We are pursuing three approaches aimed at improving treatment of cancer. 1) Diagnosis at an earlier stage. 2) Analysis of cancer dormancy at the cellular and molecular levels. Cancer dormancy is defined as cancer cells that do not grow for a long period of time in the host, e.g. breast cancer where the period of dormancy can be decades. 3) Targeted killing of human cancer cells in SCID mice by treatment with cell reactive monoclonal antibodies. We have developed a highly sensitive test to detect and characterize immunologically and genetically cancer cells in the blood of patients with carcinomas. We are in clinical trials to optimize the assay emphasizing the use of multi-color in situ hybridization on single tumor cells. Cancer dormancy, a major problem in human cancer, has been neglected experimentally. We have studied a murine B lymphoma model of dormancy and have shown that growth inhibition and apoptosis induced by crosslinking their surface IgM are responsible for the dormant state. We have isolated dormant cells from mice carrying the tumor by multi-parameter flow cytometry and showed that they display decreased cell cycling and apoptosis. We have explored the mechanisms of signal transduction that override the genetic lesions leading to the malignant phenotype. We have shown that the molecular pathways for induction of cell cycle arrest and apoptosis are different and we are exploring how the pathways are regulated. The approaches involve the use of anti-sense oligonucleotides, determination of the presence and functional activity of second messengers and other proteins in the signaling cascades.
RESEARCH INTERESTS
Tumor dormancy
HER-2
RECENT PUBLICATIONS
J. Schindler, E. Sausville, R. Messmann, J.W. Uhr and E.S. Vitetta, "The toxicity of deglycosylated ricin A-chain containing immunotoxins in patients with non-Hodgkin's lymphoma is exacerbated by prior radiotherapy: A retrospective analysis of patients in five clinical trials" Clinical Cancer Research, 7:255-258
T. Fehm, L. Morrison, H. Saboorian, L. Hynan, T. Tucker and J.W. Uhr, "Patterns of aneusomy for three chromosomes in individual cells from breast cancer tumors" Breast Cancer and Treatment, 2379:1-13, 2002
R. Marches, E.S. Vitetta and J.W. Uhr, "A role for intracellular pH in membrane IgM-mediated cell death of human B lymphomas" PNAS, 98/6:3434-3439, 2001
T. Fehm, A. Sagalowsky, E. Clifford, P. Beitsch, H. Saboorian, D. Euhus, S. Meng, L. Morrison, T. Tucker, N. Lane, M. Ghadimi, K. Heselmeyer-Hadad, T. Ried, C. Rao and J. W. Uhr, "Cytogenetic evidence that circulating epithelial cells in patients with carcinoma are malignant" Clinical Cancer Research, 8:2073-2084, 2002
T. Fehm, L. Morrison, H. Saboorian, L. Hynan, T. Tucker and J.W. Uhr, "Patterns of aneusomy for three chromosomes in individual cells from breast cancer tumors" Breast Cancer and Treatment, 2379:1-13, 2002
R. Marches, R. Hseuh and J. Uhr, "Cancer dormancy VIII. Induction of p21WAF1 initiated by membrane IgM engagement increases survival of B lymphoma cells" PNAS, 86:8711-8715, 1999
J. Schindler, E. Sausville, R. Messmann, J.W. Uhr and E.S. Vitetta, "The toxicity of deglycosylated ricin A-chain containing immunotoxins in patients with non-Hodgkin's lymphoma is exacerbated by prior radiotherapy: A retrospective analysis of patients in five clinical trials" Clinical Cancer Research, 7:255-258
R. Marches, E.S. Vitetta and J.W. Uhr, "A role for intracellular pH in membrane IgM-mediated cell death of human B lymphomas" PNAS, 98/6:3434-3439, 2001
R. Marches, R. Hseuh and J. Uhr, "Cancer dormancy VIII. Induction of p21WAF1 initiated by membrane IgM engagement increases survival of B lymphoma cells" PNAS, 86:8711-8715, 1999
T. Fehm, A. Sagalowsky, E. Clifford, P. Beitsch, H. Saboorian, D. Euhus, S. Meng, L. Morrison, T. Tucker, N. Lane, M. Ghadimi, K. Heselmeyer-Hadad, T. Ried, C. Rao and J. W. Uhr, "Cytogenetic evidence that circulating epithelial cells in patients with carcinoma are malignant" Clinical Cancer Research, 8:2073-2084, 2002
SIGNIFICANT PUBLICATIONS
Meng, S., Tripathy, D., Frenkel, E., Shete, S., Naftalis, E., Huth, J., Beitsch, P., Leitch, M., Hoover, S., Euhus, D., Haley, B., Morrison, L., Fleming, T., Herlyn, D., Terstappen, L., Fehm, T., Tucker, T., Lane, N., Wang, J., and Uhr, J., "Circulating tumor cells in patients with breast cancer dormancy" Clinical Cancer Research, 10:8152-8162, 2004
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