Exploiting the “dark matter” of the genome to defeat melanoma

The 5-year survival rates of patients with metastatic melanoma are still about 30%. The major reason for the low survival rate of melanoma patients is intrinsic and acquired resistance to the existing therapies. It is therefore essential to develop new therapeutic strategies that will help eradicating resistant cells. By single-cell RNA sequencing of BRAF mutant patient-derived xenograft (PDX) melanoma models analysis we obtained the lncRNA signatures of all the drug tolerant cell states arising upon exposure to MAPK inhibition using Dabrafenib and Trametinib. With this project we aim at designing a unique therapy to avoid relapse by targeting lncRNA specifically expressed by drug-tolerant cells. We will characterize lncRNAs common to all drug tolerant states using CRISPRi, CRISPRa, FISH and cell fractionation. From a therapeutic point of view, lncRNAs expression can be easily manipulated in vivo using antisense oligonucleotides (ASOs), a category of drugs increasingly used in clinical trials for their flexible and easy design and the relatively low cost. With this project we aim at designing a unique therapy to avoid relapse by targeting lncRNA specifically expressed by drug-tolerant cells. After identification and characterization of these lncRNAs, we will conduct preclinical testing of ASO combinations to prevent melanoma relapse in zebrafish PDX models.