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
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
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
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
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
Hoffman, Lindsey M; Fouladi, Maryam; Olson, James et al. (2015) Phase I trial of weekly MK-0752 in children with refractory central nervous system malignancies: a pediatric brain tumor consortium study. Childs Nerv Syst 31:1283-9
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
Fidel, Janean; Kennedy, Katie C; Dernell, William S et al. (2015) Preclinical Validation of the Utility of BLZ-100 in Providing Fluorescence Contrast for Imaging Spontaneous Solid Tumors. Cancer Res 75:4283-91

Showing the most recent 10 out of 22 publications