The Department of Pediatric Oncology is committed to promoting
laboratory research, translational investigation, and clinical
studies to better understand and treat childhood cancers.
Research across the continuum from laboratory research to
clinical trials is most likely to contribute to the development of
novel therapeutics. The Department's research focus accordingly
spans cancer biology, leukemia research, sarcomas, neurobiology,
and chemical biology. Through Dana-Farber/Children's Hospital
Cancer Center, the Department is developing unique clinical trials
to improve the treatment and care of children with cancer. Leading
Dana-Farber's pediatric clinical trials program is Carlos Rodriguez-Galindo, MD. The Department's clinical trials
portfolio includes investigator-initiated, cooperative group, and
company-sponsored trials for a variety of cancers at different
stages of progression.
Scott Armstrong, MD, PhD, is focusing on acute myelogenous
leukemia associated with chromosomal rearrangements of the MLL
gene, an infant leukemia that is difficult to treat. His laboratory
has shown that the MLL fusion products promote the formation of a
self-renewing cell population called leukemic stem cells. These
cells, which sustain the leukemia, express genes normally
restricted to immature blood stem cells. Armstrong and colleagues
are now examining ways to target these differentially expressed
genes. Such approaches may lead to novel therapies.
Mark Kieran, MD, PhD, and Charles Stiles, PhD, co-chair of Cancer Biology, created the Pediatric Low-Grade Astrocytoma Program at Dana-Farber.
Believed to be the first coordinated effort focusing on low-grade
gliomas, the program has a five-year objective to identify a
molecular target that can be affected with personalized therapy.
Rosalind Segal, MD, PhD, who is also a member of Cancer Biology,
is studying the pathways by which extracellular stimuli (such as
growth factors and cell-to-cell interactions) regulate development.
Segal and her group have demonstrated that neuronal precursors in
the cerebellum migrate along a gradient of the growth factor
brain-derived neurotrophic factor (BDNF). The lab has identified
critical intracellular pathways that allow this migration and is
identifying new ways in which these pathways can be selectively
turned on or off. Recent studies have highlighted a role for the
BDNF receptor in diverse metastatic diseases. Thus, Segal's studies
may lead to new cancer drugs that block cancer cell
Charles Roberts, MD, PhD, is studying the role of the SWI/SNF
protein complex in malignant rhabdoid tumors and other cancers. He
is also investigating the mechanisms by which it controls cell
growth. Roberts and his group found that aggressive cancers that
arise in mice deficient in the SNF5 gene lack widespread genome
mutations. The changes that occur following SNF5 mutation are
actually epigenetic alterations, which are potentially reversible
and, therefore, have important therapeutic implications for a wide
variety of cancers.
Stuart Orkin, MD, is leading an effort to find new approaches
to osteosarcoma, the most common primary bone tumor, using an
engineered mouse model that mimics the human cancer. His team,
along with Katherine Janeway, MD, seeks to define the pathways leading to
metastasis and to identify novel agents that may promote
differentiation of the cancer cells.
Rani George, MD, PhD, performed a genome-wide analysis of neuroblastoma tumors and found multiple copies of a
receptor tyrosine kinase gene, ALK, in up to 14 percent of
high-risk neuroblastomas. In collaboration with the Broad
Institute, George sequenced ALK in 93 primary
neuroblastoma tumor samples. She discovered five different
mutations, with one mutation recurring in four cases.
Kimberly Stegmaier, MD, focuses on genomic approaches to drug
discovery. With the Broad Institute, Stegmaier developed a new
method of chemical discovery called gene expression-based
high-throughput screening (GE-HTS). This technique led to the
discovery of chemicals that induce the maturation of acute myeloid
leukemia (AML) cells and resulted in a clinical trial for patients
with relapsed AML. Many malignancies are believed to arise from the
abnormal proliferation of cells and the failure of primitive cells
to differentiate. For this reason, Stegmaier is focusing on the differentiation defect in two model diseases, AML and neuroblastoma.
David Pellman, MD, recently developed a genome-wide imaging
approach to identify genes that are essential for abnormal cell
division. His goal is to find genes that are not necessary in
normal cells, but are required for the survival of cancer cells.
One way to distinguish cancer cells from their normal counterparts
is the presence of too many centrosomes. These are cellular
structures that initiate the cellular machine that distributes the
chromosomes in a dividing cell. This study identified a novel drug
target, the kinesin HSET. Blocking HSET kills neuroblastoma cells
with extra centrosomes, but spares normal cells. This information
may impact the treatment of leukemias and solid tumors, where
increased centrosome numbers are common.
Loren Walensky, MD, PhD, is applying novel compounds to dissect
and manipulate the cell signaling pathways that are integral in
apoptosis in order to reactivate them to overcome cancer. Walensky
inserted a chemical "staple" into a natural but otherwise unstable
cell-killing peptide. This reactivated the apoptosis cell signaling
pathway in leukemia cells. When the stapled peptide was injected
into mice, it suppressed human-type leukemia. Compounds such as
this one are now being used to study the interactions of proteins
inside cells, giving scientists a "molecular toolbox" to study and
to potentially treat cancer and other diseases.
William Nicholas Haining, BM, BCh, is identifying the molecular
characteristics of T cells associated with immunologic protection.
Using gene expression profiling, Haining has demonstrated that all
lymphocyte lineages in mice and humans use a common cell
differentiation program during memory development. With Stegmaier,
he has used GE-HTS to identify small molecules, genes, or soluble
factors that direct memory differentiation in naive human
lymphocytes. These studies may lead to the discovery of new
immunomodulatory drugs or vaccine strategies.
Andrew Kung, MD, PhD, is studying the mechanisms through which
the hypoxia-inducible factor pathway allows cells to adapt to
hypoxia. He is also focused on how to therapeutically target
hypoxic tumor cells. Kung has developed new ways to use noninvasive
imaging in order to assess molecular pathways within tumors, and
has used these approaches to validate new therapies in mouse
models. Kung leads the new Dana-Farber Lurie Family Imaging Center and helped establish
the Institute's Center for Biomedical Imaging in Oncology
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