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

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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.