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:10064616
- 负责人:
- 金额:$ 46.59万
- 依托单位:
- 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:
- 关键词:3-DimensionalActinsAnimalsAutoimmuneBRAF geneBiologyBlood VesselsBromodeoxyuridineCellsCharacteristicsCritical PathwaysDermal NeoplasmDermisDistantEndothelial CellsEpidermisFocal AdhesionsGenesGenetically Engineered MouseGenomicsGrowthHair follicle structureHealthHistologicHumanImageImmunotherapyIn VitroLabelLymphangiogenesisLymphaticLymphatic Endothelial CellsMalignant NeoplasmsMeasuresMelanoma CellMetastatic MelanomaMetastatic Neoplasm to Lymph NodesMetastatic Neoplasm to the LungModelingMolecularMonomeric GTP-Binding ProteinsNeoplasm MetastasisNevi and MelanomasNevusNutrientOncogenesOrganPatientsPharmacologyPlayPrognosisPublishingRoleSecondary toSignal TransductionSkinStressStress FibersTestingTherapeuticTherapeutic AgentsTissuesTransgenic MiceTumor AngiogenesisTumor BiologyTumor stageTumor-Associated ProcessVascular Endothelial CellWorkXenograft Modelangiogenesiscell growthhuman modelin vivoin vivo imaginginhibitor/antagonistkinase inhibitorlymph nodeslymphatic developmentlymphatic vesselmelanocytemelanomamigrationmouse modelmutantneoplastic cellnovelnovel therapeutic interventionpreventrecruitside effectsmall moleculestem cellstherapeutic targetthree-dimensional modelingtumortumor growthtumor initiationtumor progressionunpublished 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。
项目成果
期刊论文数量(0)
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Anand K Ganesan其他文献
Anand K Ganesan的其他文献
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{{ truncateString('Anand K Ganesan', 18)}}的其他基金
Identifying Therapeutic Targets for Stage III Melanoma
确定 III 期黑色素瘤的治疗靶点
- 批准号:
10520052 - 财政年份:2019
- 资助金额:
$ 46.59万 - 项目类别:
Identifying Therapeutic Targets for Stage III Melanoma
确定 III 期黑色素瘤的治疗靶点
- 批准号:
10299623 - 财政年份:2019
- 资助金额:
$ 46.59万 - 项目类别:
Uncovering the Origin and Growth Regulation of Melanocytic Nevi
揭示黑素细胞痣的起源和生长调节
- 批准号:
10013693 - 财政年份:2019
- 资助金额:
$ 46.59万 - 项目类别:
Identifying the Molecular Characteristics of Migrating Melanocytes in Vitiligo Skin
鉴定白癜风皮肤中迁移的黑素细胞的分子特征
- 批准号:
9510693 - 财政年份:2018
- 资助金额:
$ 46.59万 - 项目类别:
Identifying the Molecular Characteristics of Migrating Melanocytes in Vitiligo Skin
鉴定白癜风皮肤中迁移的黑素细胞的分子特征
- 批准号:
9762842 - 财政年份:2018
- 资助金额:
$ 46.59万 - 项目类别:
Project 2: Understanding the Cellular Origins of Melanoma
项目 2:了解黑色素瘤的细胞起源
- 批准号:
10392898 - 财政年份:2018
- 资助金额:
$ 46.59万 - 项目类别:
PAK Kinases Regulate Melanoma Chemoresistance and Metastasis
PAK 激酶调节黑色素瘤化疗耐药和转移
- 批准号:
8716685 - 财政年份:2013
- 资助金额:
$ 46.59万 - 项目类别:
Phosphoinositide Signaling Regulates Melanogenesis
磷酸肌醇信号调节黑色素生成
- 批准号:
8826025 - 财政年份:2013
- 资助金额:
$ 46.59万 - 项目类别:
PAK Kinases Regulate Melanoma Chemoresistance and Metastasis
PAK 激酶调节黑色素瘤化疗耐药和转移
- 批准号:
9262324 - 财政年份:2013
- 资助金额:
$ 46.59万 - 项目类别:
Phosphoinositide Signaling Regulates Melanogenesis
磷酸肌醇信号调节黑色素生成
- 批准号:
8456852 - 财政年份:2013
- 资助金额:
$ 46.59万 - 项目类别:
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