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

• 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
• 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

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）占所有黑色素瘤的约5%，是最常见的黑色素瘤。 致命的黑色素瘤50%的UM患者发生转移，主要转移到肝脏， 这些并发症目前无法得到有效治疗。尽管 在其他黑色素瘤亚型、免疫检查点阻断和 靶向治疗在转移性UM中很大程度上无效， 需要找到有效的治疗方法。UM缺乏BRAF、NRAS、NF 1和KIT突变 常见于皮肤黑色素瘤，由Gaq基因突变遗传定义。 信号通路我们发现RasGRP 3，一种Ras-鸟苷酸交换， 与其他黑色素瘤相比， 亚型和癌症，并将组成性激活的Gaq途径与MAP- 激酶途径RasGRP 3也通过致癌Gaq信号传导直接激活， 部分依赖于PKC的机制。我们假设RasGRP 3是一种治疗药物， 目标是UM，并试图了解其显着上调背后的机制， 确定治疗的替代靶点。我们的初步数据表明蛋白激酶D (PKD)PKC下游直接参与RasGRP 3的调节。我们的数据还 证明PKD参与了破坏疗效的适应性抗性， MEK抑制剂。PKD作为一种可药物化的激酶，因此是UM的一个可能的治疗靶点。 在本提案中，我们将使用以下方法评估RasGRP 3和PKD作为治疗靶点： 新开发的遗传工程和转移到肿瘤的UM异种移植模型 研究UM中RasGRP 3上调的潜在机制（目的1 和2）。在目标3中，我们将剖析对MEK的适应性抗性的机制 抑制，这是限制MEK治疗效果的关键瓶颈 抑制，以确定克服这种耐药性的合理治疗组合， 改善MEK抑制在转移性UM情况下的治疗功效。