Dr. Harbour’s research focuses on the use of genetic and genomic technology, cell culture experiments and genetically modified experimental 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 ocular oncology 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 North America.
Using Next Generation sequencing techniques, the ocular oncology lab then discovered that inactivating mutations in the tumor suppressor gene BAP1 are associated with 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.
Recently, the Harbour lab has made a discovery of the biomarker PRAME in uveal melanoma. Among uveal melanomas categorized as class 1, those with high levels of PRAME mRNA were more likely to metastasize than those with low levels of PRAME mRNA, indicating that these patients should be closely monitored for metastatic disease. An upcoming prospective multicenter study to validate these findings is under way. Click to read more about PRAME in uveal melanoma:
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 experimental models to understand the biological significance of these genetic alterations.
- Discovered the biomarker PRAME that puts patients at a higher risk for metastasis of uveal melanoma.
- Discovered that mutations in the splicing factor SF3B1 are associated with better prognosis in uveal melanoma.
- Discovered that mutations in the tumor suppressor gene BAP1 are associated with high metastatic risk 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.