Identifying the drivers and vulnerabilities of acral lentiginous melanoma through the study of PDX models from Latin American patients
通过研究拉丁美洲患者的 PDX 模型来确定肢端雀斑样黑色素瘤的驱动因素和脆弱性
基本信息
- 批准号:MR/S01473X/1
- 负责人:
- 金额:$ 24.06万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2018
- 资助国家:英国
- 起止时间:2018 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Melanoma is the common cancer that has increased its worldwide incidence the most in the last decades. Survival rates for cutaneous melanoma have increased dramatically in the last decades due in part to the development of drugs that specifically target disease subtypes and agents that stimulate the immune response against tumours. These breakthroughs have been possible thanks to the study of mutations in melanoma genomes and the use of pre-clinical models that faithfully resemble human tumours. However, this success has not been realised yet for patients with acral lentiginous melanoma (ALM), which constitutes the most common subtype of this disease in some Latin American countries. ALM has remained poorly studied to date due to its rarity in European-descent populations, and its causes and genetic and environmental drivers remain mostly unknown; thus survival rates and response to therapy are still poor in these patients. The long-term aim of this project is to develop novel therapies for ALM patients. In this context, we have two specific aims: 1. Generate and characterise a comprehensive collection of faithful ALM pre-clinical models in the form of patient-derived xenografts (PDX). PDX are human tumours implanted into immunodeficient mice. This collection will include tumours from a variety of body locations and will come from Brazil and Mexico to account for the large variability observed within the disease. We will sequence each PDX's protein-coding genome, and determine gene and protein expression levels to understand what biological pathways are altered in ALM tumours. We will also analyse genetic ancestry, which has been hypothesised to increase risk to develop some tumour types, such as breast cancer. An enrichment of certain genome variants in cases when compared to their population of origin might indicate regions of the genome that modify risk to develop ALM. 2. Use the PDX collection in order to explore new targets for therapy and biomarkers of ALM. The molecular characterisation of ALMs will allow us to identify potential drug targets, biomarkers useful to determine responders to a specific treatment, and potential resistance mechanisms. We plan to explore this at first by focusing on CDK4 pathway dependencies via direct treatment of PDX-carrying mice with CDK4 inhibitors followed by assessment of tumour growth, as well as the study of gene and protein profiles of responder and non-responders. We expect that the results from this project will identify genetic risk factors and suggest therapeutic alternatives for ALM patients, and that it will establish a valuable resource, in the form of a PDX collection, that can be shared with the research community.
黑色素瘤是一种常见的癌症,在过去的几十年中,其全球发病率增加最多。皮肤黑色素瘤的生存率在过去几十年中急剧增加,部分原因是开发了特异性靶向疾病亚型的药物和刺激针对肿瘤的免疫反应的药物。这些突破之所以成为可能,要归功于对黑色素瘤基因组突变的研究,以及使用与人类肿瘤非常相似的临床前模型。然而,这一成功尚未实现肢端雀斑样黑色素瘤(ALM),这是最常见的亚型,这种疾病在一些拉丁美洲国家的患者。由于其在欧洲血统人群中的罕见性,迄今为止对ALM的研究仍然很少,其原因以及遗传和环境驱动因素仍然大多未知;因此这些患者的生存率和对治疗的反应仍然很差。该项目的长期目标是为ALM患者开发新的治疗方法。在这方面,我们有两个具体目标:1。以患者来源的异种移植物(PDX)的形式生成并验证一系列完整的忠实ALM临床前模型。PDX是植入免疫缺陷小鼠体内的人类肿瘤。这一收集将包括来自不同身体部位的肿瘤,并将来自巴西和墨西哥,以解释在疾病中观察到的巨大变异性。我们将对每个PDX的蛋白编码基因组进行测序,并确定基因和蛋白表达水平,以了解在ALM肿瘤中改变了哪些生物学途径。我们还将分析遗传祖先,这被假设为增加患某些肿瘤类型的风险,如乳腺癌。某些基因组变体在与它们的起源群体相比时的情况下的富集可能指示基因组的改变发展ALM的风险的区域。2.使用PDX集合来探索新的治疗靶点和ALM的生物标志物。ALMs的分子表征将使我们能够识别潜在的药物靶点,用于确定特定治疗反应者的生物标志物,以及潜在的耐药机制。我们计划首先通过使用CDK 4抑制剂直接治疗携带PDX的小鼠,然后评估肿瘤生长,以及研究应答者和非应答者的基因和蛋白质谱,重点研究CDK 4通路依赖性来探索这一点。我们期望该项目的结果将确定遗传风险因素,并为ALM患者提出治疗替代方案,并且它将以PDX集合的形式建立一个有价值的资源,可以与研究界共享。
项目成果
期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Population-based analysis of POT1 variants in a cutaneous melanoma case-control cohort
皮肤黑色素瘤病例对照队列中 POT1 变异的人群分析
- DOI:10.1101/2022.05.16.22274971
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:Simonin-Wilmer I
- 通讯作者:Simonin-Wilmer I
More than just acral melanoma: the controversies of defining the disease.
- DOI:10.1002/cjp2.233
- 发表时间:2021-11
- 期刊:
- 影响因子:0
- 作者:Bernardes SS;Ferreira I;Elder DE;Nobre AB;Martínez-Said H;Adams DJ;Robles-Espinoza CD;Possik PA
- 通讯作者:Possik PA
Population-based analysis of POT1 variants in a cutaneous melanoma case-control cohort.
- DOI:10.1136/jmg-2022-108776
- 发表时间:2023-07
- 期刊:
- 影响因子:4
- 作者:
- 通讯作者:
Melanoma models for the next generation of therapies.
