This is a competing renewal of a highly succesful project concerning the role of the Hh pathway in medulloblastoma. Previously, we obtained dramatic results using a small molecule antagonist of the Hh pathway (HhAntag) in a spontaneous mouse model of medulloblastoma. However, recently, we also found that HhAntag treatment of young mice causes severe defects in bone development. We will now investigate the mechanism of action of HhAntag in tumor cells, as well as in developing bone, to optimize strategies for delivering this potentially revolutionary treatment for a subset of human medulloblastoma. We will also establish new pediatric brain tumor models to investigate the mechanism of action of HhAntag in human medulloblastoma as well as in a broader spectrum of pediatric brain tumors.
In Aim 1, we will address the mechanism responsible for the anti-tumor effect of HhAntag as well as its effect on bone development. We will investigate alternative delivery methods and different structural classes of inhibitors in an effort to minimize the deletrious effects on developing bone. We will also screen for other inhibitors or targets that may be more selective for brain tumors.
In Aim 2, we propose to investigate the role of the microenvironment in maintaining Hh pathway activity in vitro. We will utilize stem cell culture techniques, coculture with stromal support cells, and transplantation in an attempt to maintain pathway activity in mouse medulloblastoma cells. Once established, we will use these conditions to propagate human medulloblastoma carrying PTCH1 mutations so that we can test their response to HhAntag.
In Aim 3, we will investigate the role of the Hh pathway in pediatric brain tumors lacking known Hh pathway mutations. Tumors will be collected and characterized by genomic profiling, and used to establish new culture and transplantation models. We will investigate the effect of HhAntag on tumors and stromal support cells in a range of tumors, including Atypical Teratoid/Rhabdoid Tumors and Choroid Plexus Carcinoma.

Public Health Relevance

Cancer treatments are usually developed to treat adult disease but childrens brain tumors are very different. We are developing new approaches specifically targeted to the unique aspects of pediatric disease. Our previous work gave very promising leads that we will now follow so that we can deliver the new therapy while avoiding side effects.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-GRB-S)
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St. Jude Children's Research Hospital
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Zhan, Hong; Aizawa, Kenichi; Sun, Junqing et al. (2016) Ataxia telangiectasia mutated in cardiac fibroblasts regulates doxorubicin-induced cardiotoxicity. Cardiovasc Res 110:85-95
Grigaravicius, P; Kaminska, E; Hübner, C A et al. (2016) Rint1 inactivation triggers genomic instability, ER stress and autophagy inhibition in the brain. Cell Death Differ 23:454-68
Qaddoumi, Ibrahim; Orisme, Wilda; Wen, Ji et al. (2016) Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology. Acta Neuropathol 131:833-45
Sturm, Dominik; Orr, Brent A; Toprak, Umut H et al. (2016) New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs. Cell 164:1060-72
Baker, Suzanne J; Ellison, David W; Gutmann, David H (2016) Pediatric gliomas as neurodevelopmental disorders. Glia 64:879-95
Phoenix, Timothy N; Patmore, Deanna M; Boop, Scott et al. (2016) Medulloblastoma Genotype Dictates Blood Brain Barrier Phenotype. Cancer Cell 29:508-22
Zhai, Yali; Kuick, Rork; Tipton, Courtney et al. (2016) Arid1a inactivation in an Apc- and Pten-defective mouse ovarian cancer model enhances epithelial differentiation and prolongs survival. J Pathol 238:21-30
Zhu, Liqin; Finkelstein, David; Gao, Culian et al. (2016) Multi-organ Mapping of Cancer Risk. Cell 166:1132-1146.e7
Patel, Yogesh T; Jacus, Megan O; Davis, Abigail D et al. (2016) Simvastatin Hydroxy Acid Fails to Attain Sufficient Central Nervous System Tumor Exposure to Achieve a Cytotoxic Effect: Results of a Preclinical Cerebral Microdialysis Study. Drug Metab Dispos 44:591-4
Morfouace, Marie; Nimmervoll, Birgit; Boulos, Nidal et al. (2016) Preclinical studies of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in pediatric brain tumors. J Neurooncol 126:225-34

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