The long-term goal of this program is to improve the standard of care for pediatric astrocytomas - the most common brain cancers in children. Towards this end, we will improve our understanding of astrocytoma biology and develop new diagnostic, prognostic and therapeutic tools for these tumors. The significance of the work is that primary cancers of the central nervous system have now surpassed leukemia as the leading cause of cancer-related death in children. Project 1 draws upon recent observations of activating mutations in BRAF in ~50% of pediatric low grade astrocytomas and addresses three unresolved questions. William Hahn, MD/PhD and Jean Zhao, PhD will study: (i) what are the driving mutations in the ~50% of tumors wild type for BRAF, (ii) what are the mutations that co-occur with BRAF and (iii) what other intracellular kinases are co-activated with BRAF? An innovative feature of this project is recently developed methods for genetic profiling of formaldehyde-fixed, paraffin-embedded samples. These "paraffin-friendly" technologies greatly expand the available samples of these pediatric tumors. Project 2 addresses the bHLH transcription factor Olig2, with a chemical focus. Olig2 is a strong candidate for targeted therapy of pediatric astrocytomas. However, transcription factors are generally considered to be unattractive targets for drug development because their interactions with DNA involve large and complex surface area contacts. Another generic problem in brain tumor drug development is ensuring delivery beyond the blood/brain barrier. Charles Stiles, PhD and Loren Walensky, MD/PhD propose to develop specific inhibitors of Olig2 with good penetrance properties for the blood/brain barrier. Innovative features of this project are (i) "stapled peptide" chemistry to create Olig2 antagonists used with (ii) MALDI mass spectrometry imaging technology to address drug penetrance into the interstitial areas of the brain. Project 3 addresses the role of microenvironment in tumor growth. Rosalind Segal, MD/PhD has developed a novel assay for testing the effects of microenvironments on astrocytoma cells. In collaboration with neurosurgeon Liliana Goumerova, MD, she will use tumor cells from pediatric astrocytomas derived from different brain regions to determine whether tumor cells are "addicted" to the location where they originated, and whether tumor cell niches promote tumor growth, survival, and/or chemoattraction. These studies may lead to new strategies for disrupting the interface between astrocytoma cells and their niches. An innovative feature of this project is a consideration of cilia as signaling organelles that coordinate responses to the microenvironment. The three projects interact with one another and are further unified by economies of scale enabled by an Innovative Neuropathology (INP) core.
Brain tumors are now the leading cause of cancer-related death in children;even the children that are cured are often left with lifelong deficits. The goal of this research is to improve the standard of care for pediatric brain tumors. Our three projects are each co-directed by a basic scientist and a physician-scientist so that new insights from these studies can be rapidly translated into novel clinical treatments.
|Pak, Ekaterina; Segal, Rosalind A (2016) Hedgehog Signal Transduction: Key Players, Oncogenic Drivers, and Cancer Therapy. Dev Cell 38:333-44|
|Bandopadhayay, Pratiti; Ramkissoon, Lori A; Jain, Payal et al. (2016) MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat Genet 48:273-82|
|Yuzugullu, Haluk; Von, Thanh; Thorpe, Lauren M et al. (2016) NTRK2 activation cooperates with PTEN deficiency in T-ALL through activation of both the PI3K-AKT and JAK-STAT3 pathways. Cell Discov 2:16030|
|Stevens, Mark M; Maire, Cecile L; Chou, Nigel et al. (2016) Drug sensitivity of single cancer cells is predicted by changes in mass accumulation rate. Nat Biotechnol 34:1161-1167|
|Verreault, Maite; Schmitt, Charlotte; Goldwirt, Lauriane et al. (2016) Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas. Clin Cancer Res 22:1185-96|
|Ni, Jing; Ramkissoon, Shakti H; Xie, Shaozhen et al. (2016) Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases. Nat Med 22:723-6|
|Filbin, Mariella G; Segal, Rosalind A (2015) How neuronal activity regulates glioma cell proliferation. Neuro Oncol 17:1543-4|
|Brastianos, Priscilla K; Carter, Scott L; Santagata, Sandro et al. (2015) Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets. Cancer Discov 5:1164-77|
|Zhou, Pengcheng; Erfani, Sonia; Liu, Zeyi et al. (2015) CD151-Î±3Î²1 integrin complexes are prognostic markers of glioblastoma and cooperate with EGFR to drive tumor cell motility and invasion. Oncotarget 6:29675-93|
|Zhao, Xuesong; Ponomaryov, Tatyana; Ornell, Kimberly J et al. (2015) RAS/MAPK Activation Drives Resistance to Smo Inhibition, Metastasis, and Tumor Evolution in Shh Pathway-Dependent Tumors. Cancer Res 75:3623-35|
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