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Identifying Therapeutic Targets for Stage III Melanoma

确定 III 期黑色素瘤的治疗靶点

基本信息

批准号：
10520052
负责人：
Anand K Ganesan
金额：
$ 52.5万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
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：
2019-12-04 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10520052
关键词：
3-Dimensional Acceleration Actins Animals Apoptotic Autoimmune BRAF gene Biology Blood Vessels Bromodeoxyuridine Cells Characteristics Critical Pathways Dermal Neoplasm Dermis Distant Endothelial Cells Epidermis Focal Adhesions Genes Genetically Engineered Mouse Genomics Growth Hair follicle structure Health Histologic Human Image Immunotherapy In Vitro Invaded Label Lymphangiogenesis Lymphatic Lymphatic Endothelial Cells Malignant Neoplasms Measures Melanoma Cell Metastatic Melanoma Metastatic Neoplasm to Lymph Nodes Metastatic Neoplasm to the Lung Modeling Molecular Monomeric GTP-Binding Proteins Neoplasm Metastasis Nevi and Melanomas Nevus Nutrient Oncogenes Organ Patients Play Prognosis Publishing Role Secondary to Signal Transduction Skin Stress Stress Fibers Testing Therapeutic Therapeutic Agents Tissues Transgenic Mice Tumor Angiogenesis Tumor Biology Tumor Promotion Tumor stage Tumor-Associated Process Vascular Endothelial Cell Vascularization Work Xenograft Model angiogenesis cell growth human model in vivo in vivo imaging inhibitor kinase inhibitor lymph nodes lymphatic development lymphatic vessel melanocyte melanoma migration mouse model mutant neoplastic cell novel novel therapeutic intervention pharmacologic prevent recruit side effect small molecule stem cells therapeutic target three-dimensional modeling tumor tumor growth tumor initiation tumor progression unpublished works

项目摘要

During the process of tumor progression, melanoma cells must exit the epidermis to form a dermal tumor, recruit lymphatic vessels, and then migrate to lymph nodes before metastasizing to distant organs. Melanoma prognosis directly correlates with tumor depth and lymph node metastasis. Therefore, ideal therapeutic agents for early stage melanoma would not only block melanoma invasion but also prevent tumor cells from accessing lymphatic vessels. Published work from our group determined that RhoJ, a gene that allows melanoma cells to resist BRAF oncogene-induced stress, is highly expressed in melanoma tumors that metastasize to the lymph node. RhoJ deletion stalled the growth of BRAF mutant melanoma tumors and inhibited the formation of BRAF mutant nevi in vivo. In addition to its selective role in controlling the growth of BRAF mutant melanocytes, RhoJ plays a specific role in tumor angiogenesis. RhoJ signaling in peritumoral endothelial cells induces them to generate vessels that serve as conduits for both nutrients to enter tumors and metastasizing cells to exit tumors. Recent yet unpublished work suggested that RhoJ deletion inhibited the ability of lymphatic endothelial cells to form vessels around tumors. Moreover, small molecules that inhibit RhoJ signaling seemed to not only block the growth of melanoma tumors in vivo, but also blocked the ability of endothelial cells to generate vessels to feed tumor cells in vitro. Here we propose that RhoJ has a dual role in tumor biology- it acts within the melanocyte to promote the formation of tumors and within the endothelial cells to promote the formation of lymphatic vessels around tumors in the skin, and blood vessels around tumors in distant organs. We use a combination of state of the art single cell genomics, in vivo imaging, novel pharmacologic agents, and transgenic mouse models to: 1) determine how RhoJ acts in the melanocyte to promote the growth of early stage tumors; 2) establish whether RhoJ acts in lymphatic endothelial cells to control tumor lymphangiogenesis; 3) assess the relative contributions of RhoJ to tumor growth and lymphanigogenesis/angiogenesis in vivo and in 3D models of human tumors. Completion of these studies will define a new therapeutic strategy that halts cancer progression by simultaneously targeting both tumor cells and the vessels that feed them.

在肿瘤进展过程中，黑色素瘤细胞必须离开表皮形成真皮肿瘤，募集淋巴管，然后在转移到远处器官之前迁移到淋巴结。黑色素瘤的预后与肿瘤的深度和淋巴结转移直接相关。因此，理想用于早期黑素瘤的治疗剂不仅可以阻断黑素瘤侵袭，阻止肿瘤细胞进入淋巴管。我们小组发表的研究结果表明， RhoJ是一种允许黑色素瘤细胞抵抗BRAF癌基因诱导的应激的基因，在黑色素瘤细胞中高度表达。转移到淋巴结的黑色素瘤RhoJ缺失使BRAF突变体的生长停滞黑色素瘤肿瘤，并抑制体内BRAF突变痣的形成。除了它的选择性作用之外，在控制BRAF突变黑素细胞的生长中，RhoJ在肿瘤血管生成中发挥特异性作用。肿瘤周围内皮细胞中的RhoJ信号诱导它们产生血管，作为肿瘤生长的导管。既有营养物质进入肿瘤，又有转移细胞离开肿瘤。近期未发表的作品表明RhoJ缺失抑制淋巴管内皮细胞在周围形成血管的能力，肿瘤的此外，抑制RhoJ信号传导的小分子似乎不仅阻止了细胞的生长，在体内黑色素瘤肿瘤，而且还阻止了内皮细胞产生血管的能力，以养活肿瘤体外细胞在这里，我们提出RhoJ在肿瘤生物学中具有双重作用-它在黑素细胞内起作用，促进肿瘤的形成和内皮细胞内淋巴管的形成皮肤中肿瘤周围的血管和远处器官中肿瘤周围的血管。我们使用一个现有技术的单细胞基因组学、体内成像、新型药理学试剂和转基因小鼠模型：1）确定RhoJ如何在黑素细胞中起作用以促进早期黑素细胞的生长， 2）确定RhoJ是否在淋巴管内皮细胞中起作用以控制肿瘤 3）评估RhoJ对肿瘤生长的相对贡献，淋巴管生成/血管生成在体内和人肿瘤的3D模型中。完成这些研究将定义一种新的治疗策略，通过同时靶向两种肿瘤，细胞和供养它们的血管。