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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：
10299623
负责人：
Anand K Ganesan
金额：
$ 57.2万
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/10299623
关键词：
3-Dimensional Actins Animals 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 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 Pharmacology Play Prognosis Publishing Role Secondary to Signal Transduction Skin Stress Stress Fibers Testing Therapeutic Therapeutic Agents Tissues Transgenic Mice Tumor Angiogenesis Tumor Biology Tumor stage Tumor-Associated Process Vascular Endothelial Cell 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 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molecule stem cells therapeutic target three-dimensional modeling tumor tumor growth tumor initiation tumor progression unpublished works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.

在肿瘤发展过程中，黑色素瘤细胞必须离开表皮形成真皮肿瘤，