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Last Updated: 12/19/2009
| Norman E Sharpless, M.D.
Associate Professor |  |
Clinical Interests
Novel Cancer Therapeutics
Biomarkers of Aging
Melanoma
Cancer Genetics
Research Interests
My lab studies the role of the p16INK4a tumor suppressor gene in cancer and aging. We discovered in 2004 that the expression of p16INK4a markedly increases in most mammalian tissues with aging, and is a biomarker of physiologic age. With collaborators in 2006, we showed that p16INK4a, in the performance of its beneficial anti-cancer role, also causes a decline in the function of adult self-renewing cells, a cardinal feature of aging. Following on this work, we have recently shown that the biochemical kinase targets of p16INK4a, Cdk4/6, are only required for the proliferation of a few rare but important self-renewing cell types: for example, beta cells of the pancreatic islet; neural stem cells; some lymphocytes; and hematopoietic stem and progenitor cells (HSPC). The ability to selectively modulate the cell cycle in HSPC using small molecule Cdk4/6 kinase inhibitors allows for transient pharmacological quiescence of this tissue, which is accompanied by bone marrow protection from DNA damaging agents.
We also have a long-standing interest in cancers, especially melanoma, associated with p16INK4a inactivation. We recently described a novel form of melanoma that differs in gene expression from classical melanoma, and identified a novel therapeutic target, CD200, in this disease. As part of our cancer research effort, I co-founded the UNC Mouse Phase I Unit (MP1U) to test drugs in genetically engineered murine models of cancer. The MP1U now consists of more than 30 investigators studying a large number of clinical lead compounds in more than 10 different faithful models of murine cancer.
Recent Accomplishments and Honors
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; the Breast Cancer Research Foundation, the Ellison Medical Foundation and the Burroughs-Wellcome Foundation.
I am the Associate Director for Translational Research of the Lineberger Comprehensive Cancer Center, co-leader of the Molecular Therapeutics Program, co-founder and co-director of the UNC Mouse Phase I Unit, and Associate Director of The UNC Center for Aging and Health. I am on the scientific advisory board of several scientific foundations and am an associate editor of Aging Cell and Impact Aging. I received the 2007 recipient of the Jefferson Pilot Award, the 2009 Hettleman Prize and am an elected member of the American Society of Clinical Investigation.
Our work has been described in the lay press:
British Broadcasting Service. Hope for test to measure ageing, June 16th, 2009.
http://news.bbc.co.uk/2/hi/health/8102811.stm
Discover Magazine, Ruvinsky, J. Raw Data: Is Cancer the Price of Longevity? The same protein that prevents cancer may also encourage aging. Septmeber 12th, 2006.
http://discovermagazine.com/2006/dec/p16-protein-aging-healing-cancer/
National Public Radio, Palca, J. Research on Cancer Gene Poses a Dilemma, , September 6th, 2006.
http://www.npr.org/templates/story/story.php?storyId=5776986
The New York Times, Wade, N. Gene Called link Between Life Span and Cancers. September 7th, 2006.
http://www.nytimes.com/2006/09/07/science/07stem.html/
WebMD, Hitti, M. How Old Are You Inside? Blood Test May Tell, June 18th, 2009. http://www.webmd.com/healthy-aging/news/20090618/how-old-are-you-inside-blood-test-may-tell
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.
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.
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.
Kim WY, Sharpless NE. The regulation of INK4/ARF in cancer and aging. Cell 2006;127(2):265-75.
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 WK, Rimm DL, Sharpless NE. Lack of Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase Signaling Shows a New Type of Melanoma. Cancer Res, 2007 Feb 15;67(4):1502-1512.
Ramsey MR, Krishnamurthy J, Pei XH, Torrice C, Lin W, Carrasco DR, Ligon KL, Xiong Y, Sharpless NE. Expression of p16INK4a Compensates for p18INK4c Loss in Cyclin-Dependent Kinase 4/6-Dependent Tumors and Tissues. Cancer Res, 2007 May 15;67:4732-4741.
Ji H, Ramsey MR. Hayes DN, Fan C, McNamara K, Kozlowski P, Torrice C, Wu MC, Shimamura T, Perera S, Liang MC, Cai D, Naumov GN, Bao L, Contreras C, Li D, Chen L, Krishnamurthy J, Koivunen J, Chirieac LR, Padera R, Bronson RT, Lindeman NI, Christiani DC, Lin X, Shapiro GI, Jnne PA, Johnson B, Meyerson M, Kwiatkowski DJ, Castrillon DH, *Bardeesy N, *Sharpless NE, *Wong KK. LKB1 modulates lung cancer differentiation and metastasis. Nature, 2007 Aug 16;448(7155):807-810. (*=corresponding authors).
Petermann KB, Rozenberg GI, Zedek D, Groben P, McKinnon K, Buehler C, Kim WY, Shields JM, Penland S, Bear JE, Thomas NE, Serody J, Sharpless NE. CD200 is induced by ERK and is a potential therapeutic target in melanoma. J Clin Invest, 2007 Dec;117(12):3922-3929.
Liu Y,Sanoff HK, Cho H, Burd CE, Torrice T, Mohlke KL, Ibrahim JG, Thomas NE, Sharpless NE. INK4/ARF transcript expression is associated with chromosome 9p21 variants linked to atherosclerosis. PLoS One, 2009;4(4):e5027.
Liu Y,Sanoff HK, Cho H, Burd CE, Torrice T, Ibrahim JG, Thomas NE, Sharpless NE. Expression of p16INK4a in peripheral blood T-cells is a biomarker of human aging. Aging Cell, 2009 Aug;8(4):439-48.
Tsygankov D, Liu Y, Sanoff HK, Sharpless NE*, Elston TC*. A quantitative model for age-dependent expression of the p16INK4a tumor suppressor. Proc Natl Acad Sci USA, 2009 Sep 29;106(39):1652-7. (*=corresponding authors).
E-mail: NES@med.unc.edu
Telephone: (919) 966-1185
FAX: (919) 966-8212
Address: Lineberger Comprehensive Cancer Center, CB#7295 Chapel Hill, NC
URL: genetics.unc.edu/faculty/sharpless
