J. William Harbour

J. William Harbour, M.D., is an American ophthalmologist, ocular oncologist and cancer researcher. He currently serves as the vice chairman for translational research and director of ocular oncology at the Bascom Palmer Eye Institute and the associate director for basic research at the Sylvester Comprehensive Cancer Center of the University of Miami Miller School of Medicine. His clinical practice focuses on intraocular tumors, including uveal (ocular) melanoma, retinoblastoma, lymphoma and other neoplasms. His field of research includes the genetics and genomics of cancer, with a focus on prognostic biomarkers, mechanisms of metastasis, and molecular targeted therapies. He has given over 300 invited scientific lectures, and published over 150 peer-reviewed scientific articles and book chapters. Dr. Harbour founded the Ocular Oncology Service at the Washington University School of Medicine in St. Louis, where he was the Paul A. Cibis Distinguished Professor of Ophthalmology & Visual Sciences.[1][2][3]

J. William Harbour
Harbour in 2017
Born (1963-06-27) June 27, 1963
NationalityUnited States
Alma mater
Known for
  • Ocular oncology
  • Uveal melanoma
  • Retinoblastoma
  • Rb1 gene and its association with lung cancer
  • Intraocular lymphoma
  • Fine needle aspiration biopsy
  • Cancer genetics and genomics
  • BAP1 tumor suppressor discovery
Awards
  • Paul A. Cibis Distinguished Professor, Washington University in St. Louis
  • Cogan Award, Association for Research in Vision and Ophthalmology
  • Alcon Research Institute, Basic Sciences Award
  • Retina Research Foundation / Kayser Global Award
  • Senior Scientific Investigator, Research to Prevent Blindness, Inc.
  • Paul Henkind Memorial Award, Macula Society
Scientific career
FieldsOcular oncology, Cancer research
Institutions
  • Vice chair and director, Ocular Oncology Service, Bascom Palmer Eye Institute
  • Associate director for basic research, Sylvester Comprehensive Cancer Center

Early life and education

J. William Harbour, M.D., 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 summa cum laude. Harbour then attended medical school at Johns Hopkins, where he developed a keen interest in 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.

Medical career

After his medical training, 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 serves 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 serves as the fellowship director.

Research

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 school, 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]

Discoveries
  • Discovered that mutations in the retinoblastoma gene are common in small cell lung cancer.
  • Discovered the mechanism by which successive phosphorylation events inactivate the retinoblastoma protein.
  • Discovered a gene expression profile that predicts metastasis in uveal melanoma. This discovery led to the development of a widely used clinical prognostic test.[15]
  • Discovered driver mutations in the tumor suppressor gene BAP1 in uveal melanoma, which are associated with metastasis and poor prognosis.[8]
  • Discovered driver mutations in the splicing factor SF3B1 and other splicing factors (SF3A1, SRSF2, SRSF7 and RBM10) in uveal melanoma, which are associated with intermediate prognosis.[10][12]
  • Discovered the first germline BAP1 mutation and the BAP1 familial cancer syndrome.[8]
  • Discovered that histone deacetylase inhibitors reverse the biochemical effects of BAP1 mutation and may play a role in targeted systemic therapy for uveal melanoma.[16]
  • Discovered the biomarker PRAME as a risk factor for metastasis in uveal melanoma.[11]
  • Discovered that LAG3 is the predominant T cell checkpoint molecule in uveal melanoma as a potential target of immunotherapy. [13]

Clinical accomplishments

Dr. Harbour is fellowship trained in surgical retina and ocular oncology, and he has treated thousands of patients with uveal melanoma, retinoblastoma, ocular metastatic disease, ocular hemangiomas, ocular hamartomas and many other ocular tumors. He has trained over 50 clinical fellows, and receives patients from around the world. He has pioneered new surgical methods regarding fine needle biopsy, laser treatment, and brachytherapy of ocular tumors. He was also awarded patents for innovations in genetic prognostic testing in uveal melanoma.

Awards and recognition

In 2005, Harbour received the prestigious Cogan Award from the Association for Research in Vision and Ophthalmology (ARVO), recognizing the most promising young researcher in vision science worldwide. In 2008, he received the Rosenthal Award from the Macula Society for an "individual under 50 years of age whose work gives high promise of a notable advance in the clinical treatment of disorders of the eye." In 2012, he received the Senior Achievement Award from the American Academy of Ophthalmology. In 2013, he received the Florida Society of Ophthalmology Shaler Richardson, MD Service to Medicine Award for "personal contribution to quality patient care by collaborating and integrating ophthalmology into the medical profession on a national level." In 2014, he received the Paul Henkind Memorial Award from the Macula Society for outstanding retinal research. In 2015, he received the Retina Research Foundation / Kayser Global Award "for Dr. Harbour's breakthroughs in genetic and genomic research."

2016 Alcon Research Institute, Basic Sciences Award
2015 Retina Research Foundation / Kayser Global Award
2014 Paul Henkind Memorial Award for Outstanding Retinal Research
2014 Senior Scientific Investigator, Research to Prevent Blindness, Inc.
2013 Shaler Richardson, MD Service to Medicine Award
2012 Senior Achievement Award from the American Academy of Ophthalmology
2008 Rosenthal Award Macula Society for Advances in the Clinical Treatment of Disorders of the Eye.
2006 Paul A. Cibis Distinguished Professor, Washington University in St. Louis
2005 Cogan Award, Association for Research in Vision and Ophthalmology
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See also

References
  1. J. William Harbour, M.D., Joins Bascom Palmer Eye Institute to Lead Eye Cancer Program
  2. Dr. J. William Harbour MD – Overview, US News Com, Health Care
  3. Dr. Harbour EyeCancer
  4. Nature Cell Biology retinoblastoma review article
  5. Harbour et al. Cell (1999)
  6. Collaborative Ocular Oncology Group validation of gene expression profile test
  7. Dr. Harbour New York Times article
  8. Harbour JW, Onken MD, Roberson EDO, et al. Frequent Mutation of BAP1 in Metastasizing Uveal Melanomas. Science (New York,NY). 2010;330(6009):1410-1413.doi:10.1126/science.1194472.
  9. Dr. Harbour and team launches bench to bedside clinical trial
  10. Harbour JW, Roberson EDO, Anbunathan H, Onken MD, Worley LA, Bowcock AM. Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma. Nature genetics. 2013;45(2):133-135. doi:10.1038/ng.2523.
  11. Field MG, Decatur CL, Kurtenbach S, et al. PRAME as an independent biomarker for metastasis in uveal melanoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2016;22(5):1234-1242. doi:10.1158/1078-0432.CCR-15-2071.
  12. Field MG, Durante MA, Anbunathan H, et al. Punctuated evolution of canonical genomic aberrations in uveal melanoma. Nature Communications. 2018;9:116. doi:10.1038/s41467-017-02428-w.
  13. Durante, M. A.; Rodriguez, D. A.; Kurtenbach, S.; Kuznetsov, J. N.; Sanchez, M. I.; Decatur, C. L.; Snyder, H.; Feun, L. G.; Livingstone, A. S.; Harbour, J. W. (2020). "Single-cell analysis reveals new evolutionary complexity in uveal melanoma". Nature Communications. 11 (1): 496. doi:10.1038/s41467-019-14256-1. PMC 6981133. PMID 31980621.
  14. Dr. Harbour receives 2.5-million grant for ocular melanoma predictive test
  15. PLoS Currents Evidence of Genomic Tests
  16. Landreville, S., et al. (2012). "Histone deacetylase inhibitors induce growth arrest and differentiation in uveal melanoma." Clin Cancer Res 18(2): 408–416.
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