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Stanford University School of Medicine
Chemo resistance to Phase I/II Anti-cancer Agents
One of the key limitations of chemotherapy is the development of tumor cells that are resistant to various known chemotherapy drugs. In patients with leukemia or lymphoma who relapse following primary chemotherapy, it is common to try new anti-cancer drugs, many of them in early clinical trials (Phase I/II), in hopes of at least a temporary remission. Unfortunately, many of these cancers prove to be resistant to these drugs as well. A number of genes have been identified that make cancer cells resistant to chemotherapy. Generally, these genes induce resistance by inactivating the chemotherapy agent or causing it to be removed from the cell, or by blocking the process of apoptosis in some way. (Apoptosis is the process of cell death that occurs when cancer cells are exposed to effective chemotherapy.) It is likely that multiple genes for chemotherapy resistance exist. Identifying these resistance genes and elucidating the mechanisms by which they produce resistance should aid in the selection of chemotherapeutic agents for individual patients. This understanding may also lead to the development of methods that can modulate those resistance mechanisms. Dr. Louie Naumovski proposes to use tumor samples from patients who have relapsed and failed to respond to chemotherapy to screen for and isolate genes associated with chemotherapy resistance. These genes and their protein products will then be studied. This will help build a "library" of chemotherapy resistance genes. When patients relapse, tumor samples will be studied to determine if there is any correlation between their response to chemotherapy and the expression of the suspected drug resistance genes. Eventually, it should be possible to use this information to target therapy to individual patients, to avoid exposing them to chemotherapy that is destined to fail.