J. William Harbour
NAME: James William Harbour
eRA COMMONS USER NAME (credential, e.g., agency login): HARBOUR
POSITION TITLE: Professor and Vice Chair, Department of Ophthalmology
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
INSTITUTION AND LOCATION DEGREE
FIELD OF STUDY
Texas A&M University, College Station, TX BS 05/1985 Biochemistry
Johns Hopkins University, Baltimore, MD MD 05/1990 Medicine
Greater Baltimore Medical Center, Baltimore, MD Internship 06/1991 Internal Medicine
Wills Eye Hospital, Philadelphia, PA Residency 06/1994 Ophthalmology
Bascom Palmer Eye Institute, Miami, FL Fellowship 06/1995 Retinal Surgery
University of California, San Francisco, CA Fellowship 06/1996 Ocular Oncology
Washington University, St. Louis, MO Postdoctoral Fellowship 06/1997 Cancer Research
A. Personal Statement
I serve as the Vice Chair for Translational Research at the Bascom Palmer Eye Institute and the Associate Director for Basic Science at the Sylvester Comprehensive Cancer Center of the University of Miami Miller School of Medicine. In the latter role, I am charged with overseeing all basic science research activities across Sylvester including stimulating interdisciplinary research collaboration, evaluating new research opportunities, and overseeing Sylvester laboratory-based, shared research resources. I am also a member of the Sylvester’s Cancer Epigenetics research program. A major theme of my research is to elucidate the key genetic and epigenetic events associated with tumor progression and metastasis in uveal melanoma (UM) and retinoblastoma, the most common eye cancers in adults and children, respectively. My laboratory uses a variety of next generation sequencing-based methods to study genomic, epigenomic, and chromatin structural alterations associated with tumor progression and metastasis in order to develop new precision therapeutic strategies.
My career accomplishments include (1) discovery of a gene expression profile that predicts metastasis in uveal melanoma, which has been commercialized as the most widely used clinical test for this cancer, (2) discovery of mutations in the tumor suppressor gene BAP1 in uveal melanoma associated with poor prognosis, (3) discovery of germline BAP1 mutations and the BAP1 familial cancer syndrome, (4) discovery of mutations in the splicing factors SF3B1, SF3A1, SRSF2, SRSF7 and RBM10 in uveal melanoma associated with intermediate prognosis, (5) discovery that the oncogene PRAME is a risk factor for metastasis in uveal melanoma and a functional driver of metastasis through induction of aneuploidy, (6) discovery that histone deacetylase inhibitors reverse the genomic effects of BAP1 mutation, leading to new clinical trials across the country, and (7) development of new surgical methods for intraocular biopsy, radioactive plaque brachytherapy surgery, and vitrectomy in eyes with intraocular tumors.
B. Positions and Honors
Positions and Employment
1995-1996 Instructor, Department of Ophthalmology, University of California, San Francisco, CA
1996-2002 Assistant Professor, Department of Ophthalmology & Visual Sciences, Department of Cell Biology & Physiology (1997), and Department of Medicine/Molecular Oncology (1999), Washington University, St. Louis, MO
2002-2006 Associate Professor, Department of Ophthalmology & Visual Sciences, Department of Cell Biology & Physiology, and Department of Medicine/Molecular Oncology, Washington University, St. Louis, MO
2006-2012 Paul A. Cibis Distinguished Professor, Department of Ophthalmology & Visual Sciences, Department of Cell Biology & Physiology, and Department of Medicine/Molecular Oncology; Director of Ocular Oncology, Washington University, St. Louis, MO
2012- Professor and Vice Chairman for Translational Research, Department of Ophthalmology; Professor, Department of Biochemistry & Molecular Biology; Director of Ocular Oncology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine.
