Most cancer deaths are caused by metastasis, or spread, of the cancer to distant organs. By the time that metastasis has advanced to the point where it can be detected, the number of cancer cells in the body has doubled as many as 30 times, resulting in a large tumor burden of genetically deregulated cells that are highly resistant to treatment. Recent work has shown that molecular information or """"""""biomarkers"""""""" obtained from the primary tumor at the time of initial diagnosis can identify which patients are likely to harbor undetectable micrometastasis. This would allow adjuvant, or preemptive, treatment of these high-risk patients rather than waiting for the cancer to double many times and become more resistant to therapy. Ocular (""""""""uveal"""""""") melanoma is one such cancer where a highly accurate biomarker of micrometastasis is needed. Up to 50% of ocular melanoma patients develop metastatic disease that is invariably fatal despite successful treatment of the primary eye tumor, indicating that micrometastasis was already present in those patients when the primary eye cancer was treated. Metastatic disease usually becomes detectable 2-5 years later, which provides a window of opportunity for adjuvant systemic therapy in high risk patients. A highly predictive biomarker for ocular melanoma derived from the primary tumor was developed during the previous funding period. This biomarker is an assay that measures the coordinate expression of 12 marker genes and 3 control genes, a so-called gene expression profile. Computer programs that recognize patterns in the profile from individual tumors can distinguish with great accuracy which patients are likely to harbor micrometastasis. This assay is the most accurate predictor of metastasis to date for this cancer and can be used to guide adjuvant therapy in high risk patients. In the grant renewal, the assay will be refined and optimized for routine clinical use by collecting and analyzing a large number of tumor samples prospectively through a multi-center study. Further, the assay will be evaluated and optimized for its prognostic value in cutaneous melanoma by analyzing a large set of archival tumor specimens with long clinical follow-up. The results of this research are likely to improve patient care in ocular melanoma and perhaps in cutaneous melanoma, which is a much more common cancer. More generally, these studies provide a proof of principle for the current major emphasis of the NIH on a personalized, predictive, preemptive approach to the management of complex chronic diseases such as cancer.

Public Health Relevance

For complex diseases such as cancer, where cures have been difficult to find, it is becoming increasingly clear that a more achievable and realistic goal is to prolong survival and improve quality of life by converting a fatal disease into a long-term, chronic disease. A major strategy for achieving this goal is a personalized, predictive, preemptive approach to cancer care, in which individuals at risk for disease are identified so that they can be treated early and aggressively, rather than waiting for the disease to advance to a more severe form. This research proposal represents an application of this strategy and provides a proof of principle for similar approaches in other cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA125970-08
Application #
8459327
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Thurin, Magdalena
Project Start
2006-07-01
Project End
2015-04-30
Budget Start
2013-07-15
Budget End
2014-04-30
Support Year
8
Fiscal Year
2013
Total Cost
$207,551
Indirect Cost
$72,302
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
Guo, Ying; Yang, Hui; Chen, Shi et al. (2018) Reduced BAP1 activity prevents ASXL1 truncation-driven myeloid malignancy in vivo. Leukemia 32:1834-1837
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
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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