J. William Harbour

Last updated

J. William Harbour
Dr. William Harbour.jpg
Harbour in 2022
Born (1963-06-27) June 27, 1963 (age 60)
NationalityAmerican
Alma mater
Awards
  • Cogan Award, Association for Research in Vision and Ophthalmology
  • Paul Henkind Memorial Award, Macula Society
Scientific career
FieldsOcular oncology, Cancer research
Institutions

J. William Harbour is an American ophthalmologist, ocular oncologist and cancer researcher. He is Chair of the Department of Ophthalmology at the University of Texas Southwestern Medical Center in Dallas. He previously served as the vice chair and director of ocular oncology at the Bascom Palmer Eye Institute and associate director for basic science at the Sylvester Comprehensive Cancer Center of the University of Miami's Miller School of Medicine.

Contents

Harbour's 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 200 peer-reviewed scientific articles and book chapters. 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]

Early life and education

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 University School of Medicine in Baltimore, Maryland, 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.

Medical career

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 at 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.

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 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]

Discoveries

Awards and recognition

In 2005, Harbour received the 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 "breakthroughs in genetic and genomic research."

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

Related Research Articles

<span class="mw-page-title-main">Tumor suppressor gene</span> Gene that inhibits expression of the tumorigenic phenotype

A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or reduction in its function. In combination with other genetic mutations, this could allow the cell to grow abnormally. The loss of function for these genes may be even more significant in the development of human cancers, compared to the activation of oncogenes.

<span class="mw-page-title-main">Retinoblastoma</span> Medical condition

Retinoblastoma (Rb) is a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue of the eye. It is the most common primary malignant intraocular cancer in children, and it is almost exclusively found in young children.

In medicine, Breslow's depth was used as a prognostic factor in melanoma of the skin. It is a description of how deeply tumor cells have invaded. Currently, the standard Breslow's depth has been replaced by the AJCC depth, in the AJCC staging system of melanoma. Originally, Breslow's depth was divided into 5 stages.

<span class="mw-page-title-main">Melanoma</span> Cancer originating in melanocytes

Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye. In women, melanomas most commonly occur on the legs; while in men, on the back. Melanoma is frequently referred to as malignant melanoma. However, the medical community stresses that there is no such thing as a 'benign melanoma' and recommends that the term 'malignant melanoma' should be avoided as redundant.

<span class="mw-page-title-main">Uveal melanoma</span> Type of eye cancer

Uveal melanoma is a type of eye cancer in the uvea of the eye. It is traditionally classed as originating in the iris, choroid, and ciliary body, but can also be divided into class I and class II. Symptoms include blurred vision, loss of vision or photopsia, but there may be no symptoms.

<span class="mw-page-title-main">Eye neoplasm</span> Medical condition

An eye neoplasm is a tumor of the eye. A rare type of tumor, eye neoplasms can affect all parts of the eye, and can either be benign or malignant (cancerous), in which case it is known as eye cancer. Eye cancers can be primary or metastatic cancer. The two most common cancers that spread to the eye from another organ are breast cancer and lung cancer. Other less common sites of origin include the prostate, kidney, thyroid, skin, colon and blood or bone marrow.

p16 Mammalian protein found in humans

p16, is a protein that slows cell division by slowing the progression of the cell cycle from the G1 phase to the S phase, thereby acting as a tumor suppressor. It is encoded by the CDKN2A gene. A deletion in this gene can result in insufficient or non-functional p16, accelerating the cell cycle and resulting in many types of cancer.

<span class="mw-page-title-main">MTA1</span> Protein-coding gene in the species Homo sapiens

Metastasis-associated protein MTA1 is a protein that in humans is encoded by the MTA1 gene. MTA1 is the founding member of the MTA family of genes. MTA1 is primarily localized in the nucleus but also found to be distributed in the extra-nuclear compartments. MTA1 is a component of several chromatin remodeling complexes including the nucleosome remodeling and deacetylation complex (NuRD). MTA1 regulates gene expression by functioning as a coregulator to integrate DNA-interacting factors to gene activity. MTA1 participates in physiological functions in the normal and cancer cells. MTA1 is one of the most upregulated proteins in human cancer and associates with cancer progression, aggressive phenotypes, and poor prognosis of cancer patients.

A metastasis suppressor is a protein that acts to slow or prevent metastases from spreading in the body of an organism with cancer. Metastasis is one of the most lethal cancer processes. This process is responsible for about ninety percent of human cancer deaths. Proteins that act to slow or prevent metastases are different from those that act to suppress tumor growth. Genes for about a dozen such proteins are known in humans and other animals.

