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Targeting Hippo pathway in melanoma

靶向黑色素瘤中的 Hippo 通路

基本信息

批准号：
10589098
负责人：
Xu Wu
金额：
$ 51.87万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10589098
关键词：
Animal Model BRAF gene Binding CXCL6 gene Cancer Cell Growth Cancer cell line Cell Culture Techniques Cell Proliferation Cells ChIP-seq Cutaneous Melanoma DNA Binding Domain Development Drug resistance Enhancers Enzymes Epithelium Fatty Acids Genetic Transcription Goals Growth Human Hydrophobicity Immune response In Vitro Infiltration Lipid Binding MEK inhibition MEKs Malignant Neoplasms Mediating Melanoma Cell Mesenchymal Mitogen-Activated Protein Kinases Molecular Mutate Mutation Myeloid-derived suppressor cells NF1 gene Oncogenic Oncoproteins PIK3CG gene Palmitates Pathway interactions Pharmaceutical Preparations Play Post-Translational Protein Processing Proteins Regulation Resistance Resistance development Role Signal Transduction Skin Cancer Specificity Structure Testing Therapeutic Tissues Transactivation Transcription Coactivator Transcriptional Regulation Tumor Immunity Tumor Suppressor Proteins Up-Regulation analog cancer cell cancer therapy combat cytokine gain of function immunoregulation in vivo inhibitor loss of function melanoma migration mouse model mutant novel novel therapeutic intervention palmitoylation pharmacologic programs recruit response small molecule inhibitor therapeutically effective transcription factor transcriptome sequencing tumor tumor microenvironment tumorigenesis

项目摘要

Summary Constitutive activation mutations of BRAF account for majority of cutaneous melanoma, which activate the mitogen-activated protein kinase (MAPK) pathway, promoting tumorigenesis. While inhibitors for BRAF, alone or in combination with MEK inhibitors, have shown good initial responses, resistant tumors occur eventually, representing a major challenge in melanoma therapy. Recent studies indicate that YAP, the transcription co-activators of the Hippo pathway, plays important roles in the development of resistance to MAPK-blockade (MAPKi) in melanoma. YAP interacts with TEAD transcriptional factors to drive oncogenic transcriptional programs that are important for cancer cell growth, survival, epithelial-mesenchymal transition and regulation of immune response, such as recruitment of immunosuppressive Myeloid- derived suppressor cells (MDSCs). We have recently developed novel small molecule inhibitors of TEADs (MGH-CP1 and its analogues) that target TEAD auto-palmitoylation, disrupt the YAP- TEAD interaction and inhibit their transcriptional activities. Moreover, we have found that the levels of TEADs and MDSC-attracting cytokine CXCL6, a transcriptional target of YAP, are upregulated in MAPKi-resistant melanoma cells, compared to their MAPKi-sensitive counterparts. Based on the strong scientific premise and our preliminary results, we hypothesize that targeting the YAP-TEAD transactivation activity with TEAD inhibitors is an effective therapeutic strategy for MAPKi-resistant melanomas;? and that TEAD upregulation and YAP- dependent recruitment of MDSCs to tumor microenvironment play important role in the development MAPKi resistance in melanomas. The overall goal of the proposal is to understand the role of YAP-TEAD signaling in MAPKi-resistant melanoma and to develop therapeutic strategies to combat MAPKi resistance. In aim 1, we will investigate the contribution of TEAD upregulation to the development of MAPKi-resistance in melanoma. In aim 2, we will evaluate the effects of small molecule inhibitors of TEADs in MAPKi resistant melanomas using both cell culture and animal models. In aim 3, we will elucidate the contribution of YAP- dependent MDSC infiltration to the development of MAPKi resistance in melanoma.

总结 BRAF的组成性激活突变占皮肤黑色素瘤的大多数，激活丝裂原活化蛋白激酶（MAPK）通路，促进肿瘤发生。单独或与MEK抑制剂组合的BRAF抑制剂已经显示出良好的初始活性。反应，最终出现耐药肿瘤，代表了黑色素瘤的主要挑战最近的研究表明，雅普，Hippo途径的转录共激活剂，在对MAPK-I阻断剂（MAPKi）的抗性的发展中起重要作用，雅普与TEAD转录因子相互作用，对癌细胞生长、存活、上皮-间充质转化和免疫应答的调节，如免疫抑制性髓样细胞的募集衍生的抑制细胞（MDSC）。我们最近开发了新的小分子抑制剂靶向TEAD自身β-棕榈酰化的TEAD（MGH-β-CP 1及其类似物）的存在，破坏了雅普-β-磷酸化， TEAD相互作用并抑制其转录活性。此外，我们发现， TEAD和MDSC-1吸引细胞因子CXCL 6（雅普的转录靶点）的水平，在MAPKi-κ B抗性黑色素瘤细胞中，与MAPKi-κ B敏感性黑色素瘤细胞相比，基于强有力的科学前提和我们的初步结果，我们假设用TEAD抑制剂靶向雅普-β TEAD反式激活活性是有效的 MAPKi耐药黑色素瘤的治疗策略;？ TEAD上调和雅普-β MDSC向肿瘤微环境的依赖性募集在在黑色素瘤中产生MAPKi抗性。该提案的总体目标是了解雅普-β TEAD信号在MAPKi-β抗性黑色素瘤中的作用，治疗策略，以打击MAPKi耐药。在目标1，我们将调查的贡献， TEAD的上调对MAPKi-β抗性的发展在黑色素瘤中。在目标2中，我们将评价TEAD的小分子抑制剂在MAPKi抗性黑色素瘤中的作用，在目的3中，我们将阐明雅普-β的作用在黑素瘤中，依赖MDSC浸润的MAPKi抗性的发展。