2015- Associate Director for Basic Science, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL
Other Experience and Professional Memberships
1994 Member, American Academy of Ophthalmology
1994 Member, Association for Research in Vision and Ophthalmology
1996 Member, Society of Heed Fellows
1998 Member, Retina Society
1998 Member, American Association for Cancer Research, American Society of Retina Specialists
1999 Member, Macula Society
2000 Editorial Board, Archives of 2000 Member, American Joint Committee on Cancer Task Force, Siteman Comprehensive Cancer Center, Washington University
2002 Member, Society for Melanoma Research
2007 Member, International Society of Ocular Oncologists
2008 Member, Institute of Clinical and Translational, Society or Melanoma Research
2010 Member, American Association of Ophthalmic Oncologists and Pathologists
2011 Editorial Board, Translational Vision Science & Technology
2012 Member, Executive Committee, Sylvester Comprehensive Cancer Center, University of Miami
2012 Member, Scientific Steering Committee, Sylvester Comprehensive Cancer Center, University of Miami
2014 Editorial Board, Melanoma Management
2015 Member, Association of American Physicians
2016 Member, Florida Academic Cancer Center Alliance Review Committee, Sylvester Comprehensive Cancer Center, University of Miami
2016- Member, Cancer Epigenetics Research Program, Sylvester Comprehensive Cancer Center
Honors and Awards
1981-1985 Dean’s Honor Roll, Texas A&M University
1982 Phi Eta Sigma Honor Society, Texas A&M University
1982-1985 University Honors Program, Texas A&M University
1982-1984 Academic Scholarships, Texas A&M University
1983 Beta Beta Beta Biology Honor Society, Texas A&M University
1984 Phi Lambda Upsilon Chemistry Honor Society, Texas A&M University
1984 Phi Kappa Phi National Honor Society, Texas A&M University
1985 Phi Eta Sigma Academic Scholarship, Johns Hopkins University
1985 summa cum laude, Texas A&M University
1990 Paul Ehrlich Clinical Research Award, Johns Hopkins University
1990 Phi Beta Kappa National Honor Society, Johns Hopkins University
1990 Alpha Omega Alpha Honor Medical Society, Johns Hopkins University
1991 House Staff Research Award, Greater Baltimore Medical Center
1994-1995 Heed Ophthalmic Foundation Fellowship Award, Bascom Palmer Eye Institute
1995-1996 Heed-Knapp Ophthalmology Fellowship Award, University of California, San Francisco
2002 Physician-Scientist Award, Research to Prevent Blindness, Inc.
2003 Achievement Award, American Academy of Ophthalmology
2005 Cogan Award, given by the Association for Research in Vision and Ophthalmology
2007 Teacher of the Year Award in Research, Department of Ophthalmology & Visual Science, Washington University
2008 Rosenthal Award, Macula Society
2011 Research Award, Ocular Melanoma Foundation
2012 Senior Achievement Award, American Academy of Ophthalmology
2012 Dr. Mark J. Daily Endowed Chair, Bascolm Palmer Eye Institute
2013 Florida Society of Ophthalmology Shaler Richardson, MD, Service to Medicine Award
2013 Honor Award, American Society of Retina Specialists
2014 Paul Henkind Memorial Award and Lecture, given by the Macula Society
2014 Senior Scientific Investigator, Research to Prevent Blindness, Inc.
2014 Silver Fellow, Association for Research in Vision and Ophthalmology
2015 Retina Research Foundation/Kayser Global Award, Pan-American Association of Ophthalmology
2016 Alcon Research Institute Award
2016 Ocular Surgery News Top 150 Innovators in Retina
2018 A Cure in Sight/Jack Odell-John Dagres Research Award
2018 The Helman Family-Melanoma Research Alliance Team Science Award
C. Contributions to Science
1. Retinoblastoma Tumor Suppressor Protein (Rb) Pathway
My early work focused on the retinoblastoma tumor suppressor protein (Rb) pathway, which regulates cell cycle, differentiation, senescence, and apoptosis. Most cancer cells inactivate Rb, either by direct mutation or functional inhibition. We discovered that mutations in the retinoblastoma gene occur in most small cell lung cancers, which was unsuspected at the time. Later, we showed that the Rb protein is regulated by a hierarchical series of intramolecular conformational changes catalyzed by successive phosphorylation events, which lead to a progressive loss of transcriptional repressor and tumor suppressor activity. This discovery has since been confirmed with crystallography by several groups, and it may explain how many cancers such as melanoma partially phosphorylate and differentially inactivate the tumor suppressor function Rb without triggering apoptosis, which occurs with complete inactivation of Rb.
