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 stratificatin 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.
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.
|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|
|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|
|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|
|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|
|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|
|Parrish-Novak, Julia; Holland, Eric C; Olson, James M (2015) Image-Guided Tumor Resection. Cancer J 21:206-12|
|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|
|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|
Showing the most recent 10 out of 20 publications