Department / Division
Medicine / Medicine - Oncology
Durham, NC 27710
919-286-0411, extension 7326
Treatment of solid tumors, especially lung cancer; research on lung cancer and chordoma; chemoprevention of lung cancer
The central theme of my laboratory is application of knowledge of genetic alterations to clinical care of patient with lung cancer. A major focus of the laboratory has been the development of pharmacologic strategies targeting non-small cell lung cancer cells containing genetic alterations of chromosome 9p21. We have described the genetic alterations that occur in this region, including alterations of the cell cycle regulatory gene CDKN2A (1, 2) and the adjacent methylthioadenosine phosphorylase gene (3). CDKN2A is a tumor suppressor gene and encodes p16INK4A, which inhibits cyclin dependent kinase (CDK)4:cyclin D and CDK6:cyclin D kinase activity. Loss of p16 function leads to dysregulated G1-S checkpoint control. Analysis of compounds in the NCI's Developmental Therapeutics Program drug screen has identified small molecules that preferentially inhibit growth of p16-defective tumor cells compared with p16-normal tumor cells. Two classes of these compounds have selective in vitro CDK4 kinase inhibitory activity compared to other cyclin-dependent kinases (4). Further characterization and molecular modeling of these compounds and target kinases is being pursued with the goal of identifying a small molecule with p16-like activity to be used in treatment of patients whose tumors have lost p16 function.
A second focus of work uses classical genetic analysis to identify and characterize genes contributing to oncologic (5) and hematologic conditions (6). There are two diseases that are currently being pursued, familial chordoma and hereditary macrothrombocytopenias. Three families with predisposition to chordoma, a rare tumor arising from notochordal remnants, have been linked to a chromosomal region (5). A positional candidate approach is being used to identify the gene responsible for this disorder with the subsequent goal of understanding the gene's role in normal processes and development of more common human tumors. The familial macrothrombocytopenias are typified by the rare autosomal dominant macrothrombocytopenia with leukocyte inclusions (May-Hegglin anomaly). Approximately twenty families with this condition have been identified and a subset have been analyzed by genome wide linkage analysis. This has successfully identified the disease gene for this disorder. Current efforts are examining genotype-phenotype correlation, identification of genes and mutations associated with related disorders, and the function of the disease gene in normal platelet production through creation of transgeneic mouse models.
For more information, see http://www.canctr.mc.duke.edu/Lung/staff.htm
This faculty member has no reported relationships with industry.
Kelley, MJ; Bogart, JA; Hodgson, LD; Ansari, RH; Atkins, JN; Pang, H; Green, MR; Vokes, EE. Phase II study of induction cisplatin and irinotecan followed by concurrent carboplatin, etoposide, and thoracic radiotherapy for limited-stage small-cell lung cancer, CALGB 30206. Journal of Thoracic Oncology. 2013;8:102-108. (2013)
Williams, CD; Stechuchak, KM; Zullig, LL; Provenzale, D; Kelley, MJ. Influence of comorbidity on racial differences in receipt of surgery among US veterans with early-stage non-small-cell lung cancer. Journal of Clinical Oncology. 2013;31:475-481. (2013) Abstract
Zhang, Y; Conti, MA; Malide, D; Dong, F; Wang, A; Shmist, YA; Liu, C; Zerfas, P; Daniels, MP; Chan, CC; Kozin, E; Kachar, B; Kelley, MJ; Kopp, JB; Adelstein, RS. Mouse models of MYH9-related disease: Mutations in nonmuscle myosin II-A. Blood. 2012;119:238-250. (2012) Abstract
Zullig, LL; Jackson, GL; Dorn, RA; Provenzale, DT; McNeil, R; Thomas, CM; Kelley, MJ. Cancer incidence among patients of the U.S. Veterans Affairs Health Care System. Military Medicine: international journal of AMSUS. 2012;177:693-701. (2012) Abstract
Brüderlein, S; Sommer, JB; Meltzer, PS; Li, S; Osada, T; Ng, D; Möller, P; Alcorta, DA; Kelley, MJ. Molecular characterization of putative chordoma cell lines. Sarcoma. 2010;2010:630129. (2010) Abstract
Yang, XR; Ng, D; Alcorta, DA; Liebsch, NJ; Sheridan, E; Li, S; Goldstein, AM; Parry, DM; Kelley, MJ. T (brachyury) gene duplication confers major susceptibility to familial chordoma. Nature Genetics. 2009;41:1176-1178. (2009) Abstract
Vokes, EE; Herndon, JE; Kelley, MJ; Cicchetti, MG; Ramnath, N; Neill, H; Atkins, JN; Watson, DM; Akerley, W; Green, MR; Cancer and Leukemia Group B. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III Non-small-cell lung cancer: Cancer and Leukemia Group B. Journal of Clinical Oncology. 2007;25:1698-1704. (2007) Abstract
Kelley, MJ; Glaser, EM; Herndon, JE; Becker, F; Bhagat, R; Zhang, YJ; Santella, RM; Carmella, SG; Hecht, SS; Gallot, L; Schilder, L; Crowell, JA; Perloff, M; Folz, RJ; Bergan, RC. Safety and efficacy of weekly oral oltipraz in chronic smokers. Cancer Epidemiology, Biomarkers and Prevention. 2005;14:892-899. (2005) Abstract
Kelley, MJ; Li, S; Harpole, DH. Genetic analysis of the beta-tubulin gene, TUBB, in non-small-cell lung cancer. Journal of the National Cancer Institute. 2001;93:1886-1888. (2001) Abstract
Kelley, MJ; Jawien, W; Ortel, TL; Korczak, JF. Mutation of MYH9, encoding non-muscle myosin heavy chain A, in May-Hegglin anomaly. Nature Genetics. 2000;26:106-108. (2000) Abstract
Kubo, A; Nakagawa, K; Varma, RK; Conrad, NK; Cheng, JQ; Lee, WC; Testa, JR; Johnson, BE; Kaye, FJ; Kelley, MJ. The p16 status of tumor cell lines identifies small molecule inhibitors specific for cyclin dependent kinase (CDK) 4. Clinical Cancer Research. 1999;5:3755S-3756S. (1999)
Kelley, MJ; Linnoila, RI; Avis, IL; Georgiadis, MS; Cuttitta, F; Mulshine, JL; Johnson, BE. Antitumor activity of a monoclonal antibody directed against gastrin-releasing peptide in patients with small cell lung cancer. Chest. 1997;112:256-261. (1997) Abstract
Zimonjic, DB; Kelley, MJ; Rubin, JS; Aaronson, SA; Popescu, NC. Fluorescence in situ hybridization analysis of keratinocyte growth factor gene amplification and dispersion in evolution of great apes and humans. Proceedings of the National Academy of Sciences of USA. 1997;94:11461-11465. (1997) Abstract
Kelley, MJ; Nakagawa, K; Steinberg, SM; Mulshine, JL; Kamb, A; Johnson, BE. Differential inactivation of CDKN2 and Rb protein in non-small-cell and small-cell lung cancer cell lines. Journal of the National Cancer Institute. 1995;87:756-761. (1995) Abstract
Kelley, MJ; Pech, M; Seuanez, HN; Rubin, JS; O'Brien, SJ; Aaronson, SA. Emergence of the keratinocyte growth factor multigene family during the great ape radiation. Proceedings of the National Academy of Sciences of USA. 1992;89:9287-9291. (1992) Abstract