Children with medulloblastoma and primitive neuroectodermal (PNET) brain tumors are divided into average- and high-risk groups so that therapy intensity can be tailored. Unfortunately, the methods for stratifying patients are imperfect, so that > 25% of children categorized as average risk fail therapy and die of disease. We have identified P27 loss as a biomarker that identifies most of these children and could be used to appropriately place them in the high-risk category, where they would receive intensified therapy increasing survival chances. Another clinical problem is that PNET patients are grouped with medulloblastoma patients in clinical trials and treated identically. We have recently learned that PNET tumors are molecularly distinct from medulloblastomas and that PNET patients respond poorly to therapy that has been tailored for medulloblastoma patients. The critical barrier to tailoring sPNET therapy to the disease has been the lack of relevant sPNET pre-clinical models. We have generated patient-derived sPNET stem cell cultures and orthotopic mouse models and have used these to identify FDA-approved drugs that are more efficacious in pre-clinical studies than currently used drugs. In this renewal application, our Specific Aims are: 1) To identify prognostic indicators of therapy failure for medulloblastoma and sPNET patients. 2) To prioritize targeted therapies for future clinical trials. The expected outcomes are: 1) that we will further refine molecular biomarkers suitable for patient stratification in a prospective analysis of > 300 patients; 2) that we will generate clinically relevant sPNET and high risk medulloblastoma pre-clinical models and 3) consistent with our track record, we will promote a regimen for human sPNET and high risk medulloblastoma trials based on studies that exceed all current standards for advancement of pre-clinical results into clinical trials. The significance is that we will ultimately abandon an archaic patient stratification scheme in favor o a biologically-based strategy that appropriately directs patients into tailored therapy and that sPNET patients will be treated with therapeutic regimens that are based on relevant pre-clinical and clinical data. Ultimately both will yield higher cure rates and limit toxicity in pediatric bran tumor patients.

Public Health Relevance

This proposal integrates newly identified biomarkers that identify children who are likely to fail standard medulloblastoma or supratentorial primitive neuroectodermal therapy with novel patient-derived pre-clinical brain tumor models that are used to identify and prioritize new therapies for pediatric brain tumor patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA114567-09
Application #
8866363
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Forry, Suzanne L
Project Start
2005-04-01
Project End
2016-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
9
Fiscal Year
2015
Total Cost
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. (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
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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