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Last Updated: 2/26/2007
| Norman Sharpless, M.D.
Assistant Professor |  |
Clinical Interests
My lab is interested in the treatment and pathogenesis of solid tumors, particularly melanoma. A goal of my lab is to turn a molecular understanding of these tumor types obtained through the study of mouse models into improved diagnostic and therapeutic techniques for the human disease. I am therefore clinically interested in novel and investigational therapies for solid tumors.
We are also interested in th senescence tumor suppressor mechanism, and it role in both cancer prevention and organismal aging.
Research Interests
My lab focuses on two tumor suppressor pathways (Rb and p53) which are inactivated in most, if not all, human cancers; and in particular, two regulators of these pathways (p16INK4a and ARF). Genetic loss of p16INK4a and/or ARF is seen in a wide variety of human cancers including non-small cell lung cancer, glioblastoma, melanoma, and pancreatic cancer. Through the use of tumor-prone mice lacking p16INK4a, ARF, or both, we are studying the genetic and epigenetic events that cooperate with loss of these important tumor suppressors in murine cancer. We are also interested in understanding the regulation and function of these pathways in nascent cancers and under normal physiologic conditions, and in particular their contribution to aging. See also http://www.med.unc.edu/geneticsdept/faculty_frame2.htm for more detail.
I am also a practicing medical oncologist. My primary clinical interests are in the treatment and pathogenesis of melanoma, and the development of novel therapeutics. A principal goal of my lab is to turn an enhanced molecular understanding of cancer obtained through the study of mouse models into improved diagnostic and therapeutic techniques for the human disease.
Recent Accomplishments and Honors
My lab has shown that loss of both p16INK4a and ARF cooperates in the formation of many tumor types. Of particular interest in melanoma, the most lethal form of skin cancer, we were able to identify the p16INK4a-cdk6-Rb pathway as a primary target of mutation by UV light. This result suggests that UV light (i.e. sunburn) causes melanoma by inactivating this tumor suppressor pathway. More recently, we have describged a new type of melanoma that is genetically and biochemically distinct from the more common form.
We have also accomplished signfiicant studies to understand the role of p16INK4a in physiologic aging in mammals. We have shown that the p16INK4a tumor suppressor genes cause a cell intrinsic decline in stem cell function with aging. We are currently trying to understand how p16INK4a is regulated throughout the normal lifespan, and to determine the age-related cell-autonomous versus cell-non-autonomous effects of p16INK4a expression in a variety of tissues from aged animals. These results are of interest because they demonstrate how the beneficial anti-cancer activity of a tumor suppressor gene can also come with the unwelcome cost of organismal aging. Furthermore, they suggest both a molecular marker of the aging process (p16INK4a expression) as well as a therapeutic target for anti-aging therapies.
We have recently garnered recognition for our work. My lab has received support from the Sidney Kimmel Foundation for Cancer Research; the Aging Federation of Aging Research and Hartford Foundation as part of the Beeson Scholars program; the William Guy Forbeck Research Foundation; the Golfers Against Cancer Foundation; and the Ellison Medical Foundation. Last year, I was an invited speaker at several scientific symposia in the US and Europe. Our work has been recently featured in articles in both the scientific and lay press (New York Timse, San Francisco Chronicle, NPR, Discover Magazine, etc.). our lab is also supported by the NIH: the National Cancer Institute and the National Institute of Aging.
Training
1993-1996 Residency, Internal Medicine, The Massachusetts General Hospital, Harvard Medical School, Boston MA
1997-2000 Fellowship, Hematology and Oncology, The Dana Farber Cancer Institute, Harvard Medical School, Boston MA
2000-2002 Instructor in Medicine, Harvard Medical School
Board Certifications
Hematology 2001
Oncology 1999
Internal Medicine 1996
Publications
Selected recent publications:
Sharpless NE, Bardeesy N, Lee KH, Carrasco R, Castrillon DH, Aguirre A, Wu E, Horner JW, DePinho RA Loss of p16INK4a with Retention of p19ARF Predisposes to Tumourigenesis in Mice. Nature 2001; 413(6851):86-91.
Sharpless NE, Alson S, Chan S, Silver DP Castrillon DC, DePinho, RA. p16INK4a and p53 Deficiency Cooperate in Tumorigenesis. Canc. Res 2002; 62(10):2761-5.
Sharpless NE, Kannan K, Xu J, Bosenberg MW, and Chin L. Both products of the mouse Ink4a/Arf locus suppress melanoma formation in vivo. Oncogene 2003; 22:5055-5059.
Sharpless NE, Ramsey MR, Balasubramanian P, Castrillon DH, DePinho RA. The differential impact of p16INK4a or p19ARF deficiency on cell growth and tumorigenesis. Oncogene 2004; 23: 379-385.
Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, and Sharpless NE. Ink4a/Arf expression is a biomarker of aging. J Clin Invest, 2004; 114: 1299-307.
Sharpless NE. INK4a/ARF: a multifunctional tumor suppressor locus. Mutat Res, 2005; 576: 22-38
Molofsky AV, Slutsky SG, Joseph NM, He S, Pardal R, Krishnamurthy J, Sharpless NE, Morrison SJ Increasing Ink4a expression reduces forebrain progenitor function and neurogenesis during aging. Nature, 2006; 443, 448-452.
Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, and Sharpless NE. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature, 2006; 443, 453-457.
Janzen V, Forkert R, Fleming HE, Saito Y, Waring MT, Dombkowski DM, Cheng T, DePinho RA, Sharpless NE, and Scadden DT. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature, 2006; 443, 421-426.
Kim WY, Sharpless NE. The regulation of INK4/ARF in cancer and aging. Cell 2006;127(2):265-75.
Ramsey MR, Sharpless NE. ROS as a tumour suppressor? Nat Cell Biol 2006;8(11):1213-5.
Bell, JF, Sharpless NE. Telomeres, p21 and the cancer-aging hypothesis. Nat Genet, 2007. 39(1): 11-2.
Shields JM, Thomas NE, Cregger M, Berger AJ, Leslie M, Torrice C, Hao H, Penland S, Arbiser J, Scott G, Zhou T, Bar-Eli M, Bear JE, Der CJ, Kaufmann W, Rimm DL, Sharpless NE. Lack of ERK mitogen-activated protein kinase signaling demonstrates a new type of melanoma. Canc Res, 2007; In Press.
Penland, SK, Keku TO, Torrice C, He X, Krishnamurthy J, Hoadley KA, Woosley JT, Thomas NE, Perou CM, Sandler RS, Sharpless NE. RNA expression analysis of formalin-fixed paraffin embedded tumors. Lab Invest, 2007. In Press.
E-mail: NES@med.unc.edu
Telephone: (919) 966-1185
FAX: (919) 966-8212
Address: Lineberger Comprehensive Cancer Center, CB#7295 Chapel Hill, NC
