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）：选择性突变体BRAF抑制剂在晚期黑色素瘤患者中的单一药物疗效是一种变革性的进步，但现在均匀的短寿命反应已将治疗性抗性定义为该领域的中心问题。尽管该领域的大部分都集中在黑色素瘤细胞的体细胞变化上，但我们假设肿瘤微环境在决定最初和促进耐药性的反应时，随着时间的推移随着时间的推移而促进对抗性的抗性的出现在抗肿瘤局部变化时，与靶向治疗相同，是一种抗药性策略，从而使肿瘤的变化与临界策略相同。为了系统地解决这一问题，我们将这个U54团队汇集在一起​​，具有多种多样但互补的专业知识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，以追求以下两个高度相互依赖和相互关联的项目。项目1：鉴定抗性基质改变I BRAF突变体黑色素瘤。在这里，与基因上的类似工程小鼠模型的类似分析相比，在基线后，治疗后和选择性BRAF抑制剂复发时，全球对BRAF突变体黑色素瘤和衍生细胞的转录组，表观基因组和蛋白质组学水平的分析，将鉴定出与抗药性相互作用相互作用。这些候选者的功能相关性将通过体外和体内的遗传或药理扰动来验证，而人类相关性将通过分析较大的人类样品的分析来确认。最后，将探索作用机理，以支持调节这种基质成分以最大程度减少电阻的可能策略。项目2：免疫调节途径在抵抗BRAF靶向治疗方面的作用。在人和小鼠中受到初步数据支持的人类黑色素瘤中免疫抑制途径阻滞的临床疗效已经指出了黑色素瘤发病机理中免疫抑制的积极作用。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后果。这两个共享的资源核心在“用于TMEN研究的临床注释的人类黑色素瘤”和“用于TMEN研究的GEM模型”上不仅支持这两个项目的活动，而且预计将是整个研究网络的高影响力推动剂。最后，这支U54团队为TMEN带来了各种各样的独特功能，可以利用这些功能来研究肿瘤微环境，因此，除了确保该中心内的互补活动的紧密互动和协调外，“行政核心”还将负责 有效有效的沟通和与TMEN研究网络的互动。

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

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

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