<span class="mw-page-title-main">BAP1</span> Protein-coding gene in the species Homo sapiens

BRCA1 associated protein-1 is a deubiquitinating enzyme that in humans is encoded by the BAP1 gene. BAP1 encodes an 80.4 kDa nuclear-localizing protein with a ubiquitin carboxy-terminal hydrolase (UCH) domain that gives BAP1 its deubiquitinase activity. Recent studies have shown that BAP1 and its fruit fly homolog, Calypso, are members of the polycomb-group proteins (PcG) of highly conserved transcriptional repressors required for long-term silencing of genes that regulate cell fate determination, stem cell pluripotency, and other developmental processes.

<span class="mw-page-title-main">Sebaceous carcinoma</span> Medical condition

Sebaceous carcinoma, also known as sebaceous gland carcinoma (SGc), sebaceous cell carcinoma, and meibomian gland carcinoma is an uncommon malignant cutaneous tumor. Most are typically about 1.4 cm at presentation. SGc originates from sebaceous glands in the skin and, therefore, may originate anywhere in the body where these glands are found. SGc can be divided into 2 types: periocular and extraocular. The periocular region is rich in sebaceous glands making it a common site of origin. The cause of these lesions in the vast majority of cases is unknown. Occasional cases may be associated with Muir-Torre syndrome. SGc accounts for approximately 0.7% of all skin cancers, and the incidence of SGc is highest in Caucasian, Asian, and Indian populations. Due to the rarity of this tumor and variability in clinical and histological presentation, SGc is often misdiagnosed as an inflammatory condition or a more common neoplasm. SGc is commonly treated with wide local excision or Mohs micrographic surgery, and the relative survival rates at 5 and 10 years are 92.72 and 86.98%, respectively.

Paul T. Finger, MD, FACS, is an ophthalmologist in New York, New York, specializing in ocular oncology. Finger is a Clinical Professor of Ophthalmology at the New York University School of Medicine in New York City, New York. He is also the director of The New York Eye Cancer Center and Ocular Tumor Services at The New York Eye and Ear Infirmary of Mt. Sinai. He consults for Northwell Health Complex of affiliated Hospitals including Manhattan Eye, Ear and Throat Hospital and NYU School of Medicine. He is Chair of the Ophthalmic Oncology Task Force for the American Joint Committee on Cancer (AJCC), wrote the eye cancer staging systems section for the Union International for Cancer Control (UICC). As Chair, he brought together an OOTF to develop consensus eye plaque radiation guidelines for The American Brachytherapy Society - American Association of Physicists in Medicine. Dr. Finger was the first the only ophthalmologist asked to serve on the 2012 American Association of Physicists in Medicine’s Task Group-129 that produced both dosimetry and quality assurance standards for plaque brachytherapy. As of 2021, Dr. Finger has authored over 335 peer-review scientific articles, 2 books, 54 book chapters and 2 web sites.

DecisionDx-UM is a prognostic test that accurately determines the metastatic risk associated with ocular melanoma tumors of the eye. Ocular melanoma is a term commonly used to describe tumors of the uveal tract such as uveal melanoma, choroidal melanoma, ciliary body melanoma, and iris melanoma. The DecisionDx-UM test was clinically validated on these tumors of the uveal tract. DecisionDx-UM assesses the gene expression profile (GEP) of a subset of genes which are differentially expressed in primary tumor cells compared to cells that have undergone transformation to a metastatic phenotype.

<span class="mw-page-title-main">Cancer biomarker</span> Substance or process that is indicative of the presence of cancer in the body

A cancer biomarker refers to a substance or process that is indicative of the presence of cancer in the body. A biomarker may be a molecule secreted by a tumor or a specific response of the body to the presence of cancer. Genetic, epigenetic, proteomic, glycomic, and imaging biomarkers can be used for cancer diagnosis, prognosis, and epidemiology. Ideally, such biomarkers can be assayed in non-invasively collected biofluids like blood or serum.

Prognostic markers are biomarkers used to measure the progress of a disease in the patient sample. Prognostic markers are useful to stratify the patients into groups, guiding towards precise medicine discovery. The widely used prognostic markers in cancers include stage, size, grade, node and metastasis. In addition to these common markers, there are prognostic markers specific to different cancer types. For example estrogen level, progesterone and HER2 are markers specific to breast cancer patients. There is evidence showing that genes behaving as tumor suppressors or carcinogens could act as prognostic markers due to altered gene expression or mutation. Besides genetic biomarkers, there are also biomarkers that are detected in plasma or body fluid which can be metabolic or protein biomarkers.

The Immunologic Constant of Rejection (ICR), is a notion introduced by biologists to group a shared set of genes expressed in tissue destructive-pathogenic conditions like cancer and infection, along a diverse set of physiological circumstances of tissue damage or organ failure, including autoimmune disease or allograft rejection. The identification of shared mechanisms and phenotypes by distinct immune pathologies, marked as a hallmarks or biomarkers, aids in the identification of novel treatment options, without necessarily assessing patients phenomenologies individually.

