tretinoin and Uveal-Neoplasms

All-trans-retinoic acid (ATRA) is a differentiating agent used in the treatment of acute-promyelocytic-leukemia (APL) and it is under-exploited in other malignancies despite its low systemic toxicity. A rational/personalized use of ATRA requires the development of predictive tools allowing identification of sensitive cancer types and responsive individuals.. RNA-sequencing data for 10 080 patients and 33 different tumor types were derived from the TCGA and Leucegene datasets and completely re-processed. The study was carried out using machine learning methods and network analysis.. We profiled a large panel of breast-cancer cell-lines for in vitro sensitivity to ATRA and exploited the associated basal gene-expression data to initially generate a model predicting ATRA-sensitivity in this disease. Starting from these results and using a network-guided approach, we developed a generalized model (ATRA-21) whose validity extends to tumor types other than breast cancer. ATRA-21 predictions correlate with experimentally determined sensitivity in a large panel of cell-lines representative of numerous tumor types. In patients, ATRA-21 correctly identifies APL as the most sensitive acute-myelogenous-leukemia subtype and indicates that uveal-melanoma and low-grade glioma are top-ranking diseases as for average predicted responsiveness to ATRA. There is a consistent number of tumor types for which higher ATRA-21 predictions are associated with better outcomes.. In summary, we generated a tumor-type independent ATRA-sensitivity predictor which consists of a restricted number of genes and has the potential to be applied in the clinics. Identification of the tumor types that are likely to be generally sensitive to the action of ATRA paves the way to the design of clinical studies in the context of these diseases. In addition, ATRA-21 may represent an important diagnostic tool for the selection of individual patients who may benefit from ATRA-based therapeutic strategies also in tumors characterized by lower average sensitivity.

Topics: Breast Neoplasms; Cell Differentiation; Cell Line, Tumor; Female; Gene Expression Regulation, Leukemic; Gene Expression Regulation, Neoplastic; Glioma; Humans; Leukemia, Promyelocytic, Acute; Machine Learning; Melanoma; Models, Theoretical; Sequence Analysis, RNA; Tretinoin; Uveal Neoplasms

The current therapy of uveal melanoma (UM) metastases remains inefficient, which warrants the development of new treatment modalities. For the first time we investigated the effects of retinoic acid (RA) on a panel of UM cell lines and found that RA induces morphological changes compatible with differentiation, suppresses proliferation and causes apoptosis in these cells. RA treatment resulted in an increase of p21, p27 and p53 protein levels and G1 arrest in UM cells, which correlated with significant down-modulation of surface Her2/neu proto-oncogene expression. In addition, RA-treated UM cells exhibited increased sensitivity to both MHC class I-restricted killing by cytotoxic T lymphocytes and NK cell-mediated lysis that were accompanied by more efficient conjugate formation between UM cells and killer lymphocytes. Taken together, our results implicate UM as a new target for treatment with retinoids and suggest that retinoids and T- or NK-cell based immunotherapy can have mutually enhancing effects in UM patients.

Topics: Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Cytotoxicity, Immunologic; Flow Cytometry; Humans; Killer Cells, Natural; Melanoma; Proliferating Cell Nuclear Antigen; Proto-Oncogene Mas; Proto-Oncogene Proteins p21(ras); T-Lymphocytes; Tretinoin; Tumor Suppressor Protein p53; Uveal Neoplasms