Targeting Sox10-low cells in drug-resistant melanoma

靶向治疗耐药黑色素瘤中的 Sox10-low 细胞

基本信息

批准号：
9763322
负责人：
Sean Alexander Misek
金额：
$ 3.99万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-16 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9763322
关键词：
Affect BRAF gene Bioinformatics CD8-Positive T-Lymphocytes CD8B1 gene Cell Line Cells Clinical Data Combination Drug Therapy Combined Modality Therapy Cutaneous Melanoma Cytoskeleton Dasatinib Data Development Down-Regulation Drug resistance Epigenetic Process Equilibrium Frequencies Gene Expression Genetic Transcription Genomics Goals Growth Human Immune Evasion Immune checkpoint inhibitor MAP Kinase Gene MEKs Melanoma Cell Mission Modeling Molecular and Cellular Biology Neoplasm Metastasis Nuclear Pathway interactions Patient-Focused Outcomes Patients Pharmacology Population Public Health Relapse Research Resistance Reverse Transcription Role Signal Pathway T-Lymphocyte Testing Therapeutic Transcription Coactivator Treatment Efficacy United States National Institutes of Health Work Xenograft Model design effective therapy human disease improved in vivo inhibitor/antagonist knock-down melanoma mouse model new therapeutic target novel overexpression pre-clinical prevent resistance mechanism response role model targeted treatment tumor tumor microenvironment

项目摘要

Much of the recent focus of melanoma targeted therapy has been on the MAPK pathway, which is aberrantly activated in approximately 90% of melanoma tumors (over half of which express BRAFV600E). Current targeted therapies such as Vemurafenib (BRAFV600E inhibitor), or a combination therapy of BRAF and MEK inhibitors produce a profound initial response in a majority of BRAFV600E expressing tumors. However, these responses are often short-lived and resistance typically develops within months. Genomic analysis has failed to identify resistance mechanisms in >40% of human cutaneous melanoma tumors. Identifying novel BRAFi-resistance pathways will yield new drug targets and therapeutic approaches to treat melanoma. Sox10 downregulation promotes BRAFi resistance. My preliminary data suggests that cell line models of acquired Vemurafenib resistance with low Sox10 activate the RhoA pathway. In addition to the role of RhoA in regulating the cytoskeleton, RhoA can also regulate gene expression by activating multiple transcriptional co-activators (such as MRTF- A and YAP1). My preliminary data demonstrates that MRTF-A and YAP1 are also activated in Sox10Low BRAFi-resistant cells. The objective of this proposal is to identify the downstream mechanisms by which Sox10 loss promotes BRAFi resistance. This is important, since Sox10 loss is a major Vemurafenib resistance mechanism, but we lack approaches to effectively target these cells. Sox10 loss may also promote metastasis, and immune-evasion, so finding ways to target Sox10Low cells could be beneficial for other aspects of melanoma therapy. Using an integrated approach, work in this proposal will combine bioinformatics, molecular and cellular biology, pharmacology, and pre-clinical in vivo xenograft models I will: 1) Identify the mechanisms by which Sox10 loss promotes BRAFi resistance and 2) Test combination drug therapies targeting RhoA-regulated gene transcription and the MAPK pathway using in vivo PDX models. The long-term goal of this work is to develop effective therapies for the improved treatment of melanoma. Successful completion of this proposal will provide pre-clinical rationale for designing combination therapies targeting the MAPK pathway and RhoA-regulated gene transcription.

最近，黑色素瘤靶向疗法的许多重点都已放在MAPK途径上，在MAPK途径中，该途径被异常激活大约90％的黑色素瘤肿瘤（其中一半以上表达BRAFV600E）。当前有针对性的疗法，例如 vemurafenib（BRAFV600E抑制剂）或BRAF和MEK抑制剂的组合疗法产生了深刻的初始初始大多数BRAFV600E表达肿瘤的反应。但是，这些反应通常是短暂的和抵抗的通常在几个月内发展。基因组分析未能识别> 40％的人类的抗性机制皮肤黑色素瘤肿瘤。识别新型BRAFI抗性途径将产生新的药物靶标和治疗性治疗黑色素瘤的方法。 SOX10下调促进BRAFI抗性。我的初步数据表明获得的细胞系模型低Sox10的武马替尼电阻激活了RhoA途径。除了Rhoa在调节细胞骨架，RhoA还可以通过激活多个转录共激活剂来调节基因表达（例如MRTF- a和yap1）。我的初步数据表明，MRTF-A和YAP1也被激活细胞。该提案的目的是确定Sox10损失促进Brafi的下游机制反抗。这很重要，因为Sox10损失是一种主要的vemurafenib耐药机制，但我们缺乏方法有效靶向这些细胞。 Sox10损失也可能促进转移和免疫逃避，因此找到靶向的方法 SOX10LOW细胞可能对黑色素瘤治疗的其他方面有益。使用综合方法，该提案中的工作将结合生物信息学，分子和细胞生物学，药理学和临床前体内异种移植模型我将：1）确定SOX10损失促进的机制 BRAFI抗性和2）靶向RhoA调节基因转录和MAPK的测试组合药物疗法使用体内PDX模型的途径。这项工作的长期目标是开发有效的疗法，以改善黑色素瘤的治疗方法。成功的该提案的完成将为临床前的理由设计针对MAPK的组合疗法途径和RhoA调节的基因转录。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Inhibition of the Myocardin-Related Transcription Factor Pathway Increases Efficacy of Trametinib in NRAS-Mutant Melanoma Cell Lines.

DOI：
10.3390/cancers13092012
发表时间：
2021-04-22
期刊：
Cancers
影响因子：
5.2
作者：
Appleton KM;Palsuledesai CC;Misek SA;Blake M;Zagorski J;Gallo KA;Dexheimer TS;Neubig RR
通讯作者：
Neubig RR