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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Thurin, Magdalena
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Washington University
Schools of Medicine
Saint Louis
United States
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Harbour, J William; Chao, Daniel L (2014) A molecular revolution in uveal melanoma: implications for patient care and targeted therapy. Ophthalmology 121:1281-8
Field, Matthew G; Harbour, J William (2014) Recent developments in prognostic and predictive testing in uveal melanoma. Curr Opin Ophthalmol 25:234-9
Harbour, J William (2014) A prognostic test to predict the risk of metastasis in uveal melanoma based on a 15-gene expression profile. Methods Mol Biol 1102:427-40
Landreville, Solange; Agapova, Olga A; Matatall, Katie A et al. (2012) Histone deacetylase inhibitors induce growth arrest and differentiation in uveal melanoma. Clin Cancer Res 18:408-16
Onken, Michael D; Worley, Lori A; Char, Devron H et al. (2012) Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology 119:1596-603
Harbour, J William (2012) The genetics of uveal melanoma: an emerging framework for targeted therapy. Pigment Cell Melanoma Res 25:171-81
Landreville, Solange; Agapova, Olga A; Kneass, Zachary T et al. (2011) ABCB1 identifies a subpopulation of uveal melanoma cells with high metastatic propensity. Pigment Cell Melanoma Res 24:430-7
Harbour, J William; Onken, Michael D; Roberson, Elisha D O et al. (2010) Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 330:1410-3
Onken, Michael D; Worley, Lori A; Harbour, J William (2010) Association between gene expression profile, proliferation and metastasis in uveal melanoma. Curr Eye Res 35:857-63
Onken, Michael D; Worley, Lori A; Tuscan, Meghan D et al. (2010) An accurate, clinically feasible multi-gene expression assay for predicting metastasis in uveal melanoma. J Mol Diagn 12:461-8

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