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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：
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.

摘要： BRAF基因的结构性激活和突变是皮肤恶性黑色素瘤的主要原因，其中包括激活丝裂原激活的丝裂原激活的蛋白酪氨酸激酶(MAPK)信号通路，促进肿瘤的发生。用于BRAF的抑制剂，无论是单独使用还是与MEK受体抑制剂联合使用，在最初都显示出良好的效果。反应，耐药肿瘤最终会发生，这是黑色素瘤的一个重大挑战。治疗。最近的研究表明，河马信号通路的转录和共激活因子--Yap。在中国对MAPK的抵抗和封锁机制(MAPKi)的发展过程中发挥着重要的作用。黑色素瘤。Yap与转录因子相互作用，从而推动致癌基因转录。这些方案表明，它们对于癌细胞的生长、存活、上皮细胞-间充质细胞的转化都是非常重要的。以及免疫系统反应的调控机制，如招募免疫抑制药髓系药物-- 衍生抑制因子细胞(MDSCs)。我们最近开发了一种新型的小分子药物抑制剂。的Teads(MGH-CP1及其类似物)认为，它的靶标是自动棕榈酰化，可能会扰乱TYAP- 青少年和青少年之间的相互作用会抑制他们的转录活动。此外，我们还没有发现有可能会影响青少年的健康。 Teads的水平和MDSC-吸引细胞因子CXCL6的水平，这是Yap的一个重要转录和目标基因，它们是。与对MAPKi敏感的黑色素瘤细胞相比，MAPKi耐药的黑色素瘤细胞表达上调。同行们。基于我们强大的科学性前提和我们的初步研究结果，我们提出了假设。这是一种非常有效的方法，目的是通过使用Tetad抑制剂来抑制Yap-tead的转录激活和活性。治疗MAPKi耐药黑色素瘤的策略；？以及包括上调基因和YAP-的治疗策略 MDSC的依赖与肿瘤微环境的关系在肿瘤的发生中起着重要的作用。 MAPKi的发展是对黑色素瘤的抗药性。这是该提案的主要总体目标。了解Yap-tead在MAPKi耐药黑色素瘤中的重要作用，并帮助其发展。治疗药物策略有助于对抗MAPKi的耐药性。在目标1中，我们将不会调查这一贡献。这一上调是为了促进MAPKi-耐药基因在黑色素瘤中的进一步发展。在目标2中，我们将继续努力。评估MAPKi对黑色素瘤耐药的小分子药物Teads的临床疗效。无论是细胞培养模型还是动物模型。在目标3中，我们将进一步阐明YAP的主要贡献。依赖于MDSC的渗透可能导致MAPKi耐药基因在黑色素瘤中的进一步发展。