Abstract IA01: Strategies for targeted and immune therapy in melanoma

Abstract

Abstract Melanoma cells activate pathways that are also activated in proliferating fibroblasts, endothelial cells, or even inflammatory and immune cells. The tumor-secreted proteins and expressed cell surface receptors are associated with growth, migration, invasion, and antiapoptosis. Then there is a group of molecules that is not associated with the phenotype of differentiated cells in skin or tumor stroma but that represents re-expressed developmental genes. Several developmental pathway genes, such as those associated with noncanonical Wnt or Notch signaling, are commonly found on stem cells from the dermis that can give rise to melanocytes and on melanoma cells, but they are absent from or not activated in epidermal melanocytes. We have recently identified a G protein-coupled receptor, LPAR1, that is highly activated in neural crest-like stem cells and melanoma cells and absent from melanocytes. Expression is associated with resistance to BRAFV600E inhibition. When other subpopulations of melanoma cells were characterized that were associated with resistance to BRAF, MEK, or ERK small-molecule inhibitors, their major common property was very slow proliferation, which was in contrast to the bulk of the tumor cells. These “label-retaining cells,” characterized by expression of the H3K4 demethylase JARID1B and the protease SERPIN E2, and the EGF and NGF receptors, are not only drug resistant but also highly invasive in vitro and in experimental animal model. Nonproliferating, drug-resistant malignant cells may pre-exist in tumors. As the majority of melanoma cells are killed by kinase inhibitors, multikinase receptor-expressing cells begin proliferating to repopulate the tumor to its original heterogeneity. Thus, melanomas contain small subpopulations representing only 0.1-5% of all malignant cells that are critical for growth, invasion, and therapy resistance. To achieve total elimination of all malignant cells, we have to develop strategies to target not only the bulk of the tumor cells but also those with intrinsic resistance to common drugs. To closely mimic the conditions in patients’ tumors, we have developed >500 patient-derived xenografts. Together with the >300 permanent cell lines, they represent all clinical, genetic, and biologic groups of the disease. Since the human tumors only proliferate in immune-deficient mice, we have developed two humanized models that recapitulate the infiltration by human leukocytes into the human tumors. Inhibition of checkpoints with clinical-grade inhibitors stimulated the immune response, leading to focal or general tumor regression; thus, the models allow investigating the mechanisms of both stimulation and suppression of the immune system. Citation Format: Meenhard Herlyn. Strategies for targeted and immune therapy in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA01.