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.
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.
|Klinghoffer, Richard A; Bahrami, S Bahram; Hatton, Beryl A et al. (2015) A technology platform to assess multiple cancer agents simultaneously within a patient's tumor. Sci Transl Med 7:284ra58|
|Toledo, Chad M; Ding, Yu; Hoellerbauer, Pia et al. (2015) Genome-wide CRISPR-Cas9 Screens Reveal Loss of Redundancy between PKMYT1 and WEE1 in Glioblastoma Stem-like Cells. Cell Rep 13:2425-39|
|Herman, Jacob A; Toledo, Chad M; Olson, James M et al. (2015) Molecular pathways: regulation and targeting of kinetochore-microtubule attachment in cancer. Clin Cancer Res 21:233-9|
|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|
|Kumar, Akash; Boyle, Evan A; Tokita, Mari et al. (2014) Deep sequencing of multiple regions of glial tumors reveals spatial heterogeneity for mutations in clinically relevant genes. Genome Biol 15:530|
|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|
|Shih, David J H; Northcott, Paul A; Remke, Marc et al. (2014) Cytogenetic prognostication within medulloblastoma subgroups. J Clin Oncol 32:886-96|
|Olson, James M (2014) Therapeutic opportunities for medulloblastoma come of age. Cancer Cell 25:267-9|
|Diede, Scott J; Yao, Zizhen; Keyes, C Chip et al. (2013) Fundamental differences in promoter CpG island DNA hypermethylation between human cancer and genetically engineered mouse models of cancer. Epigenetics 8:1254-60|
Showing the most recent 10 out of 18 publications