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 chemoattractipn. 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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA142536-01A1
Application #
8019642
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (O1))
Program Officer
Forry, Suzanne L
Project Start
2011-02-16
Project End
2016-01-31
Budget Start
2011-02-16
Budget End
2012-01-31
Support Year
1
Fiscal Year
2011
Total Cost
$1,660,090
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Ni, Jing; Xie, Shaozhen; Ramkissoon, Shakti H et al. (2017) Tyrosine receptor kinase B is a drug target in astrocytomas. Neuro Oncol 19:22-30
Zhang, Jing; Gao, Xueliang; Schmit, Fabienne et al. (2017) CRKL Mediates p110?-Dependent PI3K Signaling in PTEN-Deficient Cancer Cells. Cell Rep 20:549-557
Sun, Yu; Alberta, John A; Pilarz, Catherine et al. (2017) A brain-penetrant RAF dimer antagonist for the noncanonical BRAF oncoprotein of pediatric low-grade astrocytomas. Neuro Oncol 19:774-785
Zhou, Jing; Tien, An-Chi; Alberta, John A et al. (2017) A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2. Cell Rep 18:3167-3177
Zhao, Xuesong; Pak, Ekaterina; Ornell, Kimberly J et al. (2017) A Transposon Screen Identifies Loss of Primary Cilia as a Mechanism of Resistance to SMO Inhibitors. Cancer Discov 7:1436-1449
Ilic, Nina; Birsoy, K?vanç; Aguirre, Andrew J et al. (2017) PIK3CA mutant tumors depend on oxoglutarate dehydrogenase. Proc Natl Acad Sci U S A 114:E3434-E3443
Pak, Ekaterina; Segal, Rosalind A (2016) Hedgehog Signal Transduction: Key Players, Oncogenic Drivers, and Cancer Therapy. Dev Cell 38:333-44
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
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
Edwards, Amanda L; Meijer, Dimphna H; Guerra, Rachel M et al. (2016) Challenges in Targeting a Basic Helix-Loop-Helix Transcription Factor with Hydrocarbon-Stapled Peptides. ACS Chem Biol 11:3146-3153

Showing the most recent 10 out of 57 publications