Targeting Rheostatic Mechanisms of Melanoma Progression

针对黑色素瘤进展的变阻机制

• 批准号: 10653021
• 负责人: Allie H. Grossmann
• 金额: $ 34.19万
• 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/10653021
• 关键词: ADP-ribosylation factor 6; Acceleration; 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; Invaded; 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; PIK3CG gene; Pathway interactions; Patients; Positioning Attribute; Preclinical Testing; Primary Neoplasm; Proliferating; Proteins; Proteomics; Publishing; RAS driven cancer; 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; pharmacologic; 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.

皮肤黑色素瘤具有高度致命性，是美国第五大常见癌症。高峰发病率处于中等水平 但老年人、年轻人甚至儿童都会受到影响。在所有癌症类型中，黑色素瘤是 具有极早期转移倾向的最具侵袭性的肿瘤之一。转移性黑色素瘤很难 迫切需要根除和新疗法来限制疾病进展。黑色素瘤的遗传原因 沿着 RAS 蛋白信号传导的连续体排列，其中 BRAFV600E 突变是最常见的驱动因素。这 突变型 BRAFV600E 蛋白依赖于 MAPK 信号传导来启动和维持肿瘤生长。 使用 RAF 和 MEK 抑制剂针对这种异常激活的通路在治疗方面取得的成功有限 这种疾病由于MAPK信号重新激活，引起耐药性。因此，更多的机械见解是 需要开发可以规避耐药性的联合疗法。我们报告了异常情况 小 GTP 酶 ARF6（一种控制细胞内运输的蛋白质）的激活可加速肿瘤的转移 BRAFV600E 黑色素瘤。在转移之前，我们未发表的数据表明，蛋白质 ARF6 也是转移所需的 BRAFV600E 黑色素瘤小鼠的有效肿瘤发育和生长。这将 ARF6 定位为关键 在疾病进展的多个点上发挥调节作用。事实上，我们的初步数据表明 ARF6 具有新的作用 通过调节激活的磷酸-ERK（一种关键效应蛋白）的核定位来参与 MAPK 信号传导 布拉夫。因此，我们假设 ARF6 调节 BRAFV600E 介导的肿瘤进展，控制 MAPK 信号传递并为肿瘤生长和转移的药理学抑制提供脆弱的节点。 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 我们帮助开发的，我们的目标是剖析 ARF6 在 MAPK 信号传导中的作用，发现新的作用 ARF6在肿瘤细胞中的功能，并测试ARF6抑制剂在限制肿瘤进展方面的功效。根据 为了实现这些目标，我们将： 1) 检验 ARF6 控制 BRAFV600E-黑色素瘤中 MAPK 信号传导的假设； 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 的药物抑制对 BRAFV600E 患者来源的黑色素瘤具有治疗功效 异种移植物（MPDX）。成功完成本提案中的目标将确定新的机制 黑色素瘤进展适合治疗干预，并且可能将 ARF6 定位为潜在的 RAS突变癌症的治疗靶点。