Children with medulloblastoma/PNET are currently treated with surgery, radiation, and chemotherapy. Survivors often suffer severe long-term toxicity from these treatments. Our laboratory has shown in ex vivo specimens from human medulloblastoma and mouse medulloblastoma models that targeted therapies including 13-cis retinoic acid (RA), cyclopamine, notch pathway inhibitors, histone deacetylase inhibitors and combinations of these agents induce medulloblastoma cell death as well as more toxic chemotherapy agents that are currently used for these patients. Based on our findings related to 13-cis RA, the Children's Oncology Group has developed a national Phase III clinical trial to assess efficacy of this agent. The broad long term goals of the biology correlative studies to this clinical trial are to 1) identify biomarkers with prognostic and predictive value for future clinical trials and 2) prioritize candidate targeted therapies for future clinical trials.
The specific aims of this proposal are to utilize ex vivo surgical specimens to 1) identify biomarkers predicting therapy failure in high-risk medulloblastomas/SPNETs and 2) prioritize targeted therapies for future clinical trials. The significance of this work is that it is a direct means toward replacing current pediatric brain tumor treatment modalities with more effective and less toxic alternatives.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA114567-05
Application #
7736806
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Forry, Suzanne L
Project Start
2005-12-06
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2011-11-30
Support Year
5
Fiscal Year
2010
Total Cost
$223,417
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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
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
Cook Sangar, Michelle L; Genovesi, Laura A; Nakamoto, Madison W et al. (2017) Inhibition of CDK4/6 by Palbociclib Significantly Extends Survival in Medulloblastoma Patient-Derived Xenograft Mouse Models. Clin Cancer Res 23:5802-5813
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
Pei, Yanxin; Liu, Kun-Wei; Wang, Jun et al. (2016) HDAC and PI3K Antagonists Cooperate to Inhibit Growth of MYC-Driven Medulloblastoma. Cancer Cell 29:311-323
Rosenthal, Eben L; Warram, Jason M; de Boer, Esther et al. (2016) Successful Translation of Fluorescence Navigation During Oncologic Surgery: A Consensus Report. J Nucl Med 57:144-50
Moreno-Gonzalez, Alicia; Olson, James M; Klinghoffer, Richard A (2016) Predicting responses to chemotherapy in the context that matters - the patient. Mol Cell Oncol 3:e1057315
Baik, Fred M; Hansen, Stacey; Knoblaugh, Sue E et al. (2016) Fluorescence Identification of Head and Neck Squamous Cell Carcinoma and High-Risk Oral Dysplasia With BLZ-100, a Chlorotoxin-Indocyanine Green Conjugate. JAMA Otolaryngol Head Neck Surg 142:330-8
Lindsey, J C; Kawauchi, D; Schwalbe, E C et al. (2015) Cross-species epigenetics identifies a critical role for VAV1 in SHH subgroup medulloblastoma maintenance. Oncogene 34:4746-57

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