RESUMEN
BACKGROUND: Epigenomic dysregulation has been linked to solid tumour malignancies, including ovarian cancers. Profiling of re-programmed enhancer locations associated with disease has the potential to improve stratification and thus therapeutic choices. Ovarian cancers are subdivided into histological subtypes that have significant molecular and clinical differences, with high-grade serous carcinoma representing the most common and aggressive subtype. METHODS: We interrogated the enhancer landscape(s) of normal ovary and subtype-specific ovarian cancer states using publicly available data. With an initial focus on H3K27ac histone mark, we developed a computational pipeline to predict drug compound activity based on epigenomic stratification. Lastly, we substantiated our predictions in vitro using patient-derived clinical samples and cell lines. RESULTS: Using our in silico approach, we highlighted recurrent and privative enhancer landscapes and identified the differential enrichment of a total of 164 transcription factors involved in 201 protein complexes across the subtypes. We pinpointed SNS-032 and EHMT2 inhibitors BIX-01294 and UNC0646 as therapeutic candidates in high-grade serous carcinoma, as well as probed the efficacy of specific inhibitors in vitro. CONCLUSION: Here, we report the first attempt to exploit ovarian cancer epigenomic landscapes for drug discovery. This computational pipeline holds enormous potential for translating epigenomic profiling into therapeutic leads.
Asunto(s)
Carcinoma , Cistadenocarcinoma Seroso , Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/metabolismo , Antígenos de Histocompatibilidad/uso terapéutico , N-Metiltransferasa de Histona-LisinaRESUMEN
BACKGROUND: Chromophore-containing molecules feature extensively in surgical practice, with synthetic dyes gaining popularity over endogenous optical adjuncts. New applications for chromophores in diagnostics and operative treatment exploit unique chemical structures suited for illuminating target tissues beyond the visual spectrum, ranging from ultraviolet (UV) to near-infrared (NIR). This review outlines the rationale for surgical chromophore application, the weaknesses and risks in each class of these compounds, and areas of foreseeable potential for employment of specialized contrast agents. METHOD: An English-language literature search applied the following Boolean Search String: "dye OR Lake OR Stain OR chromophore" AND "tox$ OR terato* OR carcino$ OR Allerg$ OR surg$ OR clinic" using EMBASE, PUBMED, PUBMED central and OVIDSp, with back-referencing through Web of Knowledge™. RESULTS: Based on the primary literature, this study proposes a surgically relevant classification system of chromophores in current use, which facilitates risk/benefit consideration for the surgeon who employs them, and which facilitates clinically oriented development. CONCLUSIONS: The next stage of development for optically active surgical adjuncts must address practical constraints whilst minimizing risks of adverse effects. Exploiting the technology's full potential also requires improvements in the usefulness of imagery equipment.