Uveal melanoma (UM) is the most common primary cancer of the eye with over 50% of patients developing metastatic disease, which is notoriously resistant to chemo- and immunotherapy. UMs can be categorized by gene expression profiling (GEP) into two molecular classes associated with metastatic risk using a clinically available prognostic test: Class 1 (low metastatic risk) and Class 2 (high metastatic risk). The Class 2 signature is strongly associated with inactivating mutations in the BAP1 tumor suppressor gene. Though most patients that metastasize have a Class 2 GEP, a percentage of Class 1 patients also metastasize. We have identified a new subtype of UM that is characterized by a Class 1 GEP and high PRAME expression (Class1PRAME+) that has an increased risk of developing metastasis (intermediate metastatic risk). In our data set, the 5-year actuarial rate of metastasis was 0% for Class1PRAME- tumors, 38% for Class1PRAME+ tumors, and 71% for Class 2 tumors (with similar findings in independent validation data sets). Our preliminary studies show that PRAME overexpression in UM cell lines promotes aggressive and deadly metastases in a xenograft animal model.
The first aim of this proposal is to examine the molecular interactions of PRAME in UM in order to shed light on how PRAME is promoting metastasis. Identification of binding partners and molecular interactions will help identify potential therapeutic strategies for Class1PRAME+ patients.
The second aim i s focused on studying genetic and transcriptional alterations that are present in PRAME overexpressing cells and tumors. Potential transcription factors that regulate these alterations will also be explored. Finally, this aim will explore genetc mutations in Class1PRAME+ tumors that may promote metastasis and/or trigger PRAME overexpression. Completion of this proposal will likely provide therapeutic targets that can be used to stratify UM patients into adjuvant clinical trials with the goal of improving outcome and finding a treatment for this deadly cancer.
Uveal melanoma is the most common primary eye cancer with over 50% of patients developing metastatic disease that is notoriously resistant to chemo- and immunotherapy. We have identified a new subtype of uveal melanoma that has an increased risk of metastasis characterized by a Class 1 gene expression profile and high PRAME expression. Determining the mechanistic role of PRAME in promoting metastasis in uveal melanoma will provide therapeutic targets that can be used to stratify patients with this uveal melanoma subtype into adjuvant clinical trials with the goal of improving outcome and finding a treatment for this deadly cancer.
|Field, Matthew G; Durante, Michael A; Anbunathan, Hima et al. (2018) Punctuated evolution of canonical genomic aberrations in uveal melanoma. Nat Commun 9:116|
|Swaminathan, Swarup S; Field, Matthew G; Sant, David et al. (2017) Molecular Characteristics of Conjunctival Melanoma Using Whole-Exome Sequencing. JAMA Ophthalmol 135:1434-1437|
|Gezgin, Gülçin; Luk, Sietse J; Cao, Jinfeng et al. (2017) PRAME as a Potential Target for Immunotherapy in Metastatic Uveal Melanoma. JAMA Ophthalmol 135:541-549|
|Field, Matthew G; Durante, Michael A; Decatur, Christina L et al. (2016) Epigenetic reprogramming and aberrant expression of PRAME are associated with increased metastatic risk in Class 1 and Class 2 uveal melanomas. Oncotarget 7:59209-59219|