Pediatric Oncology
Stuart Orkin, MD, Chair
The Department of Pediatric Oncology, which is part of Dana-Farber/ Children's Hospital Cancer Care, is committed to promoting laboratory research, translational investigations, and clinical studies to better understand and treat childhood cancers. We believe that research across this continuum is most likely to contribute to the development of novel therapeutics. Highlighted in this overview are recent developments in several general areas, including cancer biology, leukemia research, genomics and chemistry, stem cells, and neurobiology.
In the area of cancer biology, David E. Fisher, MD, PhD, continues to investigate the critical role of the transcription factor MITF in the survival of malignant melanoma cells. In collaboration with others at Dana-Farber, Dr. Fisher has shown that MITF can cooperate with an activated form of the kinase BRAF to transform melanocytes, implicating mitf as a melanoma oncogene. Parallel studies have identified chromosomal translocations of the protein TFEB, linking it to pediatric renal neoplasms. Together with the translocation of TFE3 in renal cell carcinomas and alveolar soft part sarcomas, these findings demonstrate an important role for the MITF family of proteins in solid tumors.
Work from David Pellman, MD, illustrates another aspect of cancer biology. For many years scientists hypothesized that cell division failure facilitates the development of malignancies. To ascertain whether this was true, Dr. Pellman and his colleagues transplanted mammary epithelial cells with a diploid or tetraploid karyotype under the skin of mice and tested the frequency with which tumors developed in each case. Their findings demonstrate that tetraploidy enhances the frequency of chromosomal aberrations and promotes tumor development — strengthening the link between chromosomal instability and tumorigenesis.
In basic leukemia research, the laboratory of A.Thomas Look, MD, generated a new zebrafish model of acute lymphoblastic leukemia (ALL) in which the myc oncogene is expressed within T cells. The power of zebrafish genetics offers the potential to uncover unknown genes that antagonize leukemia. In a second study, Dr. Look and his colleagues at Brigham and Women's Hospital discovered that activating mutations in Notch 1, a transmembrane receptor that regulates normal T cell development, are found with high frequency in human cases of T cell ALL. These findings provide a rationale for therapy that interferes with this step in the Notch signaling pathway. Since inhibitors of Notch 1 processing have been developed as a potential treatment for Alzheimer's disease, they are available for immediate clinical investigation for T cell ALL.
Because of their importance in the pathogenesis of leukemias and other cancers, kinases are under intensive study in many settings, owing in part to the success of imatinib/Gleevec therapy in patients with chronic myeloid leukemia. Scott Armstrong, MD, PhD, has studied the receptor kinase FLT3, whose expression is increased in leukemias associated with rearrangements of the gene for mixed lymphocytic leukemia (MLL) and which is mutated in some cases of typical childhood ALL. Collaborating with others at DFCI, Dr. Armstrong has shown that inhibition of FLT3 with small-molecule drugs is cytotoxic to leukemic cells. Using gene expression-based screening, Kimberly Stegmaier, MD (working with Todd Golub, MD), has observed that gefitinib, developed as an inhibitor of the epidermal growth factor receptor, induces the maturation of acute myeloid leukemia cells. These findings have stimulated efforts to test these effects in a clinical trial.
Other basic approaches to targeted therapy are being used by Andrew Kung, MD, PhD, and Loren Walensky, MD, PhD. Dr. Kung focuses on the long-standing observation that tumor cells have adapted to survive under conditions of low oxygen (hypoxia). Interference with the regulatory pathways that permit survival in hypoxic conditions offers a potential strategy for selective killing of tumor cells. Therefore, Dr. Kung and his colleagues have developed screens to identify compounds that block hypoxia-inducible pathways in cells, and demonstrated 'proof-of-principle' that disrupting the signaling pathway with small molecules is effective. In work that capitalizes on a new chemical strategy, Dr. Walensky (with the late Stanley Korsmeyer, MD) developed a method to stabilize critical portions of 'death-promoting' proteins within cells and selectively kill cancer cells in an animal model. This novel chemical approach can be applied widely to target different proteins within cancer cells and offers yet another avenue to new therapeutics. Studies in the laboratory of Rosalind Segal, MD, PhD, showed that a receptor known as CXCR4 is important for growth of neuronal and glial cells. This work provided the rationale for inhibition of CXCR4 with an antagonist (AMD3100) as a potential approach to the management of glioblastoma and medulloblastoma, two brain tumors. Experiments in animal models suggest efficacy, providing the basis for further examination of CXCR4 blockade in brain tumors.
The relationship between cancers and stem cell biology has grown stronger in recent years. Work in the laboratory of Stuart Orkin, MD, focuses on the development and function of stem cells, and on the nature of target cells for specific cancers. In recent work, Dr. Orkin identified critical roles for several transcription factors in the genesis or subsequent function of hematopoietic stem cells. Almost invariably, the genes altered by mutation or translocation in leukemia are also essential for the development or function of normal blood stem cells. Work from his laboratory has also provided evidence that the cell that is the target for transformation in one specific infant leukemia (M7 in Down syndrome) is a previously unrecognized embryonic/fetal progenitor, rather than a cell of the adult blood system. This finding may account for the age restriction of some infant or early childhood leukemias. In addition to these basic advances, important progress has been made in clinical studies. Holcombe Grier, MD, led a clinical trial that demonstrated the benefit of adding two drugs (ifosfamide and etoposide) to the normal chemotherapy regimen for patients with Ewing sarcoma and primitive neuroectodermal tumor of bone. Lewis Silverman, MD, Stephen Sallan, MD, and their colleagues showed that children with T cell ALL who were treated at DFCI fared as well as those with B cell ALL; this is notable because historically T cell ALL patients have had a worse prognosis. Moreover, Dr. Sallan and his colleagues demonstrated that a free-radical scavenger, dexrazoxane, is effective in reducing cardiac toxicity associated with the use of doxorubicin in childhood ALL, without concomitant loss of the antileukemic effect of doxorubicin. This finding is important in reducing long-term morbidity from intensive leukemia therapy.
A major goal in clinical activities is reducing potential chemotherapy errors; however, adverse events related to medication errors, though largely preventable, do occur. Amy Billett, MD, has developed standard chemotherapy templates and a computerized order entry system, which has been implemented for the joint DFCI/Children's Hospital pediatric hematology and oncology program. This advance in clinical systems will reduce medication errors and provide a framework for further study of best practices to prevent such adverse events. In addition to this work, we are also committed to clinical research that assesses the quality of life in cancer survivors. Outcome studies in this area are led by Lisa Diller, MD, director of the David B. Perini, Jr. Quality of Life Clinic, which provides an important vehicle for clinical investigation, and Mark Kieran, MD, PhD, director of Pediatric Neuro-Oncology. In one study, for example, Dr. Diller and her colleagues showed that survivors of childhood sarcoma and those who received chest radiation as part of their therapy are at increased risk for secondary breast cancer.
This brief summary of research by our faculty highlights exciting new research directions that we anticipate will lead to increasingly effective strategies for preventing, detecting, and treating childhood cancers, while reducing adverse long-term side effects of therapy.
