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Defining the role of NF1 and SPRED1 loss in melanoma

定义 NF1 和 SPRED1 缺失在黑色素瘤中的作用

基本信息

批准号：
10593075
负责人：
Iwei Yeh
金额：
$ 48.75万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593075
关键词：
Acral Lentiginous Malignant Melanoma Address Adjuvant Affect BRAF gene Binding Catalogs Cell Line Cell membrane Cells Clinical Combined Modality Therapy Complex Data Development Disease ERBB2 gene Environment Epidemiology Ethnic Origin Extinction Feedback Genetic Genetic Engineering Genetically Engineered Mouse Genome Guanosine Triphosphate Hand Human Engineering Immunotherapy In Vitro Individual Invaded Lead Light MAP Kinase Gene MEKs Malignant - descriptor Malignant Neoplasms Melanoma Cell Membrane Metastatic Melanoma Mitogen-Activated Protein Kinases Mucous Membrane Mutation NF1 gene NF1 mutation Nail plate Oncogenes Oncogenic Outcome Pathway interactions Patient-Focused Outcomes Patients Pattern Population Proliferating Receptor Protein-Tyrosine Kinases Recurrence Regimen Research Research Personnel Role Signal Pathway Signal Transduction Site Skin Skin tanning Sun Exposure Surface Testing Therapeutic Treatment Efficacy Tumor Suppressor Proteins Tumorigenicity Ultraviolet Rays Work Xenograft procedure driver mutation drug action foot gain of function genetic makeup immune checkpoint blockade improved improved outcome in vivo inhibitor innovation insight loss of function mutation melanoma member mortality mouse model mucosal melanoma mutant novel novel therapeutics patient population patient response ras GTPase-Activating Proteins response targeted treatment the sun therapeutic target treatment strategy

项目摘要

Project Summary/Abstract In melanoma, loss of function mutations in NF1 are the third most common oncogenic alteration after activating mutations in BRAF and NRAS. The RAS GTPase-activating protein NF1 provides negative feedback from the MAPK pathway to RAS by binding to SPRED1 at the plasma membrane where it is inactivates RAS-GTP. We recently discovered recurrent inactivating mutations of SPRED1 in melanoma, occurring in a mutually exclusive pattern with inactivating NF1 mutations, consistent with their functional overlap. Inactivation of either tumor suppressor often co-occurs with additional MAPK activating mutations such as activating mutations of KIT. We hypothesize that NF1 or SPRED1 inactivation may reduce the efficacy of therapeutic inhibition of KIT and similar gain of function alterations in the MAPK pathway. The objective of this research is to identify the spectrum of additional MAPK activating alterations that occur in the setting of NF1 or SPRED1 loss and to determine the role of NF1 or SPRED1 in melanoma progression and response to targeted therapies. Our central hypothesis is that NF1 or SPRED1 loss increases MAPK signaling but that full malignant transformation requires additional alterations that feed into the MAPK pathway. We will catalogue the spectrum of cooperators that form oncogenic pairs with NF1 or SPRED1 inactivation and validate their contributions to tumorigenicity both in vitro and in vivo. We hypothesize that identifying oncogenic pairs and developing therapeutic strategies that address both members of a pair will lead to improved outcomes for patients. We will provide proof of principle for this concept by building on our preliminary data that dual inhibition of KIT and MEK are synergistic for melanomas with an oncogenic pair consisting of KIT mutation and NF1 or SPRED1 loss. We will test combination therapies in genetically engineered human melanoma cell lines and mouse models. We will also investigate the direct physical interaction between KIT and SPRED1, which may lead to additional avenues for inhibiting melanomas with KIT or SPRED1 mutations. This work will provide a framework for similar studies for other cooperators of NF1 and SPRED1. This research is significant since it will lead to novel therapies for a significant number of melanoma patients for whom targeted therapies are not currently available. The proposed research is innovative because it tests a novel hypothesis why treatment of mutations such as KIT have limited efficacy in melanoma. Shedding light onto the complex signaling pathway perturbations in the considerable share of melanomas with NF1 or SPRED1 will have a considerable impact for patients with melanomas for which treatment options are currently limited.

项目概要/摘要在黑色素瘤中，NF1 功能缺失突变是继激活后第三种最常见的致癌改变 BRAF 和 NRAS 突变。 RAS GTPase 激活蛋白 NF1 提供负反馈 MAPK 通路通过与质膜上的 SPRED1 结合而使 RAS-GTP 失活。我们最近发现黑色素瘤中 SPRED1 反复失活突变，发生在相互 NF1 失活突变的独特模式，与其功能重叠一致。任一者失活肿瘤抑制因子通常与其他 MAPK 激活突变同时发生，例如成套工具。我们假设 NF1 或 SPRED1 失活可能会降低 KIT 治疗抑制的功效 MAPK 通路中类似的功能改变。这项研究的目的是确定在 NF1 或 SPRED1 缺失的情况下发生的额外 MAPK 激活改变的范围，以及确定 NF1 或 SPRED1 在黑色素瘤进展和靶向治疗反应中的作用。我们的中心假设是 NF1 或 SPRED1 缺失会增加 MAPK 信号传导，但完全恶性转化需要额外的改变进入 MAPK 通路。我们将对合作伙伴进行分类与 NF1 或 SPRED1 失活形成致癌对，并验证它们对致瘤性的贡献体外和体内。我们假设识别致癌基因对并制定治疗策略针对一对中的两个成员的治疗将改善患者的治疗结果。我们将提供证明这一概念的原理基于我们的初步数据，即 KIT 和 MEK 的双重抑制具有协同作用用于具有由 KIT 突变和 NF1 或 SPRED1 缺失组成的致癌对的黑色素瘤。我们将测试基因工程人类黑色素瘤细胞系和小鼠模型的联合疗法。我们还将研究 KIT 和 SPRED1 之间的直接物理相互作用，这可能会导致额外的途径抑制具有 KIT 或 SPRED1 突变的黑色素瘤。这项工作将为类似研究提供一个框架 NF1和SPRED1的其他合作者。这项研究意义重大，因为它将带来新的治疗方法目前还没有针对大量黑色素瘤患者的靶向治疗。这拟议的研究具有创新性，因为它测试了一个新的假设，即为什么要治疗 KIT 等突变对黑色素瘤的疗效有限。揭示复杂的信号通路扰动相当大比例的 NF1 或 SPRED1 黑色素瘤将对患有以下疾病的患者产生相当大的影响：目前治疗选择有限的黑色素瘤。