Current Molecular Medicine - Volume 5, Issue 7, 2005

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.

It is now well established that the growth of primary and metastatic tumors is associated with the formation of new blood vessels, and that the growth of these tumor cells is frequently dependent on this neovasculature. The observation that inhibition of tumor angiogenesis in mice can lead to tumor regression or dormancy generated high level of enthusiasm and interest in developing new treatment strategies for human cancer based on inhibiting tumor angiogenesis. This short review focuses on recent advances in angiogenesis-research in non-Hodgkin's lymphoma and Hodgkin's disease.

Imatinib mesylate is a major advance in the therapy of patients with chronic myelogenous leukemia (CML). Imatinib mesylate binds to the inactive conformation of BCR-ABL tyrosine kinase suppressing the Philadelphia chromosome positive clone in CML. Clinical studies have yielded impressive results in all phases of CML. With higher rates of complete cytogenetic response with imatinib, molecular monitoring of disease is now advisable in assessing response and determining prognosis. Emergence of resistance to imatinib may be manifest at the hematologic, cytogenetic, or molecular levels in patients who remain in chronic phase, or may be evidenced by the development of more advanced CML phases. Resistance and eventual clinical failure of imatinib occurs in most patients with blastic phase disease. Resistance may occur at the level of Bcr-Abl, with reduction or loss of imatinib effectiveness as a kinase inhibitor, or, despite retention of its inhibitory ability, with changes in the ability to deliver an effective dose at the cellular level, and/or, the leukemia becoming less dependent on Bcr-Abl. The various mechanisms underlying these differing, non-mutually exclusive, mechanisms of resistance must be understood to develop corresponding therapeutic remedies. We review the current data on imatinib in CML, the criteria for diagnosis of imatinib resistance, and the mechanisms that underlie such resistance in CML.

Protein kinases have emerged as one of the most promising targets for rational drug discovery. In a similar manner to imatinib mesylate (Gleevec®), hematological malignancies offer multiple pharmacologic opportunities for manipulation of kinase-induced tumor cell proliferation. Certain kinases have been validated as targets for drug discovery in hematological malignancies (such as BCR-ABL and FLT3); other novel kinases hold considerable interest for targeted intervention: myeloid leukemias (KDR, KIT, CSF-1R, RAS and RAF), lymphoid leukemias (JAK2 fusion protein, TIE-1, CDK modulators), lymphoma (ALK, CDK modulators, mTOR), myeloproliferative disorders (PDGF-R or FGF-R fusion gene products, FGF-R1) and myeloma (FGF-R3, STAT3). Over the past five years, the number of kinase-targeted drug therapies undergoing clinical development has increased exponentially. This review will focus on novel kinase targets currently undergoing preclinical and clinical investigation.

In sum, the FTIs are signal transduction inhibitors that display promising clinical activity against a broad spectrum of malignancies. We are just beginning to explore and elucidate the mechanisms by which transformed cells respond to FTIs and the optimal settings in which they do so. The clinical trials that are currently in progress and under development will provide the critical foundations for defining the optimal roles of FTIs in patients with AML and other hematologic disorders. The correlative laboratory studies to define the mechanisms by which FTIs alter cellular metabolism and modulate the activities of specific signaling pathways in both normal and malignant marrow precursors are a pivotal part of this effort. What we learn about FTIs in the clinic and the laboratory will apply broadly to the effective and safe application of all signal transduction inhibitors.

Reflecting its critical role in integrating cell growth and division with the cellular nutritional environment, the mammalian target of rapamycin *(mTOR) is a highly conserved downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway. mTOR activates both the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4E-binding protein-1. As a consequence of inhibiting its downstream messengers, mTOR inhibitors prevent cyclindependent kinase (CDK) activation, inhibit retinoblastoma protein phosphorylation, and accelerate the turnover of cyclin D1, leading to a deficiency of active CDK4/cyclin D1 complexes, all of which may help cause GI phase arrest. Constitutive activation of the PI3K/Akt kinases occur in human leukemias. FLT3, VEGF, and BCR-ABL mediate their activities via mTOR. New rapamycin analogs including CCI- 779, RAD001, and AP23573, are entering clinical studies for patients with hematologic malignancies.

MoAb-based therapies are evolving into the first broad-spectrum class of targeted antileukemic therapy. Developments in many areas, including computer modeling of receptors and ligands, and increasing sophistication in recombinant technologies may result in a rapid increase in the number and complexity of MoAb's available. We can anticipate an increase in the number of safer conjugates being delivered to leukemia cells. Further understanding of the in vitro mechanisms involved in tumor cell killing by MoAb will be important in maximizing the efficacy of this approach.

In late 2002 a new disease, severe atypical respiratory syndrome (SARS), emerged in China. A hitherto unknown animal coronavirus (CoV) that had crossed the species barrier through close contact of humans with infected animals was identified as the etiological agent. It rapidly adapted to the new host and not only became readily transmissible between humans but also more pathogenic. Air travel spread it rapidly around the world and ultimately the virus infected 8096 people and caused 774 deaths in 26 countries on 5 continents. Aggressive quarantine measures successfully terminated the disease. Currently, there are no SARS cases recorded and most likely the virus no longer circulates in the human population. In this review we present an overview over SARS-Co virus biology, the disease and discuss strategies to develop antiviral drugs and vaccines.

Advances in developmental biology combined with progress in human genetics are helping us decipher how the craniofacial region develops and how the consequences of misdirected development result in malformation. This review describes the molecular etiology of a number of craniofacial developmental anomalies. The more common craniofacial anomalies cleft lip and palate and craniosynostosis, as well as cleidocranial dysplasia, hemifacial microsomia, holoprosencephaly, enlarged parietal foramina, Treacher Collins syndrome and cherubism are discussed.

Chronic degenerative diseases and traumatic injuries are responsible for a decline in neuronal function, which often limit life span. While solid organ transplantation such as liver and kidney has been already applied for thousands of patients, great limitation exists in case of nervous system. Cell transplantation is one of the strategies with potential for treatment of such neural disorders, and many kinds of cells including embryonic stem cells and neural stem cells have been considered as candidates for transplantation therapy. Bone marrow stromal cells (MSCs) have great potential as therapeutic agents, since they are easy to isolate and can be expanded from patients without serious ethical and technical problems. We found a method for the highly efficient and specific induction of functional neurons and Schwann cells from both rat and human MSCs. Induced neurons and Schwann cells were transplanted in animal models of Parkinson's disease, stroke, peripheral nerve injury, and spinal cord injury resulting in the successful integration of transplanted cells and improvement in behavior of transplanted animals. Here we focus on the respective potentials of MSC-derived cells and discuss the possibility of clinical application in neurodegenerative and neurotraumatic diseases.