||1R21CA241840-01A1 Interpret this number
||Demirci, F. Yesim
||University Of Pittsburgh At Pittsburgh
||Metabolomic and Mirna Profiling of Vitreous Humor in Uveal Melanoma
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.