- DOI:10.1016/j.ccell.2021.01.011
- 发表时间:2021-05-10
- 期刊:
- 影响因子:50.3
- 作者:Patton EE;Mueller KL;Adams DJ;Anandasabapathy N;Aplin AE;Bertolotto C;Bosenberg M;Ceol CJ;Burd CE;Chi P;Herlyn M;Holmen SL;Karreth FA;Kaufman CK;Khan S;Kobold S;Leucci E;Levy C;Lombard DB;Lund AW;Marie KL;Marine JC;Marais R;McMahon M;Robles-Espinoza CD;Ronai ZA;Samuels Y;Soengas MS;Villanueva J;Weeraratna AT;White RM;Yeh I;Zhu J;Zon LI;Hurlbert MS;Merlino G
- 通讯作者:Merlino G
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David Adams其他文献
Patients with a gene encoding a truncated ADP-ribosyl-acceptor hydrolase 3 exhibit a progressive neurodegenerative phenotype
携带编码截短 ADP-核糖基-受体水解酶 3 基因的患者表现出进行性神经退行性表型
- DOI:
- 发表时间:
2019 - 期刊:
- 影响因子:0
- 作者:
Masato Mashimo;Xiangning Bu;Kazumasa Aoyama;Jiro Kato;Hiroko Ishiwata-Endo;Linda A. Stevens;Atsushi Kasamatsu;Lynne A. Wolfe;Camilo Toro;David Adams;Thomas Markello;William A. Gahl;Joel Moss - 通讯作者:
Joel Moss
Findings in an Unusual MELAS Case Tracking, and Single-Voxel Spectroscopy MR Diffusion Tensor Imaging, Fiber
不寻常的 MELAS 病例追踪和单体素能谱 MR 扩散张量成像、光纤的发现
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
D. Ducreux;G. Nasser;Catherine Lacroix;David Adams;P. Lasjaunias - 通讯作者:
P. Lasjaunias
Contesting urban monuments: future directions for the controversial monumental landscapes of civic grandeur
有争议的城市纪念碑:有争议的城市宏伟纪念碑景观的未来方向
- DOI:
- 发表时间:
2022 - 期刊:
- 影响因子:0
- 作者:
David Adams;Peter Larkham - 通讯作者:
Peter Larkham
An Integrated Approach to Developing Technical Communication Skills in Engineering Students
培养工程学生技术沟通技能的综合方法
- DOI:
- 发表时间:
2014 - 期刊:
- 影响因子:0
- 作者:
R. Harichandran;D. Adams;David Adams;M. Collura - 通讯作者:
M. Collura
AN ANTIFRAGILE SYSTEM FOR REDUCING PHYSICIAN BURNOUT
减少医生倦怠的抗脆弱系统
- DOI:
- 发表时间:
2017 - 期刊:
- 影响因子:0
- 作者:
Mitchell H. Tsai;Imelda R. Muller;Shelly R. Stelzer;R. Urman;David Adams - 通讯作者:
David Adams
David Adams的其他文献
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{{ truncateString('David Adams', 18)}}的其他基金
The Genomic Atlas of Dermatological Tumours (DERMATLAS)
皮肤肿瘤基因组图谱 (DERMATLAS)
- 批准号:
MR/V000292/1 - 财政年份:2021
- 资助金额:
$ 24.06万 - 项目类别:
Research Grant
A long term resource to maximise the potential of laboratory mouse strains for medical research
最大限度发挥实验室小鼠品系用于医学研究的潜力的长期资源
- 批准号:
BB/M000281/1 - 财政年份:2015
- 资助金额:
$ 24.06万 - 项目类别:
Research Grant
Integrating innovative technologies for genotyping and phenotyping in stratified medicine
在分层医学中整合基因分型和表型分型的创新技术
- 批准号:
MR/M009157/1 - 财政年份:2015
- 资助金额:
$ 24.06万 - 项目类别:
Research Grant
University of Birmingham MRC Proximity to Discovery: Open Innovation Through LocalIntegration
伯明翰大学 MRC 接近发现:通过本地整合进行开放式创新
- 批准号:
MC_PC_14123 - 财政年份:2015
- 资助金额:
$ 24.06万 - 项目类别:
Intramural
Maximising the potential of wild-derived laboratory mouse strains for medical research
最大限度地发挥野生实验室小鼠品系在医学研究中的潜力
- 批准号:
MR/L007428/1 - 财政年份:2014
- 资助金额:
$ 24.06万 - 项目类别:
Research Grant
Trafficking of monocytes and their differentiation to dendritic cells and macrophages in the human liver
人肝脏中单核细胞的贩运及其分化为树突状细胞和巨噬细胞
- 批准号:
G0700301/1 - 财政年份:2007
- 资助金额:
$ 24.06万 - 项目类别:
Research Grant
The iBAC genomic DNA expression library
iBAC 基因组 DNA 表达文库
- 批准号:
BB/D012759/1 - 财政年份:2006
- 资助金额:
$ 24.06万 - 项目类别:
Research Grant
Issues-Directed Introductory Chemistry for Business Students
面向商科学生的问题导向化学入门课程
- 批准号:
9150553 - 财政年份:1991
- 资助金额:
$ 24.06万 - 项目类别:
Standard Grant
Mathematical Sciences: Theory of Capacities
数学科学:能力理论
- 批准号:
8702755 - 财政年份:1987
- 资助金额:
$ 24.06万 - 项目类别:
Standard Grant
Some Questions in Potential Theory and Partial Differential Equations Related to the Lp-Theory of Capacities
势论和偏微分方程中与Lp-容量理论相关的一些问题
- 批准号:
8002840 - 财政年份:1980
- 资助金额:
$ 24.06万 - 项目类别:
Standard Grant
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