The net effect of growth factors on a tumor cell population is determined by a balance of their pleiotropic effects on cell self-renewal, survival, and differentiation. The preferential enhancement of self-renewal and/or survival could hasten tumor progression; conversely, a predominant or selective induction of differentiation would exhaust the neoplastic clone. Although it appears that the clinical use of growth factors can, in fact, worsen the outcome of acute myeloid leukemia (AML) treatment, we found that growth factors induce terminal differentiation of chronic myeloid leukemia (CML). Moreover, our preliminary data demonstrate that agents that induce growth arrest enhance growth factor-mediated differentiation of myeloid malignancies, including AML. When used in the appropriate settings, growth factor-mediated induction of differentiation appears to the be an effective anti-tumor strategy in pan-resistant myeloid malignancies. The overall objective of this proposal is to study approaches for optimizing growth factor-mediated induction of differentiation in the laboratory and to continue to translate promising strategies into the clinic, in order to improve the treatment of CML and other myeloid malignancies. Specifically, we plan to: 1) investigate growth factor-mediated differentiation of myeloid malignancies in the laboratory, 2) investigate growth factor-mediated differentiation in clinical trials that stem from the preclinical studies, and 3) Evaluate the relative roles that differentiation and immunomodulation play in the clinical antitumor effects of GM-CSF and other agents (e.g., interferon, bryostatin-1) being studied in the clinical trials. The laboratory studies will study the role of the cell cycle checkpoints in the induction of terminal differentiation, and examine potential clinical approaches for enhancing growth factor-mediated differentiation via inducing growth arrest. There are 4 proposed clinical trials the stem from our preclinical studies: 1) autologous bone marrow transplantation (BMT) + GM-CSF in CML, 2) allogeneic BMT + GM-CSF for MDS, 3)interferon + GM-CSF in newly-diagnosed CML, and 4) bryostatin-1 + GM-CSF in resistant myeloid malignancies.
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