权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Targeting Hippo pathway in melanoma

靶向黑色素瘤中的 Hippo 通路

基本信息

批准号：
10377554
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10377554
关键词：
Animal Model BRAF gene Binding CXCL6 gene Cancer Cell Growth Cancer cell line Cell Culture Techniques Cell Proliferation Cells ChIP-seq Crystallization Cutaneous Melanoma DNA Binding Domain Development Drug resistance Enhancers Enzymes Epithelial Fatty Acids Genetic Transcription Goals Human Hydrophobicity Immune response In Vitro Infiltration Lipid Binding MAP Kinase Gene MEK inhibition MEKs Malignant Neoplasms Mediating Melanoma Cell Mesenchymal Mitogen-Activated Protein Kinases Molecular Mutate Mutation Myeloid-derived suppressor cells NF1 gene Oncogenic Oncoproteins Palmitates Pathway interactions Pharmaceutical Preparations Pharmacology Play Post-Translational Protein Processing Proteins Regulation Resistance Resistance development Role Signal Transduction Skin Cancer Specificity Structure Testing Therapeutic Tissues Transactivation Transcription Coactivator Tumor Immunity Tumor Suppressor Proteins Up-Regulation analog base 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 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