In progressive disease, tumor growth and metastasis can be interpreted as failure of antitumor immune responses. To improve therapeutic strategies, we need to understand the basic causes of this failure, and the limited success of vaccination and adoptive T cell transfer strategies. There is also the recent revelation that the host innate immune response is partner in crime, and cooperates with cancer cells to promote their growth and dissemination. There is therefore promise of novel therapeutic interventions on a different front, pending our understanding of the basic mechanisms involved.
The major focus of our group is to develop animal models that closely resemble human cancer and to exploit these models to understand the mechanisms underlying immune evasion and cooperation with cancer . Using conditional mutagenesis and tissue-specific promoters, we manipulate key pathways of carcinogenesis - those regulated by the adenomatous polyposis coli gene and beta-catenin and those that control inflammation and tumor progression - by inactivating the PTEN or SMAD-4 genes. The engineered mice are thus susceptible to developing progressive tumors in the gastrointestinal tract (colon cancer).
We track the course of tumor and immune cell interactions from initiation of the cancers through their progression, and use vaccination, adoptive T cell transfer, and interfere with cancer associated inflammation to influence the outcome of disease. We use transgenic mice harboring lymphocytes that recognize specific tumor-associated antigens as the source of CD4 or CD8 T cells, and mice that are genetically defective in pro-inflammatory leukocytes or their products. These studies provide explanations for progressive tumor growth in patients bearing tumor-specific T lymphocytes, and are useful in designing successful strategies for therapeutic intervention.
We also are using these animal models for screening enzyme-specific molecular probes that will eventually allow the noninvasive imaging of similar lesions in patients. The probes report the presence and activity of defined proteolytic enzymes, and reveal the status of a lesion and its response to targeted therapies.
Publications:
Marten, K., Bremer, C., Khazaie, K., Hsuan-Tung, C., Weissleder, R. 2002 Detection of dysplastic intestinal adenomas using enzyme sensing molecular beacons. Gastroenterology 122: 406-414.
Fuvonic, M., Alencar, H., Su, H., Khazaie, K, Weissleder, R., Mahmood, U. 2003 Miniaturized multichannel NIR endoscopy for mouse imaging. Molecular Imaging Oct;2(4):350-7.
Karagianni, N., Ly, M.-C., Psarras, S., Chlichlia, K., Schirrmacher, V., H., Gounari, F., Khazaie, K. 2005. Novel adenomatous polyposis coli gene promoter is located 40 kb upstream of the initiating methionine. Genomics, 2005 Feb;85(2):231-7.
Gounari, F., Chang, R., Cowan, J., Guo, Z, Dose, M. , Gounaris, E., Khazaie, K. 2005 Loss of the Adenomatous-Polyposis-Coli gene function disrupts thymic development. Nature Immunology Aug;6(8):800-9.
Gounaris, E., Erdman, S.E., Restaino, C., Gurish,, M.F., McNagny, K.M., Friend, D.S., Lee, D.M., Zhang, G., Shin, K., Rao, V.P. , Poutahidis, T., Weissleder, R., Gounari, F., Khazaie, K. 2007. Mast cells are an essential hematopoietic component to polyp development. (Proc Nat. Acad. Sci USA, in press).
