Using Single Cell Analysis to identify therapeutic vulnerabilities in leptomeningeal melanoma metastases
使用单细胞分析确定软脑膜黑色素瘤转移的治疗漏洞
基本信息
- 批准号:9452934
- 负责人:
- 金额:$ 22.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-03-13 至 2019-02-28
- 项目状态:已结题
- 来源:
- 关键词:Arachnoid MembraneAreaBRAF geneBiologyBrainCellsCerebrospinal FluidCessation of lifeClinical TrialsClonal EvolutionClonalityCollectionCombined Modality TherapyDNADNA Sequence AlterationDNA analysisDNA sequencingDataDevelopmentDiseaseDrug CombinationsDrug TargetingGeneticGenetic TranscriptionGoalsHeterogeneityHome environmentHumanImmunotherapyImplantIncidenceInfiltrationLabelLeptomeningeal MelanomaLeptomeningesLungMEKsMelanoma CellMessenger RNAMetastatic Neoplasm to the LeptomeningesMetastatic malignant neoplasm to brainMethodsModelingMusMutationNeoplasm Circulating CellsNeoplasm MetastasisOncogenicOrganPathway interactionsPatient-Focused OutcomesPatientsPatternPharmacotherapyPhylogenetic AnalysisPia MaterPopulationProtocols documentationRNA amplificationRNA analysisRelapseResearchSamplingSeedsSignal PathwaySiteSkinSpecimenSubarachnoid SpaceTestingTherapeuticTimeValidationVisceralVisceral metastasisXenograft ModelXenograft procedureactionable mutationbaseclinical developmentclinically relevantcohorteffective therapyexperienceexperimental studygenetic profilingimproved outcomeinhibitor/antagonistinsightmelanomamouse modelmutantnew therapeutic targetnoveloutcome forecastprogramsprospectiveresistance mechanismresponsesingle cell analysistargeted agenttargeted treatmenttherapeutic targettumor
项目摘要
Project summary
The long-term goal of this research program is to develop therapeutic strategies that
improve the outcome of patients with disseminated melanoma. Melanoma is a highly
metastatic tumor, with a propensity to disseminate to the skin, lungs and brain. In ~5% of
cases, patients also develop leptomeningeal melanoma metastases (LMM: e.g.
melanoma cell infiltration into the pia mater, the arachnoid membranes and
cerebrospinal fluid) which have an even worse prognosis and a median survival of 8-10
weeks. It is likely that the leptomeninges represent “sanctuary sites” for melanoma cells
that evade both targeted and immune therapies. At this time, no therapeutic strategies
have been identified that are effective against LMM. Melanomas are genetically
heterogeneous, suggesting that distinct genetic clones/patterns of mutation determine
which cells home to the brain and leptomeninges. Progress in this area has been limited
due to the technical difficulties of obtaining specimens from the leptomeninges,
cerebrospinal fluid (CSF) and sub-arachnoid space. Recently our group has begun the
routine collection of CSF from patients with LMM, which we have shown to contain
circulating melanoma cells (circulating tumor cells: CTCs). We have also established
protocols to obtain serial CSF samples from patients undergoing off-label treatment
BRAF-MEK inhibitor treatment for LMM. Methods for the isolation and amplification of
RNA and DNA from single cells have become available and are ideally suited for
analyzing rare populations of cells, such as those found in the CSF. The overarching
goal of this R21 is to define the genetic and transcriptional profiles of the CTCs from
patients with LMM and to identify novel therapeutic targets for these tumors. We will use
the Fluidigm C1 platform to perform sophisticated single cell RNA and DNA analysis to
define the clonal relationship between LMM CTCs and matched melanoma specimens
from other sites. We will then collect serial CSF specimens from LMM patients
undergoing treatment with targeted therapy and will determine how treatment drives
clonal selection. Validation experiments will be performed in which BRAF-mutant LMM
cells are orthotopically implanted into the leptomeninges of mice and treated with
personalized drug combinations based upon dabrafenib-trametinib and drugs targeted
against the actionable mutations/pathways that we identify. These studies are expected
to provide critical new insights into the biology of brain and leptomeningeal melanoma
metastases and form the groundwork for the development of clinically relevant drug
combinations.
项目总结
这项研究计划的长期目标是开发治疗策略,
改善播散性黑色素瘤患者的预后。黑色素瘤是一种高度
转移性肿瘤,有扩散到皮肤、肺和脑的倾向。在~5%的
例,患者还发生软脑膜黑色素瘤转移(LMM:例如:
黑色素瘤细胞渗入软脑膜、蛛网膜下腔和
脑脊液)预后更差,中位生存期为8-10
几周。软脑膜很可能是黑色素瘤细胞的“避难所”。
既逃避靶向治疗又逃避免疫治疗。在这个时候,没有治疗策略
已经发现对LMM有效的药物。黑色素瘤是由基因决定的
异质性,这表明不同的基因克隆/突变模式决定了
这些细胞是大脑和软脑膜的家园。这方面的进展有限。
由于从软膜中获取标本的技术困难,
脑脊液(CSF)和蛛网膜下腔。最近我们小组开始了
从LMM患者的常规脑脊液收集,我们已经证明含有
循环黑色素瘤细胞(循环肿瘤细胞:CTCs)。我们还建立了
从接受非标签治疗的患者获取连续脑脊液样本的方案
BRAF-MEK抑制剂治疗LMM。细菌分离扩增方法的研究进展
来自单细胞的RNA和DNA已经变得可用,并且非常适合用于
分析稀有细胞群,例如在脑脊液中发现的那些。最重要的是
本R21的目标是定义CTC的基因和转录图谱
并为这些肿瘤寻找新的治疗靶点。我们将使用
用于执行复杂的单细胞RNA和DNA分析的Fluidigm C1平台
确定LMM CTCs与匹配的黑色素瘤标本之间的克隆关系
来自其他网站。然后我们将收集LMM患者的连续脑脊液样本
正在接受靶向治疗,并将决定治疗如何推动
克隆选择。将进行BRAF突变体LMM的验证实验
将细胞原位移植到小鼠的软脑膜中,并进行治疗
基于达普拉非尼-曲美替尼和靶向药物的个性化药物组合
针对我们确定的可操作的突变/途径。这些研究是预期的
为脑和软脑膜黑色素瘤的生物学提供重要的新见解
转移并为临床相关药物的开发奠定了基础
组合。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Oncolytic Virotherapy for Malignant Gliomas.
- DOI:10.1200/jco.2017.77.3192
- 发表时间:2018-02
- 期刊:
- 影响因子:0
- 作者:P. Forsyth;D. Abate-Daga
- 通讯作者:P. Forsyth;D. Abate-Daga
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