University of California San Francisco
Helen Diller Family Comprehensive Cancer Center

Pediatric Malignancies

The Pediatric Malignancies Program includes 23 members from 9 academic departments from the UCSF Schools of Dentistry and Medicine. The overarching goal of the Program is to improve the outcome for children with cancer by investigating links between normal development and the aberrant signaling networks of childhood malignancies, and to leverage these genetic networks to identify new therapeutic targets that we integrate into innovative clinical trials. 
The Pediatric Malignancies Program conducts research under four themes:
  • Theme 1: Neuroblastoma
  • Theme 2: Brain Tumors
  • Theme 3: Leukemia
  • Theme 4: Sarcomas and Developmental Therapeutics for Pediatric Solid Tumors

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.


Programmatic Themes

> Neuroblastoma
> Brain Tumors
> Leukemia
> Sarcomas and Developmental Therapeutics for Pediatric Solid Tumors
> Epidemiology and Late Effects

Theme 1: Neuroblastoma

N-myc proto-oncogene protein (MYCN) drives half of high-risk neuroblastoma cases. Over the past year, Dr. William Weiss with Drs. Clay Gustafson (Associate Member), Kate Matthay, and Kevan Shokat identified CD532: a novel inhibitor of Aurora Kinase A, itself a cancer target in neuroblastoma, that blocks the scaffolding functions of Aurora that normally stabilize MYCN. They solved the co-crystal structure of CD532 bound to Aurora, and demonstrated efficacy against MYCN-driven neuroblastoma and medulloblastoma xenografts in vivo (Gustafson et al., Cancer Cell, 2014). Mice carrying a MYCN transgene driven by the rat tyrosine hydroxylase promoter develop neuroblastoma in a strain-specific manner. The Weiss lab, with Drs. Allan Balmain and Gustafson, combined genetics with gene expression analysis in normal peripheral ganglia in this model, to implicate arginase 1 and GABA signaling in tumor formation in vivo. In human neuroblastoma cells, drugs that blocked ARG1 that activated GABA-A receptors induced apoptosis and inhibited mitogenic signaling through AKT and MAPK (Hackett et al., Cell Rep, 2014). These results suggest that ARG1 and GABA influence both neural development and neuroblastoma and that benzodiazepines in clinical use may have potential applications for neuroblastoma therapy.

An ongoing phase I study in the New Approaches to Neuroblastoma Therapy (NANT) consortium is led by Dr. Steven DuBois, testing the tolerability and activity of combining a clinical AURKA inhibitor MLN8237 (acting in part through blockade of MYCN) with standard chemotherapy, irinotecan and temozolomide, for neuroblastoma. Drs. Matthay and Youngho Seo have published the results of the first neuroblastoma patient to receive 124I-metaiodobenzylguanidine (MIBG) PET/CT pretherapy dosimetry scans prior to 131I-MIBG treatment and used data generated from these scans to calculate radiation doses to organs and tumors. In addition, a follow-up 124I-MIBG PET/CT scan six weeks post-therapy showed the utility of 124I-MIBG as a diagnostic and therapy response evaluation tool (Huang et al., Mol Imaging Biol, 2014). Based on preclinical studies, a NANT phase I study combining vorinostat with MIBG was completed, in collaboration with Drs. Daphne Haas-Kogan, Matthay, DuBois, and Kathleen Giacomini, which included correlative studies of histone acetylation and radiation biomarkers (DuBois et al., Clinical Cancer Research, 2015). A local UCSF study to establish a five-day irinotecan schedule with the MIBG therapy was also completed (DuBois et al., British J Cancer 2015).

Theme 2: Brain Tumors

Using an unbiased, in vivo analysis of mouse tumors, the Weiss lab identified intronic splicing motifs that translated into sites for recurrent somatic mutations in human cancers. His lab applied these motifs in human glioblastoma (GBM), for which whole genome and RNA sequencing were available on the same tumors and identified genes with mutations located in sites correlated with changes in alternative splicing in glioblastoma patients (Chen et al., Cancer Discov, 2015). Dr. Claudia Petrisch collaborated with Drs. Rintaro Hashizume, Sabine Mueller, and Nalin Gupta (Associate Member) to show that increasing H3K27 methylation by inhibiting K27 demethylase is a therapeutic strategy for treating H3.3K27M-expressing pediatric brainstem glioma (Hashizume et al., Nat Med, 2014). Drs. Weiss and Davide Ruggero were awarded a new multi-PI R01 grant to study intersections between MYCN and mTOR signaling in medulloblastoma.

