Lysosomal TRP channels in metastatic melanoma

转移性黑色素瘤中的溶酶体 TRP 通道

基本信息

批准号：
10428490
负责人：
Wanlu Du
金额：
$ 11.99万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10428490
关键词：
Affinity Agonist Arteries Brain Cations Cell Culture Techniques Cell Death Cell Membrane Permeability Cell Survival Cells Chelating Agents Clinical Cutaneous Melanoma Cytosol Dominant-Negative Mutation Failure Genetic Engineering Glycolysis Glycolysis Inhibition Goals Hour Human Image Immunocompromised Host In Vitro Injections Intracarotid Ions Knock-out Lead Link Luciferases Lysosomes Malignant Neoplasms Measures Mediating Melanoma Cell Metabolic Metastatic Melanoma Metastatic malignant neoplasm to brain Methods Mitochondria Modeling Molecular Monitor Mus Neoplasm Metastasis Normal Cell Organelles Outcome Patients Permeability Pharmaceutical Preparations Pharmacology Predisposition Production Prognostic Marker Property Recycling Regimen Reporting Research Skin Cancer Specificity Suggestion Survival Rate TRP channel Testing Therapeutic Vesicle Work anti-cancer antitumor effect bioluminescence imaging cancer cell cancer type cell type chelation clinically relevant cytotoxicity imaging modality in vivo inhibitor innovation insight intraperitoneal late endosome melanocyte melanoma mitochondrial dysfunction mouse model mutant nanomolar novel novel therapeutic intervention response small molecule treatment strategy tumor growth tumor progression

项目摘要

Lysosomal TRP channels in metastatic melanoma Melanoma is the most aggressive form of skin cancer of the highest propensity to metastasize into the brain. Up to 75% of patients with advanced melanoma eventually develop brain metastases. Of patients with melanoma brain metastases (MBM), therapeutic regimens are quite limited and the 5-year survival rate is below 5%. Thus, it is of urgent need to develop new therapeutic strategies to specifically eradicate metastatic melanoma cells while sparing normal cells. We hypothesize that vesicular TRP channels can be pharmacologically targeted to reduce melanoma cell survival by modulating channel properties. We have developed a new method to measure lysosomal TRP channel activity of melanoma cells using genetically-engineered ion indicators and small-molecule TRPML1 modulator. The primary goals of this R21 application are to test a clinically-relevant hypothesis that pharmacologically modulation of ML1 reduces melanoma cell survival. Aim 1 is to investigate the molecular mechanisms underlying melanoma cell susceptibility induced by small-molecule TRPML1 modulator. Aim 2 is to determine the in vivo efficacy of such modulator in melanoma brain metastases mouse model. Our long-term goal is to develop new and efficient therapeutic approaches for eradicating metastatic melanoma.

转移性黑色素瘤中的溶酶体TRP通道黑色素瘤是最侵略性的皮肤癌，是转移到大脑的最高倾向。多达75％的晚期黑色素瘤患者最终会发展出脑转移。在黑色素瘤脑转移（MBM）的患者中，治疗方案非常有限，5年生存率低于5％。因此，迫切需要开发新的治疗策略，以在避免正常细胞的同时特别根除转移性黑色素瘤细胞。我们假设可以将囊泡TRP通道用于药理靶向，以通过调节通道特性来降低黑色素瘤细胞的存活。我们开发了一种新方法，使用遗传工程的离子指示剂和小分子TRPML1调节剂测量黑色素瘤细胞的溶酶体TRP通道活性。该R21应用的主要目标是检验与临床上相关的假设，即ML1的药理调节可降低黑色素瘤细胞的存活。目的1是研究小分子TRPML1调节剂引起的黑色素瘤细胞易感性的分子机制。目的2是确定这种调节剂在黑色素瘤脑转移小鼠模型中的体内功效。我们的长期目标是开发新的有效的治疗方法来消除转移性黑色素瘤。