We are pursuing two approaches:
- Diagnosis of genetic changes during cancer progression
- Analysis of cancer dormancy at the molecular and cellular levels
It is well known that as cancer progresses, the highly unstable cancer clones are mutating at a high rate and variants are constantly appearing to various treatment regimens. It is a classical Darwinian evolution in vivo. At present, the diagnosis of an important genetic change, such as Her-2-gene amplification is only made on the primary tumor. Twenty-five percent of breast cancer patients have this amplification and have a very poor prognosis. However, there is a humanized antibody to HER-2 (Herceptin), and it can neutralize the effect of Her-2 gene amplification. However, there is no technique available to determine if acquisition of Her-2 gene amplification can be acquired. We have an extremely sensitive blood test that can capture circulating tumor cells (CTCs) and using fluorescence in situ hybridization (FISH), we can determine if amplication has occurred. At present, such patients do not receive the required treatment. If we can prove that patients who acquire Her-2 gene amplification in their CTCs respond to therapy, it will be a major step forward. Not only will these patients receive the proper targeted treatment, but the blood test can be used to detect other genetic changes for which additional targeted treatments will be developed in the next few years.
Cancer dormancy refers to an unconventionally long time between ablation of the primary tumor and a recurrence. We have studied CTCs in patients seven to 22 years after mastectomy for breast cancer who have no evidence of disease. We have found CTCs in a significant proportion of these patients. The short half-life of CTCs (one to two hours) indicates that replication is taking place at a rapid rate to replenish the CTCs but is precisely balanced by cell death. We are exploring the molecular mechanism responsible for this precise balance because they may reveal new approaches for controlling breast and other cancers which in many instances are chronic diseases.
Marches, R. and Uhr, J.W. Chloroquine enhances the antiproliferative effect of Herceptin on Her2-overexpressing tumor cells. (Submitted, 2004).
Fehm, T., Sagalowsky, A., Clifford, E., Beitsch, P., Saboorian, H., Euhus, D., Meng, S., Moorison, L., Tucker, T., Lane, N., Ghadimi, BM., Heselmeyer-Haddad, K., Ried, T., Rao, C. and Uhr, J.W. Cytogenetic evidence that circulating epithelial cells in patients with carcinoma are malignant. Clinical Cancer Research, 8: 2073-2084, 2002.
Uhr, J.W., R. Scheuermann, N. Street, and E.S. Vitetta. Cancer dormancy: Opportunities for new therapeutic approaches. Nature Med. 3: 505-509, 1997.