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molecule stem cells therapeutic target three-dimensional modeling tumor tumor growth tumor initiation tumor progression unpublished works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.

在肿瘤进展过程中，黑色素瘤细胞必须退出表皮以形成真皮肿瘤，募集淋巴管，然后迁移到淋巴结，然后转移到远处的器官。黑色素瘤的预后与肿瘤深度和淋巴结转移直接相关。因此，理想早期黑色素瘤的治疗剂不仅会阻止黑色素瘤侵袭，还会阻止防止肿瘤细胞进入淋巴管。我们小组的发表工作确定 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，在向淋巴结转移的黑色素瘤肿瘤。 Rhoj缺失拖延了BRAF突变体的生长黑色素瘤肿瘤并抑制体内Braf突变体Nevi的形成。除了其选择性角色在控制BRAF突变体黑素细胞的生长时，RhoJ在肿瘤血管生成中起着特定的作用。周围内皮细胞中的Rhoj信号传导诱导它们产生作为导管的血管两种营养素都进入肿瘤和转移细胞以退出肿瘤。最近未发表的作品提出Rhoj缺失抑制了淋巴内皮细胞在周围形成血管的能力肿瘤。此外，抑制Rhoj信号传导的小分子似乎不仅阻止了体内黑色素瘤肿瘤，但也阻塞了内皮细胞产生血管喂养肿瘤的能力细胞体外。在这里，我们建议Rhoj在肿瘤生物学中具有双重作用 - 它在黑素细胞中起作用促进肿瘤的形成和内皮细胞内以促进淋巴的形成皮肤肿瘤周围的血管，以及远处器官中肿瘤周围的血管。我们使用一个最先进的单细胞基因组学，体内成像，新型药理学和转基因小鼠模型：1）确定RhoJ在黑素细胞中的作用如何促进早期的生长阶段肿瘤； 2）确定RHOJ是否在淋巴内皮细胞中作用以控制肿瘤淋巴管生成； 3）评估Rhoj对肿瘤生长的相对贡献体内和人类肿瘤3D模型中的淋巴作用/血管生成。这些研究的完成将定义一种新的治疗策略，该策略通过同时靶向两个肿瘤来阻止癌症的进展细胞和喂养它们的容器。