. This project will study the roles of immune regulatory pathways (through molecules such as CTLA4 and PD-L1) in melanoma and explore the consequences of such modulation on therapeutic response. The two Shared Resource Cores on "Clinically annotated human melanoma for TMEN research" and "GEM models for TMEN research" will not only support activities of these two projects but are expected to be high impact enablers for the entire research network. Finally, this U54 team brings to TMEN a diverse set of unique capabilities that can be leveraged for studies of the tumor microenvironment Thus, in addition to ensuring close interaction and coordination of complementary activities within this center, the 'Administrative Core' will also be responsible for efficient and effective communication and interaction with the TMEN research network.

描述（由申请人提供）：选择性突变 BRAF 抑制剂对晚期黑色素瘤患者的单药疗效是一项革命性的进步，但普遍的短期反应现已将治疗耐药性定义为该领域的核心首要问题。虽然该领域的大部分关注点都集中在黑色素瘤细胞中可以驱动耐药性的体细胞改变，但我们假设肿瘤微环境在决定最初对治疗的反应以及随着时间的推移促进耐药性的出现方面发挥着积极的贡献作用，从而调节肿瘤基质改变与靶向治疗是一种合理的组合策略，可以最大限度地减少耐药性的出现。为了系统地解决这个问题，我们聚集了这个 U54 团队，他们在黑色素瘤生物学和遗传学、免疫学和癌症基因组学领域的临床、转化和基础研究方面拥有多样化但互补的专业知识，以开展以下两个高度相互依赖和相互关联的项目。项目 1：鉴定 BRAF 突变黑色素瘤中赋予抗性的基质改变。在这里，与基因工程小鼠模型中的类似分析相比，对 BRAF 突变人类黑色素瘤和衍生细胞在基线、治疗后和选择性 BRAF 抑制剂复发时的转录组、表观基因组和蛋白质组水平进行全面无偏分析，将识别与基因工程小鼠模型相关的候选基质改变具有依赖于肿瘤基质相互作用的抵抗力。这些候选药物的功能相关性将通过体外和体内的遗传或药理学扰动来验证，而人类相关性将通过分析更大的人类样本群来确认。最后，将探索作用机制以支持调节此类基质成分以最小化阻力的可能策略。项目2：免疫调节途径在BRAF靶向治疗耐药中的作用。免疫抑制途径阻断对人类黑色素瘤的临床疗效得到了人类和小鼠初步数据的支持，表明免疫抑制在黑色素瘤发病机制中发挥着积极作用。该项目将研究免疫调节途径（通过 CTLA4 和 PD-L1 等分子）在黑色素瘤中的作用，并探讨这种调节对治疗反应的影响。 “用于 TMEN 研究的临床注释人类黑色素瘤”和“用于 TMEN 研究的 GEM 模型”的两个共享资源核心不仅将支持这两个项目的活动，而且预计将成为整个研究网络的高影响力推动者。最后，这个 U54 团队为 TMEN 带来了一系列独特的能力，可用于肿瘤微环境的研究。因此，除了确保该中心内互补活动的密切互动和协调外，“行政核心”还将负责为了 与 TMEN 研究网络进行高效、有效的沟通和互动。

项目成果

The immune microenvironment confers resistance to MAPK pathway inhibitors through macrophage-derived TNFα.

• DOI: 10.1158/2159-8290.cd-13-1007
• 发表时间: 2014-10
• 期刊: Cancer discovery
• 影响因子: 28.2
• 作者: Smith MP;Sanchez-Laorden B;O'Brien K;Brunton H;Ferguson J;Young H;Dhomen N;Flaherty KT;Frederick DT;Cooper ZA;Wargo JA;Marais R;Wellbrock C
• 通讯作者: Wellbrock C

Universes collide: combining immunotherapy with targeted therapy for cancer.

• DOI: 10.1158/2159-8290.cd-14-0477
• 发表时间: 2014-12
• 期刊: Cancer discovery
• 影响因子: 28.2
• 作者: Wargo JA;Cooper ZA;Flaherty KT
• 通讯作者: Flaherty KT

An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition.

• DOI: 10.1084/jem.20160855
• 发表时间: 2017-06-05
• 期刊: The Journal of experimental medicine
• 作者: Young HL;Rowling EJ;Bugatti M;Giurisato E;Luheshi N;Arozarena I;Acosta JC;Kamarashev J;Frederick DT;Cooper ZA;Reuben A;Gil J;Flaherty KT;Wargo JA;Vermi W;Smith MP;Wellbrock C;Hurlstone A
• 通讯作者: Hurlstone A

Update on use of aldesleukin for treatment of high-risk metastatic melanoma.

• DOI: 10.2147/itt.s61590
• 发表时间: 2015
• 期刊: ImmunoTargets and therapy
• 影响因子: 7.2
• 作者: Amaria RN;Reuben A;Cooper ZA;Wargo JA
• 通讯作者: Wargo JA

The intersection of immune-directed and molecularly targeted therapy in advanced melanoma: where we have been, are, and will be.

• DOI: 10.1158/1078-0432.ccr-13-2151
• 发表时间: 2013-10-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Sullivan RJ;Lorusso PM;Flaherty KT
• 通讯作者: Flaherty KT