Pediatric Malignancies Program

Program Leaders

Education and Training Liaison: Tiffany Lucas, MD

Community Engagement Liaison: Lena Winestone, MD
The overall goals of the Pediatric Malignancies Program are (1) to understand the biology of pediatric malignancies and uncover links between normal development and cancer to identify therapeutic targets; and (2) to translate laboratory discoveries into clinical trials, and epidemiological and survivorship studies to improve clinical outcomes for children with cancer.

Pediatric cancers are unique in their morphology, tissues of origin, and behavior. They provide an opportunity to understand the link between normal development and the aberrant signaling networks of childhood malignancy; to discover through these genetic networks new therapeutic targets; and then integrate these into innovative clinical trials. These molecular studies can lead to a new understanding of the interactions of genetics and environment in cancer development and the late effects of treatment, thus improving the outcome for survivors of pediatric cancer. The Program’s efforts will also affect future advances through our excellent physician scientist training programs and our outreach and education of the public.

Acute Leukemia

Resistance to PI3K Inhibition is Associated with Loss of Activated Notch Signaling in T-cell Acute Lymphoblastic Leukemia (T-ALL) In a publication in Nature, Kevin Shannon, MD showed that in vivo treatment with chemical inhibitors of PI3K and Raf/MEK/ERK signaling markedly prolonged the survival of mice transplanted with primary T-ALLs. Importantly, these aggressive leukemias invariably relapsed due to outgrowth of drug resistant clones that showed reduced Notch1 protein expression and upregulated PI3K signaling. These findings suggest that the rational therapeutic strategy of combining Notch and PI3K inhibitions might inadvertently promote drug resistance in T-ALL.

Genomic Landscape of Juvenile Myelomonocytic Leukemia (JMML) Mignon Loh, MD and Elliott Stieglitz, MD made a major step in elucidating genomic changes and prognostic importance of mutations in JMML, a deadly childhood neoplasm. In work published in Nature Genetics, they established the genomic landscape of JMML and extended the understanding of additional mutations beyond the known Ras/MAPK alterations. Furthermore, with Joseph Costello, PhD   and Adam Olshen, PhD, they used whole-exome sequencing to characterize serial samples from patients at diagnosis through relapse and transformation to acute myeloid leukemia.

Brain Tumors


Drugging MYCN via Allosteric Transition in Aurora Kinase A Clay Gustafson, MD, PhD; William Weiss, MD, PhD; Katherine Matthay, MD; and Kevan Shokat, PhD synthesized and characterized a class of inhibitors that disrupted the native conformation of Aurora A and drove degradation of MYCN protein across MYCN-driven cancers, reported in Cancer Cell. They identified CD532 as potently inhibiting Aurora A, driving proteolytic degradation of MYCN protein, and as cytotoxic in MYCN-amplified neuroblastoma cells, prolonging survival in neuroblastoma and medulloblastoma xenografts. Translation into the clinic was then undertaken using an Aurora kinase inhibitor (alisertib) combined with irinotecan and temozolomide chemotherapy, and published in JCO by previous member Steve DuBois, MD and Matthay, in collaboration with the New Advances in Neuroblastoma Therapy (NANT) phase I consortium.

Sarcomas and Developmental Therapeutics for Pediatric Solid Tumors

A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma and Medulloblastoma Weiss; Theodore Nicolaides, MD; Gustafson; and Shokat reported in Cancer Cell that PI3K or AKT inhibition shows limited efficacy preclinically in glioblastoma and in medulloblastoma,5 despite the fact that signaling pathway linking PI3K to mTOR is dysregulated prominently in these tumors. Weiss, working with Nicolaides, Gustafson, Shokat, and Joanna Phillips, MD, PhD, demonstrated that second-generation active site inhibitors of mTORC1/2 inhibited both effectors of mTORC1 (S6K and EIF4E), and also blocked AKT, a substrate of mTORC2; however, poor pharmacology led to poor responses. To improve efficacy and pharmacology, Shokat  linked an active site inhibitor of mTOR to the mTORC1 specific targeting domain of rapamycin. This compound, RapaLink-1, a third-generation mTOR inhibitor, showed mTORC1-specific binding and blood-brain barrier permeability similar to rapamycin, but with improved pharmacology. RapaLink-1 had a superior pharmacokinetic profile in vivo in glioma and medulloblastoma.