Targeting Rheostatic Mechanisms of Melanoma Progression

针对黑色素瘤进展的变阻机制

• 批准号: 10441460
• 负责人: Allie H. Grossmann
• 金额: $ 34.88万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441460
• 关键词: ADP-ribosylation factor 6; Adult; Affect; Aftercare; Anoikis; Apoptosis; Apoptotic; BRAF gene; Biological Assay; Biological Markers; CRISPR/Cas technology; Cell Line; Cell Proliferation; Cell Survival; Cell physiology; Child; Clinical; Combined Modality Therapy; Cutaneous Melanoma; Data; Disease; Disease Progression; Drug resistance; Elderly; Engineering; Genes; Genetic; Goals; Growth; Growth and Development function; Human; Impairment; In Situ Nick-End Labeling; In Vitro; Incidence; Link; MAP Kinase Gene; MEK inhibition; MEKs; Maintenance; Malignant Neoplasms; Measures; Mediating; Melanoma Cell; Metastatic Melanoma; Mitosis; Modeling; Molecular; Monomeric GTP-Binding Proteins; Mus; Mutation; Neoplasm Metastasis; Nuclear; Oncogenic; PI3K/AKT; Pathway interactions; Patients; Pharmacology; Positioning Attribute; Preclinical Testing; Primary Neoplasm; Proteins; Proteomics; Publishing; Recurrence; Regulation; Reporting; Resistance; Role; Safety; Serum; Signal Transduction; Signaling Protein; Specificity; Stains; Testing; Therapeutic Intervention; Treatment Efficacy; Treatment outcome; Withdrawal; anticancer research; burden of illness; cancer type; cohort; efficacy testing; experimental study; improved; in vivo; inhibitor; insight; melanocyte; melanoma; middle age; mouse model; mutant; neoplastic cell; novel; novel therapeutics; patient derived xenograft model; protein transport; ras Proteins; response; standard of care; success; targeted treatment; therapeutic target; trafficking; transcriptome; tumor; tumor DNA; tumor growth; tumor initiation; tumor progression; young adult

Cutaneous melanoma is highly lethal and the fifth most common cancer in the U.S. Peak incidence is in middle age adults but the elderly, young adults and even children are affected. Among all cancer types, melanoma is one of the most aggressive in its propensity for extremely early metastasis. Metastatic melanoma is difficult to eradicate and new therapies are urgently needed to limit disease progression. Genetic causes of melanoma align along a continuum of RAS protein signaling whereby BRAFV600E mutation is the most common driver. The mutant BRAFV600E protein depends on MAPK signaling for both initiation and maintenance of tumor growth. Targeting this abnormally-activated pathway with RAF and MEK inhibitors have had limited success in treating this disease due to MAPK signaling reactivation, causing drug resistance. Thus, more mechanistic insights are needed in order to develop combination therapies that can circumvent resistance. We reported that aberrant activation of the small GTPase ARF6, a protein that controls intracellular trafficking, accelerates metastasis of BRAFV600E melanoma. Prior to metastasis, our unpublished data reveal that the protein ARF6 is also required for efficient tumor development and growth in mice with BRAFV600E melanoma. This positions ARF6 as a key regulator at multiple points in disease progression. Indeed, our preliminary data suggest a novel role for ARF6 in MAPK signaling by regulating the nuclear localization of activated, phospho-ERK, a key effector protein for BRAF. Thus, we hypothesize that ARF6 modulates BRAFV600E-mediated tumor progression, controlling MAPK signaling and providing a vulnerable node for pharmacologic inhibition of both tumor growth and metastasis. Using genetic and pharmacologic approaches, including our unique mouse models and a specific ARF6 inhibitor that we helped develop, our goals are to dissect the roles of ARF6 in MAPK signaling, discover new role(s) for ARF6 in tumor cell function, and test the efficacy of ARF6 inhibitors in restricting tumor progression. Pursuant to these goals, we will: 1) Test the hypothesis that ARF6 controls MAPK signaling in BRAFV600E-melanoma; 2) Test the hypothesis that ARF6 is critical for proliferation and survival of BRAFV600E melanoma; 3) Test the hypothesis that pharmacologic inhibition of ARF6 has therapeutic efficacy in BRAFV600E melanoma patient-derived xenografts (MPDX). Successful completion of the aims in this proposal will identify new mechanisms of melanoma progression that are amenable to therapeutic intervention and may position ARF6 as a potential therapeutic target in RAS-mutant cancers.

皮肤黑色素瘤高度致命，美国第五大癌症是中间的峰值发病率 年龄的成年人，但老年人，年轻人甚至儿童受到影响。在所有癌症类型中，黑色素瘤是 它对极早转移的倾向最具侵略性的是。转移性黑色素瘤很难 迫切需要根除和新疗法以限制疾病进展。黑色素瘤的遗传原因 沿着RAS蛋白信号的连续体对齐，BRAFV600E突变是最常见的驱动因素。这 突变的BRAFV600E蛋白依赖于MAPK信号传导肿瘤生长的启动和维持。 针对RAF和MEK抑制剂的这种异常激活的途径在治疗方面的成功有限 由于MAPK信号转导重新激活而引起的这种疾病，导致耐药性。因此，更多的机械见解是 为了开发可以规避耐药性的组合疗法所需的。我们报告了异常 小型GTPase ARF6的激活，一种控制细胞内运输的蛋白质，加速了转移的转移 BRAFV600E黑色素瘤。转移之前，我们未发表的数据表明，蛋白质ARF6也需要 BRAFV600E黑色素瘤小鼠的有效肿瘤发育和生长。这将ARF6定位为钥匙 疾病进展多个点的调节剂。实际上，我们的初步数据表明ARF6的新作用 在MAPK信号传导中，通过调节激活的核定位置，磷酸化，一种关键效应蛋白 布拉夫。因此，我们假设ARF6调节BRAFV600E介导的肿瘤进展，控制MAPK 信号传导并提供了对肿瘤生长和转移的药理抑制的脆弱节点。 使用遗传和药理学方法，包括我们独特的小鼠模型和特定的ARF6抑制剂 我们帮助发展的，我们的目标是剖析ARF6在MAPK信号传导中的作用，发现新角色 ARF6在肿瘤细胞功能中，并测试ARF6抑制剂在限制肿瘤进展中的功效。根据 这些目标，我们将：1）检验以下假设：ARF6控制BRAFV600E-Melanoma中的MAPK信号； 2）测试 ARF6对于BRAFV600E黑色素瘤的增殖和存活至关重要的假设； 3）检验假设 ARF6的药理抑制作用在BRAFV600E黑色素瘤患者衍生方面具有治疗功效 异种移植物（MPDX）。在此提案中成功完成目标将确定 黑色素瘤的进展适合治疗干预，可能将ARF6定位为潜力 RAS突变癌的治疗靶标。