a. Harbour JW, Lai SL, Whang-Peng J, Gazdar AF, Minna JD, Kaye FJ. Abnormalities in structure and expression of the human retinoblastoma gene in SCLC. Science. 1988 Jul 15;241(4863):353-7. PMCID: PMC5480895.
b. Harbour JW, Luo RX, Dei Santi A, Postigo AA, Dean DC. Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell 1999;98:859-69. PMID: 10499802.
c. Zhang HS, Gavin M, Dahiya A, Postigo AA, Ma D, Luo RX, Harbour JW, Dean DC. Exit from G1 and S phase of the cell cycle is regulated by repressor complexes containing HDAC-Rb-hSWI/SNF and Rb- hSWI/SNF. Cell 2000;101:79-89. PMID: 10778858.
d. Brantley MA Jr, Harbour JW. Inactivation of retinoblastoma protein in uveal melanoma by phosphorylation of sites in the COOH-terminal region. Cancer Res. 2000 Aug 15;60(16):4320-3. PMCID: PMC5395201.
2. Precision Molecular Prognostication in Uveal Melanoma
More recently my laboratory identified by gene expression profiling that there are two fundamental molecular UM sub-types: class 1 tumors have a low risk and class 2 tumors have a high risk of metastasis. We showed that the high-risk class 2 tumors are characterized by a loss of melanocyte differentiation, emergence of a primitive neural crest progenitor phenotype, and acquisition of loss-of-function mutations in the tumor suppressor BAP1. This work has led to the most widely used prognostic test and the first ever adjuvant therapy clinical trials for this uveal melanoma.
a. Onken MD, Worley LA, Ehlers JP, Harbour JW. Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death. Cancer Res. 2004 Oct 15;64(20):7205-9. PMCID: PMC5407684.
b. Onken MD, Ehlers JP, Worley LA, Makita J, Yokota Y, Harbour JW. Functional gene expression analysis uncovers phenotypic switch in aggressive uveal melanomas. Cancer Res. 2006 May 1;66(9):4602-9. PMCID: PMC5407689.
c. Onken MD, Worley LA, Tuscan MD, Harbour JW. An accurate, clinically feasible multi-gene expression assay for predicting metastasis in uveal melanoma. J Mol Diagn. 2010 Jul;12(4):461-8. PMCID: PMC2893630.
d. Onken MD, Worley LA, Char DH, Augsburger JJ, Correa ZM, Nudleman E, Aaberg TM Jr, Altaweel MM, Bardenstein DS, Finger PT, Gallie BL, Harocopos GJ, Hovland PG, McGowan HD, Milman T, Mruthyunjaya P, Simpson ER, Smith ME, Wilson DJ, Wirostko WJ, Harbour JW. Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology. 2012 Aug;119(8):1596-603. PMCID: PMC3404209.
3. Tumor Progression and Metastasis in Uveal Melanoma
Using next generation sequencing methods, we discovered several key driver mutations in uveal melanoma. We discovered that inactivating mutations in the tumor suppressor gene BAP1 are associated with highly metastatic class 2 tumors. Further work showed that histone deacetylase inhibitors reverse the biochemical and cellular effects of BAP1 loss and are now being tested in adjuvant clinical trials. We then created a novel bioinformatic pipeline to show that all of the key driver mutations and chromosomal copy number alterations in UM arise in an early punctuated burst, which provides new insights into tumor evolution and micrometastasis.
a. Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA, Council ML, Matatall KA, Helms C, Bowcock AM. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science. 2010 Dec 3;330(6009):1410-3. PMCID: PMC3087380.
