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Overcoming drug resistance in small cell lung cancer

Institution: The Burnham Institute for Medical Research
Investigator(s): Kristiina Vuori, M.D., Ph.D.
Award Cycle: 2001 (Cycle 10) Grant #: 10IT-0246 Award: $141,340
Subject Area: Cancer
Award Type: Inno Dev & Exp Awards (IDEAS)

Initial Award Abstract
Small cell lung cancer constitutes about 25% of all lung cancers. This form of cancer is characterized by early and widespread metastases, which makes the treatment of the disease difficult. Most patients with small cell lung cancer initially respond to chemotherapy, but small cell lung cancer almost invariably relapses and becomes resistant to chemotherapeutic treatment. Therefore, the patient 2-year survival rate remains less than 5%. The reasons why small cell lung cancer is especially resistant to chemotherapy are not clear. Most chemotherapy drugs are thought to work so that they activate self-destructive mechanisms in cancer cells and these cells therefore "commit suicide" in response to chemotherapy. It has been hypothesized that resistant cancer cells somehow refuse to commit suicide in response to chemotherapeutic drugs. Our studies in this application attempt to find out what are the mechanisms by which cancer cells escape the suicide-command in response to cancer therapy. We have found that certain molecules that are on the cell surface, known as integrins, may block suicide signals in cancer cells. Normally, the role of integrins is to anchor cells in their place within a tissue. It is thought that in cancer cells, integrins have lost their normal function and instead, they may aid the movement and metastasis of cancer cells. We hypothesize that they may also be crucial for the development of drug resistance. This possibility will be studied in the present application. We will also try to identify the molecular mechanisms by which integrins instruct the cancer cells not to commit suicide, and identify the gene targets that ultimately mediate the integrin-effect on the inhibition of cell suicide. If these studies prove to be successful, our findings may provide a considerable benefit in the therapy of small cell lung cancer.