Abstract A28: Challenging new epigenetic vulnerabilities in human metastatic melanoma PDXs

Metastatic melanoma is one of the most aggressive cancers, refractory to most of the current therapies in its late stage. Melanoma is characterized by a strong molecular heterogeneity, and patients can be stratified in different subtypes according to genetic alterations. Despite the approval of new targeted drugs, patient treatment produces only partial responses and frequent and rapid relapses, mostly due to increased resistance. Mounting evidence highlights the necessity to better stratify melanomas on the basis of altered molecular pathways and to define new specific and effective tailored therapies. Our main goal is the genetic and functional characterization of metastatic melanomas aimed to generate new predictive and prognostic biomarkers and to identify new potential “druggable” candidates involved in melanoma progression. We have generated a series of human-in-mouse melanoma models, by xeno-transplantation of a cohort of human melanoma samples in immune-compromised mice. Our patient-derived xenografts (PDXs) faithfully recapitulate the heterogeneity of the original tumors at phenotypic and genetic level. Taking advantage of our model, we performed the first in vivo genetic screen on patient-derived tumors, using metastatic NRAS- and BRAF-mutant melanomas and targeting chromatin genes (~240). Our screens revealed unprecedented numerosity of tumor drivers (~50% of tested genes) and unexpected functional heterogeneity among patients (~60 drivers per tumor; Citation Format: Daniela Bossi, Angelo Cicalese, Ivan Gaetano Dellino, Lucilla Luzi, Simona Punzi, Carolina D9Alesio, Elena Cavallaro, Saverio Minucci, PierGiuseppe Pelicci, Luisa Lanfrancone. Challenging new epigenetic vulnerabilities in human metastatic melanoma PDXs. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A28.