RasGRP3 and Protein Kinase D as therapeutic targets for Uveal Melanoma

RasGRP3 和蛋白激酶 D 作为葡萄膜黑色素瘤的治疗靶点

基本信息

批准号：
10584705
负责人：
Xu Chen
金额：
$ 45.47万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10584705
关键词：
Automobile Driving BRAF gene Binding CRISPR/Cas technology Cell Proliferation Cell membrane ChIP-seq Clinical Trials Combined Modality Therapy Complication Coupled Cutaneous Melanoma Data Diglycerides Disease Enhancers Epigenetic Process Feedback Future GNAQ gene Generations Genetic Genetic Engineering Genetic Transcription Genetically Engineered Mouse Goals Guanine Nucleotide Exchange Factors Knock-in Mouse Knock-out Knockout Mice Link Liver MAP Kinase Gene MAP kinase activator MEK inhibition MEKs Malignant Neoplasms Mediating Metastatic Neoplasm to the Liver Metastatic to Mitogen-Activated Protein Kinases Molecular Molecular Biology Molecular Genetics Molecular Target Mutation NF1 gene Neoplasm Metastasis Oncogenic Output Pathway interactions Patients Phospholipase Phospholipase C Phosphorylation Phosphotransferases Proliferating Protein Inhibition Protein Kinase C Reagent Regulation Research Personnel Resistance Signal Pathway Signal Transduction Somatic Mutation System Testing Toxic effect Treatment Efficacy Up-Regulation Uveal Melanoma Xenograft Model clinical efficacy design effective therapy experience experimental study immune checkpoint blockade improved inhibitor innovation knock-down malignant neoplasm of eye melanoma molecular pathology mortality mouse model mutant new therapeutic target novel novel therapeutic intervention overexpression pharmacologic phosphoproteomics pre-clinical prevent protein kinase D receptor response success targeted treatment therapeutic target tool transcription factor transcriptome sequencing

项目摘要

Project summary: Uveal melanoma (UM) accounts for approximately 5% of all melanomas and is the most lethal type of melanoma. 50% of UM patients develop metastasis, mostly to the liver, an invariably lethal complication, which currently cannot be effectively treated. Despite dramatic successes in other melanoma subtypes, immune checkpoint blockade, and targeted therapies have been largely ineffective in metastatic UM and there is an urgent need to identify effective therapies. UM lacks mutations in BRAF, NRAS, NF1 and KIT common in cutaneous melanomas and is genetically defined by mutations in the Gaq signaling pathway. We discovered that RasGRP3, a Ras-guanyl nucleotide exchange factor (RasGEF), is dramatically overexpressed in UM compared to other melanoma subtypes and cancers and links the constitutively activated Gaq pathway to the MAP- kinase pathway. RasGRP3 is also directly activated by oncogenic Gaq signaling via mechanisms that partially depend on PKC. We hypothesize that RasGRP3 is a therapeutic target in UM and seek to understand the mechanism behind its marked upregulation to identify alternative targets for therapy. Our preliminary data implicate protein kinase D (PKD) downstream of PKC to be directly involved in RasGRP3 regulation. Our data also demonstrate that PKD is involved in the adaptive resistance that undermines the efficacy of MEK inhibitors. As a druggable kinase, PKD thus is a possible therapeutic target in UM. In this proposal, we will evaluate both RasGRP3 and PKD as therapeutic targets using newly developed genetically engineered and xenograft models of UM metastatic to the liver and investigate the underlying mechanism of RasGRP3 upregulation in UM (Aim 1 and 2). In Aim 3, we will dissect the mechanism underlying the adaptive resistance to MEK inhibition, which represents a key bottleneck limiting the therapeutic efficacy of MEK inhibition, to identify rational therapy combinations that overcome this resistance and improve the therapeutic efficacy of MEK inhibition in the setting of metastatic UM.

项目概要：葡萄膜黑色素瘤 (UM) 约占所有黑色素瘤的 5%，是最常见的黑色素瘤。致命类型的黑色素瘤。 50% 的 UM 患者出现转移，主要转移至肝脏，总是致命的并发症，目前无法有效治疗。尽管在其他黑色素瘤亚型、免疫检查点阻断和靶向治疗对转移性 UM 基本上无效，因此迫切需要需要确定有效的治疗方法。 UM 缺乏 BRAF、NRAS、NF1 和 KIT 突变常见于皮肤黑色素瘤，基因上由 Gaq 突变决定信号通路。我们发现RasGRP3，一种Ras-鸟苷酸交换与其他黑色素瘤相比，RasGEF 因子在 UM 中显着过度表达亚型和癌症，并将组成型激活的 Gaq 通路与 MAP-联系起来激酶途径。 RasGRP3 还可通过致癌 Gaq 信号直接激活部分依赖于 PKC 的机制。我们假设 RasGRP3 是一种治疗药物以 UM 为目标，并寻求了解其显着上调背后的机制确定替代治疗目标。我们的初步数据表明蛋白激酶 D (PKD) PKC 下游直接参与 RasGRP3 调节。我们的数据还证明 PKD 参与了破坏疗效的适应性抵抗 MEK 抑制剂。作为一种可药物激酶，PKD 因此是 UM 的一个可能的治疗靶点。在本提案中，我们将使用 RasGRP3 和 PKD 作为治疗靶点来评估新开发的 UM 转移到的基因工程和异种移植模型肝脏并研究 UM 中 RasGRP3 上调的潜在机制（目标 1 和2）。在目标 3 中，我们将剖析 MEK 适应性抵抗的机制抑制，这是限制 MEK 治疗效果的关键瓶颈抑制，以确定克服这种阻力的合理治疗组合提高 MEK 抑制在转移性 UM 中的治疗效果。