Editorial [Hot Topic: Mammalian Target of Rapamycin as a Therapeutic Target in Leukemia (Executive Editors: Francis J. Giles / Maher Albitar)]

Targeted Therapy in Hematologic Maligancies - Progress Made, Lessons Learned? In this issue, we focus on progress being made in defining appropriate targets for novel therapeutic agents in patients with hematological malignancies. The targets dealt with range from the proven (associated with dramatic improvements in patient outcomes) e.g. CD20, Bcr-Abl to the modest (associated with some progress) e.g. CD33, to the unproven if promising e.g. mTOR. Success brings more resources and more ambition. Failures breed caution and educate us on better drug development. A hierarchy of desirable properties in a targeted therapy has emerged. We would like the target to be confined to clonogenic tumor cells. It should be critical to the pathophysiology of the disease. It should be "druggable". The drug should have a tolerable adverse event profile and be affordable. We must anticipate that some degree of resistance will inevitably develop. Understanding the basis of such resistance allows us to optimize the dose and schedule of the agents we have, to more rationally plan for combination therapies using currently available agents, and to speed the development of next generation compounds. A recent illustrative example is the development of Bcr-Abl targeted inhibitors for patients with CML. The initial presentations on Imatinib were made at the American Society of Hematology (ASH) in 1999. This agent was then demonstrated to improve survival in all phases of chronic myeloid leukemia (CML). As the clinical data evolved, so did our understanding of the precise mechanisms involved in its activity as did an appreciation for the development of mutations within Bcr- Abl as a mechanism of resistance to Imatinib. At ASH 2004, initial clinical data on two novel Bcr-Abl kinase inhibitors with significant activity in patients with Imatinib-resistant CML and Philadelphia-chromosome positive acute lymphocytic leukemia (ALL) - an interval of less that five years to develop two oral next generation compounds. Either or both may replace Imatinib. Progress has become more rapid, in terms of drug synthesis, that our clinical ability to assess these new agents unless we evolve new clinical study designs. This latter challenge has not been risen to for a regrettably long period. The rate of availability of new active targeted therapies will accelerate. The development of AMN107 (sequential chemical substitution of part of Imatinib to create a derivative that is more powerful, specific, and less toxic) and BMS-354825 (a search for a SRCinhibitor which yields a "bystander" effect on Bcr-Abl by a Imatinib-unrelated chemical entity) are but two examples of approaches that are accelerated the development of targeted therapies. If SRC inhibition proves of significance in any malignancy, another druggable target has been defined. If not, CML patients will still have a new powerful option. If one reviews the overall field of targeted therapies, one need dominates. We need to be able to combine unapproved agents in clinical studies. The paradigm of demanding that each targeted therapy needs to demonstrate single agent objective response as if they were traditional cytotoxic agents is flawed and retarding. Once adequate safety data has been generated for each constituent, clinical studies of combination need to be performed. We all hope and have data to support the expectation that combinations of mTOR, VEGF, PI3Kinase, and/or Pim kinase inhibitors will be more potent that the individual drugs. If we continue to wait until at least one agent within each potential doublet has received regulatory approval to study such combinations, we will have failed our patients. Progress on preclinical science needs parallel progress in clinical science, particularly in the areas of study design and supervision. When these avenues of progress merge, I anticipate even more rapid increments in the cure fractions of patients with hematologic malignancies.