J. William Harbour

J. William Harbour is a native of Dallas, Texas. He graduated from Hillcrest High School and earned his undergraduate degree in biochemistry at Texas A&M University, where he graduated. Harbour then attended medical school at Johns Hopkins, where he developed a keen interest in cancer biology. He completed medical school in 1990, followed by ophthalmology residency at the Wills Eye Hospital in Philadelphia, clinical fellowship in vitreoretinal diseases and surgery at the Bascom Palmer Eye Institute, and ocular oncology fellowship at the University of California, San Francisco.

Harbour accepted a position as assistant professor at Washington University in St. Louis, where he remained for 16 years and rose through the ranks to the title of Paul A. Cibis Distinguished Professor of Ophthalmology, professor of medicine and professor of cell biology and physiology. In 2012, he was recruited to the Bascom Palmer Eye Institute and Sylvester Comprehensive Cancer Center of the University of Miami as professor of ophthalmology, biochemistry and molecular biology. He served as vice chair for translational research, medical director of the echography and clinical research units, and director of ocular oncology at Bascom Palmer, and associate director for basic research at Sylvester. He established the Bascom Palmer ocular oncology fellowship program and served as the fellowship director.

Harbour developed a keen interest in research during his undergraduate years at Texas A&M, where he studied the function of the copper protein ceruloplasmin in the laboratory of Dr. Edward Harris. During medical school at Johns Hopkins, he was accepted to the Howard Hughes Medical Institute–National Institutes of Health (HHMI–NIH) Research Scholars Program in Bethesda, MD, where he carried out research in the National Cancer Institute laboratory of Dr. John Minna. This research resulted in a breakthrough discovery published in the journal Science in 1988, with Harbour as first author. Previously it had been thought that mutations in the retinoblastoma gene, the first tumor suppressor gene to be discovered, would be limited to the rare eye cancer retinoblastoma. However, Harbour and co-authors showed that the gene was commonly mutated in a common form of lung cancer. This discovery added to increasing recognition of the retinoblastoma tumor suppressor pathway as a common target of mutation in the vast majority of human cancers.[4]

When Harbour joined Washington University in 1996, he undertook a three-year postdoctoral research training program in molecular oncology, which resulted in a first author publication in the journal Cell showing that the retinoblastoma protein is regulated by successive phosphorylation events. This discovery was subsequently corroborated by protein crystallography and other lines of investigation and have helped to explain how some cancer cells inactivate the retinoblastoma protein by phosphorylation rather than mutation.[5]

In the early 2000s, the focus of Harbour's research turned to uveal melanoma, in which he discovered a gene expression profile that predicted with great accuracy which of these cancers would remain localized to the eye (class 1 profile) and which would metastasize (class 2 profile). Based on this discovery, his group developed a highly accurate clinical prognostic test with high technical performance and prognostic accuracy. The prognostic accuracy of the test was validated in the largest multicenter prospective validation study of its kind ever conducted in the field of ocular oncology. This study also demonstrated the prognostic superiority of the gene expression profile test over traditional clinical features used in the TNM classification, as well as chromosome 3 status, neither of which provided prognostic information that was independent of the gene expression profile test.[6]

Subsequently, the test has been showcased in a front-page story in The New York Times,[7] in a segment on CBS News Sunday Morning, and other media outlets, and it has been licensed to Castle Biosciences, Inc. which provides the test for clinical use under the trade name DecisionDx-UM.

In 2010, Harbour was first author on a landmark paper in the journal Science describing frequent mutations in the tumor suppressor gene BAP1 in uveal melanoma. These mutations were strongly associated with metastasis, thereby opening a new avenue of research into the cause of metastasis in this cancer.[8]

In 2012, the Harbour lab discovered that the histone deacetylase inhibitors may be repurposed to also treat uveal melanoma by reversing the high risk class 2 profile. Subsequently, this discovery has formed the basis for an innovative clinical trial at Bascom Palmer Eye Institute and Sylvester Comprehensive Cancer Center to assess the use of the histone deacetylase inhibitor Vorinostat in patients with high risk uveal melanoma.[9]

In 2013, Harbour was first author on another landmark paper in the journal Nature Genetics describing frequent mutations in the splicing factor SF3B1 in uveal melanoma. Unlike BAP1, mutations in SF3B1 were associated with better clinical outcome. [10]

In 2016, the Harbour lab discovered that the cancer-testis antigen PRAME is yet another prognostic biomarker in uveal melanoma. Both class 1 and class 2 uveal melanomas expressing PRAME were shown to have a worse prognosis, but these tumors may also be subject to immunotherapy directed against PRAME.[11]

In 2018, the Harbour lab reported the largest number of uveal melanomas analyzed to date with next generation sequencing. In this report in Nature Communications, they created a customized bioinformatic pipeline that detected twice as many BAP1 mutations than previous methods, they discovered new driver mutations in the splicing factors SF3A1, SRSF2, SRSF7 and RBM10, and they used new clonality algorithms to reveal that all of the canonical genomic aberrations in uveal melanoma occur relatively early in tumor evolution.[12]

In 2020, the Harbour lab was the first to publish single-cell sequencing data in uveal melanoma, showing previously unrecognized evolutionary and microenvironmental complexity in primary and metastatic tumors. They also discovered LAG3 as the predominant checkpoint molecule in this cancer, opening up new possibilities for immunotherapy in patients with uveal melanoma.[13]

Harbour was awarded a $2.5 million grant from the NCI (National Cancer Institute) entitled "Molecular Predictive Testing in Uveal Melanoma," which will involve approximately 30 centers in the U.S. and Canada, with about half of the patients diagnosed annually with ocular melanoma in the U.S. expected to be enrolled.[14]

• Bascom Palmer Eye Institute, University of Miami