Pediatric Malignancies Program

Program Leaders

Education and Training Liaison: Christine Higham, 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.

  • Theme 1: Leukemia
  • Theme 2: Brain Tumors
  • Theme 3: Neuroblastoma
  • Theme 4: Sarcoma and other solid tumors

Scientific Accomplishments By Theme

Theme 1: Leukemia

Stieglitz co-led an international collaboration that defined DNA methylation subgroups in juvenile myelomonocytic leukemia (JMML). Stieglitz and Loh published the largest series to date of CBL-mutated subtype of JMML and are co-leading a clinical trial in relapsed/refractory JMML (NCT03190915) testing the efficacy of the MEK inhibitor trametinib. This study is funded by the Developmental and Hyperactive Ras Tumor (DHART) SPORE (U54CA196519), led by Wade Clapp and Kevin Shannon, and a Leukemia Lymphoma Society Translational Research Program to Loh. The SPORE (Loh and Shannon co-lead Project 3) is the only one in the NCI portfolio that focuses on an inherited cancer predisposition syndrome (NF1) and tests new therapies in pediatric patients. Its renewal received a score of 19. Loh, Stieglitz, and Sweet-Cordero secured a CCSG supplement through the new Children’s Cancer Data Initiative (CCDI) to deposit genomic data from rare tumors sequenced at UCSF. Braun and Shannon described novel hematopoietic and developmental phenotypes of germline Kras mutations in mouse models of Rasopathies. Shannon delineated somatic mutations in the Nr3c1 gene in T lineage acute lymphoblastic leukemia (T-ALL) which encodes the glucocorticoid receptor (GR), and down-regulation of GR protein expression as a major mechanism of in vivo resistance to dexamethasone. Shannon also generated knock-in mice harboring a second site mutation in the NrasG12D oncogene to show that palmitoylation is essential for myeloid transformation. These data, which are being extended through a new NCI collaborative R01 grant (R01CA193994) with Benjamin Cravatt (Scripps). 

Loh continues to Chair COG’s ALL committee, supervising over eight clinical trials for newly diagnosed and relapsed ALL. Loh is also PI on a MPI U24 grant (2U24CA196173-06) that focuses on ALL biology initiatives. She demonstrated the benefits of blinatumomab, a bi-specific T cell engaging therapy, for children, adolescents, and young adults with first relapse of ALL. Translational genomics remains an area of interest, and she recently published a paper in Cancer Discovery funded by a St Baldrick’s Consortium grant. 

Winestone continues her work to address health disparities in leukemia and bone marrow transplant. She has linked administrative data with COG trial data to demonstrate disparities in enrollment in pediatric leukemias. She also received a CCSG supplement as part of the National Children’s Cancer Registry (NCCR). Hermiston, with Shannon and Olshen (CBI Shared Resource), evaluated primary diagnostic samples from the COG T-cell leukemia and lymphoma front-line trial AALL1231.

Dvorak chairs COG’s Cancer Control and Supportive Care Committee and is working to understand patterns of response in determining optimal transplant-approach for high-risk pediatric leukemias, collaborating with Stieglitz and Winestone

Theme 2: Brain Tumors

Weiss has a new R01 (R01CA255369) with Raleigh, Michael Taylor (Toronto), and Livia Garzia (McGill). He has co-published with Bivona, Fan, Phillips, and Shokat. The Pacific Pediatric Neuro-Oncology consortium (PNOC), led by Mueller and Prados (NE Program), has enrolled over 450 patients and currently has 25 clinical trials with eight new to open in 2021. Mueller received DoD funding to study the role of EGFR and FOXG1 in ONC201 response, building on tissue collected as part of a PNOC trial. Mueller and Prados published several collaborative papers based on PNOC trials. The PNOC program has expanded the UCSF-led clinical trial consortium Pacific Pediatric Neuro Oncology DOD to study a modified measles virus for medulloblastoma and ATRT (CA181015). In collaboration with Elliott Sherr (UCSF) and Deborah Silver (Duke), the Floor lab identified connections between genetic alterations to DDX3X RNA helicase and neurodevelopment as described in a recent paper, leading to an R01b(R01NS120667).

