Michael J. Kelley, MD

Related Content

Services

• Lung Cancer

Department / Division:
Medicine / Medical Oncology

Address:
DUMC 3396
Durham, NC 27710

Appointment Telephone:
(919) 286-6944

Office Telephone:
(919) 286-0411 ext. 7326

Fax Telephone:
(919) 286-6896

• M.D., University of Michigan, 1985

• Internal Medicine, Duke University Medical Center, 1985-1988

• Medical Oncology, National Cancer Institute, Maryland, 1993

Clinical Interests:
Specialize in treatment of solid tumors, especially lung cancer, conduct research on lung cancer, chordoma, and hereditary thrombocytopenia

Research Interests:
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

Representative Publications:
2. Nakagawa, K., Conrad, N. K., Williams, J. P., et al. Mechanism of inactivation of CDKN2 and MTS2 in non-small cell lung cancer and association with advanced stage. Oncogene. 11: 1843-51, 1995. (1995)

4. Kubo, A., Nakagawa, K., Varma, R. K., et al. The p16 Status of Tumor Cell Lines Identifies Small Molecule Inhibitors Specific for Cyclin Dependent Kinase 4. Clin Cancer Res. 5: 4279-4286, 1999. (1999)

1. Kelley, M. J., Nakagawa, K., Steinberg, S. M., et al. Differential inactivation of CDKN2 and Rb protein in non-small cell and small-cell lung cancer cell lines. J Natl Cancer Inst. 87: 756-761, 1995. (1995)

Kelley, M. J., Allikian, K., Russell, E., et al. Selective cytotoxicity with inhibitors of de novo purine synthesis in combination with 5'-deoxy-5'-methylthioadenosine in lung cancer cells deficient in 5'-

methylthioadenosine phosphorylase activity. In: Annual Meeting of the American Society of Clinical Oncology, Philadelphia, 1996. (1996)

5. Kelley, M. J., Korczak, J. F., Shah, A. A., et al. Genetic linkage and loss of heterozygosity analyses in a family with autosomal dominant chordoma. In: Annual Meeting of the American Association of Cancer Research, New Orleans, 1998. (1998)

6. Kelley, M. J., Jawien, W., Lin, A., et al. Autosomal dominant macrothrombocytopenia with leukocyte inclusions (May-Hegglin anomaly) is linked to chromosome 22q12-13. Human Genetics. In press:, 2000. (2000)