Dr. Haas-Kogan with Drs. Mueller, Michael Prados, and former member Dr. David James reported the radiosensitizing effects of the WEE1 inhibitor MK-1775 on pediatric high grade glioma (Mueller et al., Neuro Oncol, 2013). Based on these laboratory investigations, a clinical trial has now opened through COG, and is actively accruing children with diffuse intrinsic pontine gliomas (DIPG) to be treated with the WEE1 inhibitor MK-1775 in combination with radiation.

Dr. Mueller has now developed the Pacific Pediatric Neuro-Oncology Consortium (PNOC; co-led with Dr. Mike Prados. PNOC consists of 15 member institutions with the goal to provide access to trials based on biology of the tumor. Three studies are currently open, and three more in development, with funding from the Pediatric Brain Tumor Foundation, The V Foundation, and Novartis.

Theme 3: Leukemia

Acute Lymphoblastic Leukemia (ALL) is the most common cancer of childhood. Dr. Mignon Loh published a seminal paper this year describing a subset of children, adolescents, and young adults characterized by gene expression signatures to exhibit features consistent with BCR/ABL-positive leukemia (Roberts et al., N Engl J Med, 2014). However, alternative genomic lesions give rise to these “Ph-like” ALL patients that may be targetable with kinase inhibitors. She and her colleagues are amending the largest clinical trial in childhood high-risk ALL to incorporate genetic testing and therapeutic interventions with dasatinib and chemotherapy.

Dr. Loh is also studying how the genetic alterations in leukemia result in perturbed biochemical signaling, and has harnessed phosphoflow cytometry to answer these questions in order to identify new drugs to treat the aberrant signaling. She and Dr. Elliot Stieglitz showed that subclonal mutations of SETBP1 detected on digital droplet PCR were also significantly predictive of early disease progression (Stieglitz et al., Blood, 2014, Stieglitz et al., Blood, 2015). Drs. Joe Costello and Adam Olshen, are providing expertise in methylation profiling of JMML and the informatics required to analyze the data. Drs. Biljana Horn and Chris Dvorak continue their research into improving stem cell transplantation for pediatric malignancies, with a recent study to personalize busulfan therapy, and numerous COG supportive care studies for transplant (Long-Boyle et al., Ther Drug Monit, 2014).

Theme 4: Sarcomas and Developmental Therapeutics for Pediatric Solid Tumors

Drs. DuBois and Rob Goldsby lead several translational and clinical projects in sarcomas. Dr. DuBois has an ongoing project to study bone marrow micrometastatic disease in Ewing sarcoma, which continues to accrue well. Dr. DuBois is leading a phase II national trial in the COG, which opened to accrual in December 2014 for patients with newly diagnosed metastatic Ewing sarcoma. In this trial, patients will receive standard interval compressed chemotherapy with or without the addition of an anti-IGF-1R monoclonal antibody. Dr. Dubois has also just published a comprehensive analysis of local control strategies on COG trials in Ewing Sarcoma (DuBois et al., Cancer, 2015).

Theme 5: Epidemiology and Late Effects

Dr. Joe Wiemels collaborated with Dr. Loh to study genetic risk factors for childhood acute lymphoblastic leukemia (Xiao et al., Int J Cancer, 2014). Dr. Wiemels also worked with Drs. John Wiencke and Margaret Wrensch to study the genetic and immunologic factors influencing risk of brain cancer (Walsh et al., Nat Genet, 2014). Dr. Mark Rubinstein continues his prevention program and studies of adolescent smoking (Rubinstein et al., Addict Behav, 2014). The Pediatric Cancer Survivor Program, under the direction of Dr. Goldsby, continues to grow, and was recently highlighted on the PBS news hour. Drs. Goldsby, DuBois and Rosanna Wustrack, published a study of the risk of second neoplasms in survivors of osteosarcoma (Lee et al., Cancer, 2014). Drs. Haas-Kogan and Mueller studied the characteristics of intracerebral cavernous malformations after radiotherapy for pediatric brain tumors (Gastelum et al., J Child Neurol, 2014).