CXCR4 antagonists in acute lymphoblastic leukemias in NOD/SCID mice

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Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer and a major cause of death in children. Although ALL is usually responsive to chemotherapy, about 25% of children and 65% of adults with ALL develop a relapse of their disease. The majority of these patients will die of leukemia. New approaches to the treatment of ALL are necessary to obtain cures for these patients. We have identified stromal-derived factor (SDF)-1 as a major regulator of ALL cell growth and survival. It is currently the only known factor that significantly stimulates the growth-survival of cells from the majority of patients with ALL. Specific antagonists of the SDF-1 receptor, CXCR4, are available. Depriving ALL cells of SDF-1 by the use of these antagonists provides a radically new approach for the treatment of ALL. CXCR4 antagonists also increase the susceptibility of ALL cells to cytotoxic drugs. The mechanisms by which SDF-1 promotes ALL cell growth and survival are not known but appear to be largely due to synergistic interactions with other molecules that have little or no effect on their own. Knowledge of the underlying mechanisms of action of SDF-1 and the factors with which it synergises will facilitate for the further development of this approach. This project will examine the modulation of the expression of proteins that regulate ALL cell growth and survival by CXCR4 antagonists, providing insights into how CXCR4 antagonists work. This project will also extend our encouraging data obtained using tissue culture to an animal model of leukemia. The antagonists will be tested in isolation and in combination with currently used chemotherapy agents. It is expected that CXCR4 antagonists will inhibit the growth of ALL cells and increase their sensitivity to chemotherapy agents in the animal model as we have seen in laboratory culture. The addition of CXCR4 antagonists to current treatment protocols is expected to significantly improve the outcome for patients.