Future Directions

A number of chapters in this volume focus on current research that could lead to future clinical applications. Croker and Nicola review the pathways of cytokine signaling. These pathways when aberrant could be involved in oncogenesis, and thus an understanding of signaling may lead to new targets for the development of therapeutics. It is also possible that for some applications, targeting of the intracellular signaling pathway will lead to more selective and orally active stimulants of hematopoietic cells. It may be possible to stimulate selectively early cells, mature cells, or mature cell function. Identifying more effective ways of reconstituting the marrow of patients with severe aplastic anemia or other forms of aplasia or dysplasia, would also be an important clinical objective. The development of antagonists for the treatment of inflammatory states or some types of leukemia may prove valuable.

An important area for future development arises from structure and function analyses of HGF. For example, at one time, it was not considered possible to modify the protein backbone of the HGF and thereby improve their pharmacologic properties, because of the risk of a loss of efficacy or the induction of immunogenicity. The recent regulatory approval of darbepoetin alfa, however, shows that changing the amino acid sequence of rHuEPO to produce a hyperglycosylated molecule results in prolonged half-life and maintained efficacy without inducing neutralizing antibodies. It is likely that further modifications will be explored.

We are currently able to stimulate the neutrophil and erythroid lineage effectively; however, Kuter reviews the data demonstrating that although recombinant TPO is effective in preclinical and clinical studies to increase platelet counts, it does not work rapidly enough to prevent platelet transfusions now that the trigger for these is as low as 10 x 109/L. In addition, the immunogenicity of the first-generation molecules needs to be overcome. Much work needs to be done to define better both the clinical need, and the optimal properties of a platelet stimulant.

Although in retrospect the clinical success of recombinant human HGF may seem to have been easily achieved, the chapter by Farese and MacVittie describes preclinical studies of chimeric growth factor receptor agonists that have not transitioned successfully to the clinic.

New anticancer agents are continually being developed, and these need to be integrated with current chemotherapy and radiotherapy regimens and hematologic support. A major area of investigation discussed by Fox and by Lyman and Kuderer is the effect on cost of introducing new agents. A positive development has been the objective review of data and the production of treatment guidelines by societies such as ASCO and ASH. Although such guidelines need to be updated, they have become an objective standard by which to define therapy for individual patients. The field of HGF has developed in 40 years from an in vitro cell culture phenomenon to an established field providing benefit to patients. The specificity of the late-acting factors and the ability to measure blood cell counts as surrogate endpoints greatly facilitated dose finding and clinical development.

Science now moves more quickly, and there is an expectation that basic discoveries can be applied clinically in 2-3 years. Perhaps an understanding of how the biologic effects of HGF were applied clinically will be useful for the successful development of other areas of translational medicine.

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