Metabolomic and miRNA profiling of vitreous humor in uveal melanoma

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PROJECT SUMMARY / ABSTRACT The uveal tract (iris, ciliary body, and choroid) of the eye contains melanocytes and can develop melanoma. Although overall rare, accounting for about 5% of all melanomas, uveal melanoma (UM) represents the most common primary intraocular cancer observed in adult population. UM is a highly aggressive cancer with a strong propensity to metastasize, often to the liver. Currently, there is no effective therapy for metastatic UM, which leads to death in less than a year in most cases. Ongoing clinical trials, however, provide some hope with promising results for adjuvant therapy and better management of metastatic disease; hence effective prognostication and optimal surveillance remain essential. A commercial prognostic test currently available for UM involves gene expression profiling (GEP) of primary tumor samples, often obtained by fine-needle aspiration biopsy prior to commonly used eye-preserving brachytherapy. GEP identifies two major prognostic categories (class 1 with low and class 2 with high metastatic risk); however, patients with class 1 tumors may still develop metastases. Moreover, because of well-known tumor biopsy-related issues/concerns, there remains a need for a more accurate and tumor biopsy-free (biofluid-based) prognostic testing in primary UM. Given that UM predominantly involves the choroid at posterior eye segment (~90%), the vitreous humor that fills the posterior eye cavity, constitutes an excellent candidate for biofluid-based UM biomarker development. Unlike the systemic fluids, which can be affected by multiple factors/conditions, the vitreous' composition predominantly reflects/mirrors local eye environment. Cancer has the hallmarks of metabolomic and epigenetic reprogramming and, in recent years, cancer-associated metabolic and epigenetic perturbations have emerged as new potential biomarkers and therapeutic targets. To our knowledge, UM-related metabolomics studies are lacking and vitreous miRNA studies are very limited. Considering the feasibility and potential clinical utility of small molecule (metabolite and miRNA) profiling of biofluids, we propose to comprehensively examine the vitreous metabolites and miRNAs in UM patients in order to investigate the potential utility of vitreous profiling to distinguish different UM prognostic subtypes and utilize our findings to (i) advance our understanding of molecular perturbations underlying the UM biology, (ii) unravel new potential biomarkers for future UM prognostication improvement efforts, and (iii) uncover new therapeutic targets for future clinical interventions. Our preliminary metabolomics data provide support for potential utility of vitreous profiling to distinguish between UM subtypes and also implicate some new intriguing biological pathways/mechanisms. Hence, the results of our study are expected to advance our knowledge of UM and serve as an essential first step towards improving the UM diagnosis, prognostication, and management.