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.
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.
|Yoo, Jae Hyuk; Shi, Dallas S; Grossmann, Allie H et al. (2016) ARF6 Is an Actionable Node that Orchestrates Oncogenic GNAQ Signaling in Uveal Melanoma. Cancer Cell 29:889-904|
|Rao, Rajesh C; Harbour, J William (2016) An Iris Tumor. JAMA Ophthalmol 134:1063-4|
|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|
|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 :|
|Harbour, J William (2016) Uveal and Conjunctival Melanoma: Close Together-but Only Distantly Related. Oncology (Williston Park) 30:44, 48|
|Field, Matthew G; Decatur, Christina L; Kurtenbach, Stefan et al. (2016) PRAME as an Independent Biomarker for Metastasis in Uveal Melanoma. Clin Cancer Res 22:1234-42|
|Rao, Rajesh C; Khan, Mehnaz; Badiyan, Shahed N et al. (2015) Gene expression profiling and regression rate of irradiated uveal melanomas. Ophthalmic Surg Lasers Imaging Retina 46:333-7|
|Asnaghi, Laura; Gezgin, GÃ¼lÃ§in; Tripathy, Arushi et al. (2015) EMT-associated factors promote invasive properties of uveal melanoma cells. Mol Vis 21:919-29|
|Herlihy, Naoimh; DogrusÃ¶z, Mehmet; van Essen, T Huibertus et al. (2015) Skewed expression of the genes encoding epigenetic modifiers in high-risk uveal melanoma. Invest Ophthalmol Vis Sci 56:1447-58|
Showing the most recent 10 out of 47 publications