Editorial [Hot Topic: Current Drug Targets in Childhood Acute Leukemia (Guest Editor: R.B. Lock)]

Pediatric acute lymphoblastic leukemia, the most common childhood malignancy, represents a profound cancer therapy success story of the 20th Century. Well-designed clinical trials, coupled with improvements in supportive care, have increased the likelihood of cure from almost nil prior to the 1960s to approaching 80% at the present day. Nevertheless, our rejoicing that the most common pediatric malignancy is also one of the most curable should be tempered by the realization that a significant number of children still relapse and die from the disease, that survivors suffer significant longterm effects of cytotoxic chemotherapy, and that the cure rates for other less common acute leukemia subtypes remain at less than 50%. The identification of novel targets for drug development in pediatric acute leukemia provides the vision to protect our most valuable resource, by saving those children who have relapsed, by developing drugs that more specifically target leukemia cells (and thereby spare the normal cells of the body), and by improving the likelihood of survival from the leukemias currently considered for the most part incurable. A substantial number of biomedical researchers remain committed to understanding the molecular basis for pediatric acute leukemogenesis, its progression, and in too many cases its resistance to conventional treatment. The current issue highlights exciting developments in this field of research. It has long been established that the microenvironment influences the development and progression of acute leukemia. The chapter by Konopleva and Andreef summarizes our current understanding, and explores the possibility of targeting microenvironment/leukemia interactions in the development of novel therapies. Furthermore, it has become increasingly evident that dysregulation of tyrosine kinases is intimately involved in leukemogenesis. Stubbs and Armstrong describe the role of mutations in the FLT3 receptor tyrosine kinase in leukemia, and summarize current clinical development of FLT3 inhibitors. Inappropriate activation of the RAS signaling pathway is commonly observed in juvenile myelomonocytic leukemia (JMML), a rapidly fatal myeloproliferative disorder of early childhood. The chapter by Flotho and colleagues summarizes current understanding of JMML, and offers insight into how the RAS signaling pathway might be exploited in the development of novel therapeutics to improve the outcome for this devastating disease. Transcription factors are dysregulated in many childhood acute leukemias by chromosomal translocations that result in their repressed activity or inappropriate activation. Berman and Look review the current state of knowledge in the field, and focus on recent attempts to target transcription factors in leukemia, and in particular acute promyelocytic leukemia and T-lineage acute lymphoblastic leukemia, as well as predictions for future drug targeting. Tubulin-binding agents, in particular the Vinca alkaloids vincristine and vinblastine, have become central components of combination chemotherapy regimens used in the treatment of a wide range of malignancies, including pediatric acute leukemia. Liaw and colleagues review the mechanism action of tubulin-binding agents, how drug resistance can emerge, and provide insight into current and future clinical development of novel tubulin-binding drugs. While tubulin-binding drugs exert their anti-leukemic effects via induction of apoptosis (programmed cell death), the chapter by Grant and Dent explores the rational combination of drugs that simultaneously target signal transduction and cell cycle regulatory pathways to specifically induce apoptosis in acute leukemia cells. Den Boer and Pieters then review the use of microarray analysis of gene expression to identify new drug targets in acute leukemia subtypes.........