Identifying the drivers and vulnerabilities of acral lentiginous melanoma through the study of PDX models from Latin American patients

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ALM在欧洲裔人群中很少见，迄今为止对其研究仍然很少，而且其病因以及遗传和环境驱动因素仍然大部分未知;因此这些患者的生存率和治疗反应仍然很差。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。

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.