Uveal melanoma (UM) is a highly aggressive eye cancer that leads to metastatic death in up to half of patients. UM has a propensity to undergo early micrometastasis prior to treatment of the primary tumor, with later emergence of overt metastatic disease. Consequently, there has been no measurable improvement in survival over the past half century. The overall objective of our research program is to improve survival by developing highly accurate prognostic tests, based on biomarkers we discovered in the lab. In this proposal, we propose to (1) stratify patients with high-risk medium and large UMs to adjuvant therapy and increased metastatic surveillance, and (2) stratify patients with high-risk small UMs to early preemptive treatment of the primary tumor. During previous funding periods, we developed a highly innovative UM gene expression profile-based prognostic test (UM-GEP) that has been commercialized and is now used by a majority of centers in the US and beyond, to asses metastatic risk and make management decisions. Despite being recognized as the first- in-class industry standard in the field, there is a critical need to further improve its prognostic accuracy. We have since discovered new prognostically significant mutations in BAP1 and SF3B1 and a new mRNA biomarker (PRAME) that will set a new standard for prognostic accuracy, while also guiding the choice of systemic therapy. In this competitive renewal, we propose (1) to perform a landmark prospective 28-center study to optimize and validate these new biomarkers to expand the prognostic ability of the UM-GEP test and guide the choice of systemic therapy, and (2) to develop a ground breaking new prognostic test based on circulating exosomal microRNA profiling performed on routine blood samples, which will greatly expand the number of patients with benign and malignant uveal melanocytic tumors who will directly benefit from this personalized genomic medicine approach.

Public Health Relevance

In previous funding periods of this grant, we developed a highly innovative gene expression profile-based prognostic test for uveal melanoma that is now the widely used first-in-class industry standard in the field. We have since discovered new prognostically significant mutations in BAP1 and SF3B1 and a new mRNA biomarker (PRAME) that will set a new standard for prognostic accuracy, while also guiding the choice of systemic therapy. In this competitive renewal, we propose a landmark prospective 28-center study to optimize and validate these new biomarkers, and to develop a ground breaking new prognostic test based on circulating exosomal microRNA profiling performed on routine blood samples, which will greatly expand the number of patients with uveal melanocytic tumors who will benefit from personalized genomic medicine.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA125970-12
Application #
9463641
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Thurin, Magdalena
Project Start
2006-07-01
Project End
2022-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
12
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Kurtenbach, Stefan; Reddy, Rohit; Harbour, J William (2018) ChIPprimersDB: a public repository of verified qPCR primers for chromatin immunoprecipitation (ChIP). Nucleic Acids Res :
Field, Matthew G; Durante, Michael A; Anbunathan, Hima et al. (2018) Punctuated evolution of canonical genomic aberrations in uveal melanoma. Nat Commun 9:116
Peng, Hongzhuang; Prokop, Jeremy; Karar, Jayashree et al. (2018) Familial and Somatic BAP1 Mutations Inactivate ASXL1/2-Mediated Allosteric Regulation of BAP1 Deubiquitinase by Targeting Multiple Independent Domains. Cancer Res 78:1200-1213
Cai, Louis; Paez-Escamilla, Manuel; Walter, Scott D et al. (2018) Gene Expression Profiling and PRAME Status Versus Tumor-Node-Metastasis Staging for Prognostication in Uveal Melanoma. Am J Ophthalmol 195:154-160
Guo, Ying; Yang, Hui; Chen, Shi et al. (2018) Reduced BAP1 activity prevents ASXL1 truncation-driven myeloid malignancy in vivo. Leukemia 32:1834-1837
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
Walter, Scott D; Chao, Daniel L; Feuer, William et al. (2016) Prognostic Implications of Tumor Diameter in Association With Gene Expression Profile for Uveal Melanoma. JAMA Ophthalmol 134:734-40
Decatur, Christina L; Ong, Erin; Garg, Nisha et al. (2016) Driver Mutations in Uveal Melanoma: Associations With Gene Expression Profile and Patient Outcomes. JAMA Ophthalmol 134:728-33

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