Uveal melanoma (UM) is a rare form of melanoma that is lethal once metastatic. Primary tumors in the iris, ciliary body, and choroid of the eye metastasize in 50% of patients, despite effective treatment of the initial tumor. The majority of uveal melanomas harbor activating mutations in GNAQ or GNA11, which relay signaling to downstream effectors including protein kinase C (PKC) and the mitogen-activated protein kinase (MAPK) signaling pathway (RAF-MEK-ERK). Both PKC and MEK inhibitors are currently in clinical trials, however, MEK inhibition alone is insufficient to improve overall survival. These observations highlight a need to identify new drug targets for the design of novel therapies including combinations.
To uncover novel UM biology and nominate strategies for combination therapy, genomic and functional genomic approaches were applied. Whole exome sequencing of primary and metastatic tumors identified somatic genetic alterations that drive tumorigenesis. Recurrent mutations in GNAQ, GNA11, BAP1, SF3B1, and EIF1AX were confirmed. Mutations in potential drivers of metastasis, SMARCA4 and IQGAP1, were also identified. Furthermore, the function of N-terminal tail mutations in the translation initiation factor EIF1AX was probed using loss of function studies to assess both viability and mRNA regulation at the level of translation. Upon EIF1AX knockdown, the efficiency of ribosomal protein translation was reduced in wild type, but not mutant cells. Deregulated translation may play an important role in UM tumorigenesis.
To identify putative co-targets of MEK and PKC inhibitors, genome-scale RNA interference drug enhancer screens were performed. These screens nominated several novel genes and pathways for further study in UM. In particular, the mitochondrial folate pathway enzyme MTHFD2 was identified as a novel PKC inhibitor sensitizer. The strongest MEK inhibitor enhancer was the MAPK pathway member, BRAF. Indeed, targeting multiple nodes of the MAPK signaling pathway achieved stronger pathway suppression and synergistic effects. Co-inhibition of RAF/MEK or MEK/ERK may warrant clinical investigation in patients. Overall, these studies provide a foundation for our understanding of UM genomics and combination therapy opportunities. Several novel avenues for future study of UM biology and co-dependencies are uncovered. Translation of these findings into clinical studies will be of the utmost importance. / Medical Sciences
| Identifer | oai:union.ndltd.org:harvard.edu/oai:dash.harvard.edu:1/17464154 |
| Date | 01 May 2017 |
| Creators | Place, Chelsea Schwartz |
| Publisher | Harvard University |
| Source Sets | Harvard University |
| Language | English |
| Detected Language | English |
| Type | Thesis or Dissertation, text |
| Format | application/pdf |
| Rights | embargoed |
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