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.

概括 BRAF的本构激活突变是大多数皮肤黑色素瘤，这是激活有丝分裂原激活的蛋白激酶（MAPK）途径，促进肿瘤。尽管单独或与MEK抑制剂结合的BRAF抑制剂已显示出良好的初始反应，抗性肿瘤最终发生，代表了黑色素瘤的重大挑战治疗。最近的研究表明YAP是河马途径的转录共激活因子，在对MAPK-BLOCKADE（MAPKI）的抵抗力发展中起着重要作用黑色素瘤。 YAP与TEAD转录因子相互作用以驱动致癌转录对于癌细胞生长，生存，上皮间质转变很重要的程序和免疫反应的调节，例如募集免疫抑制性髓样衍生的抑制细胞（MDSC）。我们最近开发了新型的小分子抑制剂靶向tead tead自动甲酰化的Teads（MGH-CP1及其类似物）绑扎相互作用并抑制其转录活动。而且，我们发现 teads和吸引MDSC的细胞因子CXCL6（YAP的转录靶）是与MAPKI敏感的MAPKI抗性黑色素瘤细胞中上调同行。基于强大的科学前提和我们的初步结果，我们假设用TEAD抑制剂靶向YAP-TEAD反式激活活性是有效的 MAPKI耐药性黑色素瘤的治疗策略;那把上调和yap- MDSC的依赖招募到肿瘤微环境在发育中的MAPKI抗黑色素瘤。该提议的总体目标是了解Yap-tead信号在MAPKI耐药性黑色素瘤中的作用，并发展打击MAPKI抗性的治疗策略。在AIM 1中，我们将调查贡献将MAPKI抗性在黑色素瘤中的发展。在AIM 2中，我们将使用使用MAPKI抗性的梅卢姆斯（Mapki）抗性的小分子抑制剂的影响细胞培养和动物模型。在AIM 3中，我们将阐明YAP的贡献依赖MDSC渗透到黑色素瘤中MAPKI抗性的发展。