b. Landreville S, Agapova OA, Matatall KA, Kneass ZT, Onken MD, Lee RS, Bowcock AM, Harbour JW. Histone deacetylase inhibitors induce growth arrest and differentiation in uveal melanoma. Clin Cancer Res. 2012 Jan 15;18(2):408-16. PMCID: PMC3261307.
c. 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. 2013 Feb;45(2):133-5. PMCID: PMC3789378.
d. Field MG, Durante MA, Anbunathan H, Cai LZ, Decatur CL, Bowcock AM, Kurtenbach S, Harbour JW. Punctuated evolution of canonical genomic aberrations in uveal melanoma. Nat Commun. 2018 Jan 9;9(1):116. PMCID: PMC5760704.
Complete List of Published Work in MyBibliography:
D. Research Support
Ongoing Research Support
R01CA125970 Harbour (PI) 07/01/2006 - 03/31/2022
Molecular Predictive Testing in Ocular Melanoma
The goal is to develop accurate, clinically feasible prognostic testing platforms for uveal melanoma.
559058 Aplin (PI) 07/01/2018 - 06/30/2021
The Helman Family-Melanoma Research Alliance Team Science Award
Targeting BAP1-dependent Alterations in Metastatic Uveal Melanoma
The goal is to identify epigenetic changes associated with BAP1 loss.
Alex’s Lemonade Stand Foundation Harbour (PI) 10/01/2018 - 09/30/2020
Molecular Landscaping for Targeted Therapy in Retinoblastoma
The goal is to develop novel targeted treatments for children with retinoblastoma.
A Cure in Sight Harbour (PI) 07/01/2018 - 06/30/2019
Jack Odell-John Dagres Research Award
Diverse GNAQ/11 mutations as the Basis for New Personalized Treatment Strategies for Metastatic Diseases in Uveal Melanoma
The goal is to develop a methodology for screening variants of unknown significance in uveal melanoma.
7BC05 Smalley (PI) 04/12/2017 - 02/29/2020
Florida Biomedical Research Program
Defining and Targeting Aberrant Chromatin Function in Uveal Melanoma
The goal of this research project is to determine the epigenetic deregulation in high-risk uveal melanoma.
F30CA206430 Field (PI) 04/01/2016 - 03/31/2019
The Role of PRAME in Promoting Metastasis in Uveal Melanoma (UM)
The goal of this project is to determine how the oncogene and cancer-testis antigen PRAME promotes metastasis in UM using genetic, genomic, epigenomic, biochemical and cell-based methods. Our goal is to identify therapeutic strategies for treating patients with PRAME-positive uveal melanoma.
W81XWH-15-10578 Harbour (PI) 09/30/2015 - 09/29/2018
Development of Targeted Molecular Therapy for Cancers Harboring BAP1 Mutations
The goal of this project was to rescue the phenotype caused by BAP1 loss in human cancers.
1400144 Harbour (PI) 12/01/2013 - 11/30/2018
Research to Prevent Blindness
Biomarkers for Malignancy in Suspicious Uveal Nevus
The goal of this project is to validate candidate proteomic biomarker in uveal nevus. This is done by proposing non-invasive optical biopsy in suspicious uveal nevus.
Completed Research Support
1600047 Harbour (PI) 09/01/2016 - 08/31/2017
The Florida Academic Cancer Center Alliance
Defining and Targeting the Epigenetic Landscape of Uveal Melanoma
The goal of this project was to determine the epigenetic and signaling landscape of high-risk uveal melanoma.
R01CA161870 Bowcock (PI) 07/01/2011 - 04/30/2016
Genetics of Ocular Melanoma
The goal of this project was to identify new driver mutations in uveal melanoma.
Attribution:SelfType of financial relationship:PatentIneligible company:Washington UniversityTopic:RoyalitesDate added:12/17/2021Relationship end date:12/31/2022
Attribution:SelfType of financial relationship:TravelIneligible company:Castle BiosciencesTopic:ConsultingDate added:12/17/2021Relationship end date:12/31/2022