Santosh Gajanan Honavar is an Indian ophthalmologist and is currently the Honorary General Secretary of the All India Ophthalmological Society; Director of Medical Services ; Director, Department of Ocular Oncology and Oculoplasty at Centre for Sight, Hyderabad; and Director, National Retinoblastoma Foundation. He was the Editor of the Indian Journal of Ophthalmology and Indian Journal of Ophthalmology - Case Reports, the official journals of the All India Ophthalmological Society from 2017 to 2023.

<span class="mw-page-title-main">Sarah Coupland</span> Australian clinical pathologist

Sarah Coupland is an Australian-born pathologist and professor who is the George Holt Chair in Pathology at the University of Liverpool. Coupland is an active clinical scientist whose research focuses on the molecular genetics of cancers, with particular interests in uveal melanoma, conjunctival melanoma, intraocular and ocular adnexal lymphomas and CNS lymphoma. Coupland is also an NHS Honorary Consultant Histopathologist at the Royal Liverpool University Hospital. Since 2006, Coupland has been head of the Liverpool Ocular Oncology Research Group; from which she runs a multidisciplinary oncology research group focussing on Uveal melanoma, based in the Department of Molecular and Clinical Cancer Medicine at the University of Liverpool. Her research laboratory is currently located in the Institute of Translational Medicine From April 2014 to December 2019, Coupland was also Director of the North West Cancer Research Centre, @UoL. In both 2019 and 2020, Coupland was included on the 'Pathology Powerlist' on The Pathologist website.

<span class="mw-page-title-main">Choroidal nevus</span> Medical condition

Choroidal nevus is a type of eye neoplasm that is classified under choroidal tumors as a type of benign (non-cancerous) melanocytic tumor. A choroidal nevus can be described as an unambiguous pigmented blue or green-gray choroidal lesion, found at the front of the eye, around the iris, or the rear end of the eye.

CP-GEP is a non-invasive prediction model for cutaneous melanoma patients that combines clinicopathologic (CP) variables with gene expression profiling (GEP). CP-GEP is able to identify cutaneous melanoma patients at low-risk for nodal metastasis who may forgo the sentinel lymph node biopsy (SLNB) procedure. The CP-GEP model was developed by the Mayo Clinic and SkylineDx BV, and it has been clinically validated in multiple studies.

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. ↑ Harbour, J. William; Dean, Douglas C. (2000). "Rb function in cell-cycle regulation and apoptosis". Nature Cell Biology. 2 (4): E65–E67. doi:10.1038/35008695. PMID   10783254. S2CID   24140994.
  5. ↑ Harbour, J.William; Luo, Robin X.; Santi, Angeline Dei; Postigo, Antonio A.; Dean, Douglas C. (1999). "CDK Phosphorylation Triggers Sequential Intramolecular Interactions that Progressively Block Rb Functions as Cells Move through G1". Cell. 98 (6): 859–869. doi: 10.1016/S0092-8674(00)81519-6 .
  6. ↑ Collaborative Ocular Oncology Group validation of gene expression profile test
  7. ↑ Dr. Harbour New York Times article
  8. 1 2 3 Harbour, J. William; Onken, Michael D.; Roberson, Elisha D. O.; Duan, Shenghui; Cao, Li; Worley, Lori A.; Council, M. Laurin; Matatall, Katie A.; Helms, Cynthia; Bowcock, Anne M. (2010). "Frequent Mutation of BAP1 in Metastasizing Uveal Melanomas". Science. 330 (6009): 1410–1413. Bibcode:2010Sci...330.1410H. doi:10.1126/science.1194472. PMC   3087380 . PMID   21051595.
  9. ↑ Dr. Harbour and team launches bench to bedside clinical trial
  10. 1 2 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. 1 2 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. 1 2 Field, Matthew G.; Durante, Michael A.; Anbunathan, Hima; Cai, Louis Z.; Decatur, Christina L.; Bowcock, Anne M.; Kurtenbach, Stefan; Harbour, J. William (2018). "Punctuated evolution of canonical genomic aberrations in uveal melanoma". Nature Communications. 9 (1): 116. Bibcode:2018NatCo...9..116F. doi:10.1038/s41467-017-02428-w. PMC   5760704 . PMID   29317634.
  13. 1 2 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. Bibcode:2020NatCo..11..496D. 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. ↑ Harbour, J. William; Chen, Royce (April 9, 2013). "The DecisionDx-UM Gene Expression Profile Test Provides Risk Stratification and Individualized Patient Care in Uveal Melanoma". PLOS Currents Evidence on Genomic Tests. 5. doi: 10.1371/currents.eogt.af8ba80fc776c8f1ce8f5dc485d4a618 (inactive June 5, 2024). PMC   3625622 . PMID   23591547.{{cite journal}}: CS1 maint: DOI inactive as of June 2024 (link)
  16. ↑ Landreville, S., et al. (2012). "Histone deacetylase inhibitors induce growth arrest and differentiation in uveal melanoma." Clin Cancer Res 18(2): 408–416.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.