Dr. Smith is a junior faculty member at Johns Hopkins Oncology Center who has spent the past several years developing an understanding of the basic biology of drug resistance in acute leukemia. His observations have clearly pointed to the association between anti-apoptotic signals and drug resistance in both in vitro and in vivo studies. He has also been involved in developing clinical strategies to overcome the drug resistance that results from inhibited apoptosis. His career development plan is to obtain formal training in the theory and methods of clinical investigation leading to a Master of Health Sciences degree, while conducting translational research with mentorship from Richard Jones, M.D., the Director of the Bone Marrow Transplantation Program. Steven Piantadosi, M.D, Ph.D. will serve as co-mentor with expertise in epidemiology, biostatistics, and clinical trial design. It is now clear that signals that block apoptosis are important mechanisms by which cancers are pan-resistant to cytotoxic anti- cancer agents and result in poor clinical outcomes. Our preliminary data suggest that growth factor-mediated differentiation therapy is one strategy that may circumvent resistance secondary to anti-apoptotic signals. 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. Preferential enhancement of self- renewal and/or survival could hasten tumor progression; conversely, selective induction of differentiation would exhaust the neoplastic clone. We have found that growth factors induce selective terminal differentiation of chronic myeloid leukemia (CML) at doses that normal hematopoetic progenitors require for optimal growth. Moreover, agents that induce growth arrest, including interferon and bryostatin-1 enhance growth factor- mediated differentiation of CML and other myeloid malignancies in vitro. Based on pre-clinical work that suggests growth factor- mediated induction of differentiation is an effective anti-tumor strategy in pan-resistant myeloid malignancies, three clinical trials of growth factor-mediated differentiation therapy are proposed: 1) GM-CSF + autologous BMT for CML, 2) interferon + GM- CSF in chronic phase CML and 3) bryostatin-1 + GM-CSF in refractory myeloid leukemias. Throughout the course of our proposed trials, we will have the opportunity to further study the biologic impact of growth factor-mediated differentiation. Our current data suggest that the anti-tumor effects of our therapy results from terminal differentiation, however, the agents we are studying in the clinical trials (e.g., GM-CSF, interferon, bryostatin-1) also have immunomodulatory effects which may contribute to an anti- tumor effect. A major objective of our studies will be to evaluate the relative roles that induction of differentiation and immunomodulation play in the anticipated anti-tumor effects of the growth factors and cytostatic agents in the clinical trials. One intriguing possibility is that the induction of differentiation and immunomodulation could be potentially linked. It is now clear that CML, and even AML, progenitors can be differentiated in vitro into dendritic cells (DC) by cytokines that include GM-CSF; moreover, these leukemic DC can stimulate autologous anti-leukemic T cell responses in vitro. Thus, it is possible that strategies that induce differentiation of myeloid malignancies could lead to eradication of the malignant clone via both induction of terminal differentiation and enhanced immunologic anti-leukemic activity.
| Levis, Mark; Murphy, Kathleen M; Pham, Rosalyn et al. (2005) Internal tandem duplications of the FLT3 gene are present in leukemia stem cells. Blood 106:673-80 |
| Levis, Mark; Pham, Rosalyn; Smith, B Douglas et al. (2004) In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects. Blood 104:1145-50 |
| Smith, B Douglas; Levis, Mark; Beran, Miloslav et al. (2004) Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood 103:3669-76 |
| Levis, Mark; Allebach, Jeffrey; Tse, Kam-Fai et al. (2002) A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Blood 99:3885-91 |
