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.
|Crook, Zachary R; Sevilla, Gregory P; Friend, Della et al. (2018) Publisher Correction: Mammalian display screening of diverse cystine-dense peptides for difficult to drug targets. Nat Commun 9:1072|
|Morris, Shelli M; Mhyre, Andrew J; Carmack, Savanna S et al. (2018) A modified gene trap approach for improved high-throughput cancer drug discovery. Oncogene 37:4226-4238|
|Xu, Tao; Zhang, Honglai; Park, Sung-Soo et al. (2017) Loss of Pin1 Suppresses Hedgehog-Driven Medulloblastoma Tumorigenesis. Neoplasia 19:216-225|
|Crook, Zachary R; Sevilla, Gregory P; Friend, Della et al. (2017) Mammalian display screening of diverse cystine-dense peptides for difficult to drug targets. Nat Commun 8:2244|
|Ding, Yu; Herman, Jacob A; Toledo, Chad M et al. (2017) ZNF131 suppresses centrosome fragmentation in glioblastoma stem-like cells through regulation of HAUS5. Oncotarget 8:48545-48562|
|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 13:2425-2439|
|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|
|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|
|Shih, David J H; Northcott, Paul A; Remke, Marc et al. (2014) Cytogenetic prognostication within medulloblastoma subgroups. J Clin Oncol 32:886-96|
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