Despite aggressive treatment with surgery, combination chemotherapy with stem cell rescue, and in some cases radiation, young children with malignant brain tumors have a 5-year event-free survival rate of 15-30%. A critical barrier to more effective and less toxic therapies for these children is the paucity of functional knowledge about the molecular pathways that are critical for survival of these age-specific tumors. Furthermore, the incidence of infant and toddler brain tumors is low enough that they are orphan diseases, which attract no appreciable industry interest. In this proposal, we bring together some of the world's leading experts on high throughput RNAi assays to identify candidate therapeutic targets with an innovative new approach to test and prioritize potentially synergistic combination therapies and a highly experienced brain tumor translational research team to solve the specific clinical problem that highly aggressive therapies are failing to improve outcomes in infants and toddlers with brain tumors. Our broad, long-term goal is to double the cure rate for infants and toddlers with brain cancer.
Our specific aims are 1) To assess the efficacy of Cdk 4/6 inhibition in clinically relevant mouse models of ATRT and medulloblastoma;2) To identify novel therapeutic targets in infant and toddler brain tumors;3) To advance one highly effective drug combination to the point of human clinical trials for infants and toddlers with brain tumors. The expected outcome is a combination therapy regimen that produces durable remission in established, bulky, clinically relevant mouse models of infant and toddler brain cancer. The significance of this work is that pediatric neuro-oncologists will abandon the highly toxic and ineffective therapeutic regimens that we are currently using in favor of a targeted approach that has higher efficacy and less toxicity.

Public Health Relevance

This proposal integrates drug target identification and an innovative approach to prioritizing highly effective combinations of cancer drugs to advance more effective and less toxic therapy regimens for infants and toddlers with brain tumors.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Forry, Suzanne L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Fred Hutchinson Cancer Research Center
United States
Zip Code
Gottardo, Nicholas G; Hansford, Jordan R; McGlade, Jacqueline P et al. (2014) Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group. Acta Neuropathol 127:189-201
Toledo, Chad M; Herman, Jacob A; Olsen, Jonathan B et al. (2014) BuGZ is required for Bub3 stability, Bub1 kinetochore function, and chromosome alignment. Dev Cell 28:282-94
Shih, David J H; Northcott, Paul A; Remke, Marc et al. (2014) Cytogenetic prognostication within medulloblastoma subgroups. J Clin Oncol 32:886-96
Morfouace, Marie; Shelat, Anang; Jacus, Megan et al. (2014) Pemetrexed and gemcitabine as combination therapy for the treatment of Group3 medulloblastoma. Cancer Cell 25:516-29
Olson, James M (2014) Therapeutic opportunities for medulloblastoma come of age. Cancer Cell 25:267-9
Hubert, Christopher G; Bradley, Robert K; Ding, Yu et al. (2013) Genome-wide RNAi screens in human brain tumor isolates reveal a novel viability requirement for PHF5A. Genes Dev 27:1032-45
Ding, Yu; Hubert, Christopher G; Herman, Jacob et al. (2013) Cancer-Specific requirement for BUB1B/BUBR1 in human brain tumor isolates and genetically transformed cells. Cancer Discov 3:198-211
Leary, Sarah E S; Olson, James M (2012) The molecular classification of medulloblastoma: driving the next generation clinical trials. Curr Opin Pediatr 24:33-9