Theme 3: Neuroblastoma

Weiss and Matthay continue developing a non-germline GEMM model for neuroblastoma in a B6 background, for immune-oncology studies. Weiss was part of a team awarded an Alex Lemonade Stand Crazy 8 grant to develop drugs against N-myc. Matthay continues as senior advisor in the Neuroblastoma Executive committee in COG and the New Approaches to Neuroblastoma Therapy (NANT) Consortium. Matthay completed studies capitalizing on her expertise in 131MIBG therapy. NANT1101 was a randomized phase 2 study showing that vorinostat with MIBG was significantly superior to irinotecan with MIBG or MIBG alone (Dubois et al., ASCO 2020 Abstract 10500). She also collaborated with Seo to show the increased sensitivity of 124I-MIBG PET for tumor detection.

Vo worked with Sweet-Cordero to analyze the serial ctDNA samples of patients enrolled on the investigator-initiated study of the targeted multi-kinase inhibitor, pazopanib, with irinotecan and temozolomide (PAZIT). The study findings were presented at the annual ASCO 2020 meeting. In Vo’s capacity as Director of the Early Phase Clinical Trials Program in Pediatric Oncology, she has been able to continue enrollment on phase 1 and 2 studies at full capacity despite the COVID pandemic. The program enrolled a total of 42 patients on early-phase studies in December 2019 to December 2020, including 29 phase 1, 6 phase 1/2, and 7 phase 2. They have opened 13 new early phase studies this year, with a portfolio of 60 open early phase studies, including 25 phase 1, 6 phase 1/2, and 28 phase 2 or phase 2/3), and 1 pilot trial. Led by Vo, UCSF’s MIBG program has treated over 20 patients on the national COG phase 3 trial, ANBL1531.

Theme 4: Sarcoma and other solid tumors

The Sweet-Cordero laboratory has generated over 40 PDX models for sarcomas, many of which have been shared with investigators around the country and internationally (Australia), including through the PDX development core of an Ewing sarcoma U54 grant (U54CA231637). Sweet-Cordero and Mueller evaluated the feasibility and utility of incorporating comparative gene expression information into the precision medicine framework for difficult-to-treat pediatric and young adult patients with cancer. Sweet-Cordero also directs the HDFCCC Molecular Oncology Initiative (MOI) and leads the Pediatric Precision Medicine Program at UCSF Benioff Children’s Hospital. As part of the efforts of the MOI, Sweet-Cordero is actively involved in the GENIE AACR consortium which is a large consortium of institutions for data sharing. UCSF has contributed over 5,000 cases to this effort. Together with Loh, Sweet-Cordero established a UCSF Destination Program in Solid Tumors which is a clinical effort to expand precision cancer medicine for sarcomas and other solid tumors at UCSF. Sabnis is vice-chair of Vo’s COG protocol APEC1621J testing the ERK inhibitor ulixertinib in genotype-informed cohorts of pediatric cancer patients, and published with Nakamura on germline genomic findings associated with the development of secondary malignant neoplasms.

Nakamura’s lab published a paper anticipating resistance mechanisms likely to arise with chronic mTORi and MEKi. Robert Goldsby directs the Pediatric Survivor Program and has an active role in the Sarcoma Program. The Survivor Program recently published a randomized trial assessing the value or a portable Survivor card and showed it improved survivors’ knowledge of treatment and follow up recommendations. Goldsby also contributed to a study investigating the impact of low income on survival in young people with sarcomas.

Janel Long Boyle published on the pharmacokinetics of vemurafenib in brain tumor patients with BRAF mutations and astrocytomas (PNOC-002, co-authors Mueller, Prados), genotype-guided dosing of therapeutics, and the optimized exposure of busulfan in pre-transplant conditioning of pediatric stem cell transplantation (HCT) (co-author Dvorak).