J. William Harbour, M.D.
Professor of Opthalmology
Description of Research
Dr. Harbour’s research focuses on the use of genetic and genomic technology, cell culture experiments and genetically modified animal models to understand mechanisms of tumor progression in major forms of eye cancer, including uveal melanoma, retinoblastoma, intraocular lymphoma and others. All of these cancers are highly aggressive and frequently lethal.
The Harbour laboratory has made great strides in understanding uveal melanoma, the most common primary cancer of the eye. The lab found that primary uveal melanomas can be divided based on gene expression profile into class 1 (low metastatic risk) and class 2 (high metastatic risk). The metastasizing class 2 tumors show a loss of melanocyte differentiation and reversion to a primitive stem-like phenotype. The lab developed a clinical prognostic test based on a 15-gene signature that has been validated in multiple studies, including a prospective multicenter study. This test is now being used for routine clinical testing at the vast majority of ocular oncology centers in the Unites States, Canada, Australia and several other countries.
Using Next Generation sequencing techniques, the Harbour lab then discovered that inactivating mutations in the tumor suppressor gene BAP1 are responsible for metastasis of class 2 tumors. Further work in the lab showed that a class of therapeutic compounds called histone deacetylase inhibitors can reverse the biochemical effects of BAP1 loss and may play a role in the clinical care of cancer patients. Clinical trials are in the planning stages to test this hypothesis.
Discovery of mutations in BAP1 by the Harbour lab has led to the discovery of the BAP1 familial cancer syndrome, which is transmitted in an autosomal dominant fashion and can include uveal and cutaneous melanoma, atypical cutaneous nevi, mesothelioma, meningioma, lung and breast cancer, and several other cancers. A clinical genetic test is being developed for screening high risk families.
The two major research directions in the lab are: (1) continue to use genomic techniques to identify new genetic alterations associated tumor initiation and progression in major forms of eye cancer, and (2) use cell-based and animal models to understand the biological significance of these genetic alterations.
- Discovered that mutations in the tumor suppressor gene BAP1 are responsible for metastatic death in uveal melanoma.
- Discovered that histone deacetylase inhibitors reverse the biochemical effects of BAP1 mutation and may have a role in targeted therapy of uveal melanoma metastasis.
- Discovered a gene expression signature that predicts metastasis in uveal melanoma. This discovery has led to a routine clinical test that is used around the world.
- Discovered that the retinoblastoma protein is regulated by a hierarchical series of intramolecular conformational changes catalyzed by discrete phosphorylation events.
- Discovered that mutations in the retinoblastoma gene occur in most small cell lung cancers.
Selected Cancer-Related Publications
- Asnaghi L, Handa JT, Merbs SL, Harbour JW, Eberhart CG. A role for jag2 in promoting uveal melanoma dissemination and growth. Invest Ophthalmol Vis Sci 54:295-306,2013 Read more »
- Dimaras H, Parulekar MV, Kwok G, Simpson ER, Ali A, Halliday W, Shago M, Harbour JW, Héon E, Gallie BL, Chan HS. Molecular testing prognostic of low risk in epithelioid uveal melanoma in a child. Br J Ophthalmol 97:323-6,2013 Read more »
- Harbour JW. Genomic,prognostic,and cell-signaling advances in uveal melanoma. Am Soc Clin Oncol Educ Book 2013:388-91,2013 Read more »
- Laurent C, Gentien D, Piperno-Neumann S, Némati F, Nicolas A, Tesson B, Desjardins L, Mariani P, Rapinat A, Sastre-Garau X, Couturier J, Hupé P, de Koning L, Dubois T, Roman-Roman S, Stern MH, Barillot E, Harbour JW, Saule S, Decaudin D. Patient-derived xenografts recapitulate molecular features of human uveal melanomas. Mol Oncol 7:625-36,2013 Read more »
- Harbour JW, Chen R. The DecisionDx-UM Gene Expression Profile Test Provides Risk Stratification and Individualized Patient Care in Uveal Melanoma. PLoS Curr 5:,2013 Read more »
- Harbour JW, Roberson ED, Anbunathan H, Onken MD, Worley LA, Bowcock AM. Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma. Nat Genet 45:133-5,2013 Read more »
- Harbour JW, Wilson D, Finger PT, Worley LA, Onken MD. Gene expressing profiling of iris melanomas. Ophthalmology 120:213-213.e3,2013 Read more »
- Harbour JW. The genetics of uveal melanoma: an emerging framework for targeted therapy. Pigment Cell Melanoma Res 25:171-81,2012 Read more »
- Asnaghi L, Ebrahimi KB, Schreck KC, Bar EE, Coonfield ML, Bell WR, Handa J, Merbs SL, Harbour JW, Eberhart CG. Notch signaling promotes growth and invasion in uveal melanoma. Clin Cancer Res 18:654-65,2012 Read more »
- Harbour JW. A new mutation with staggering effects. Pigment Cell Melanoma Res 24:1081-2,2011 Read more »
Collaborating in the Multidisciplinary Research Program(s):