No cures exist for patients with glioblastoma (GBM) due to the resistance of tumor cells to standard therapies. Stem-like tumor subpopulations seem especially refractory to most treatments, and it is becoming increasingly clear that specific tumor microenvironments can promote stem cell properties and chemoresistance. However, poor understanding of how emerging targeted therapies interact with other agents and the tumor microenvironment has limited their development. The long-term goal of the project is to develop Notch inhibitors as effective new therapies for glioblastoma and other malignant brain tumors. The objective of this proposal is to elucidate how Notch interacts with the tumor microenvironment and other treatments so pathway inhibitors can be effectively used in the clinic. The Notch pathway, which is required for generation and maintenance of non-neoplastic neural stem cells, also plays a key role in GBM cancer stem cells (CSC). It has been shown that the perivascular microenvironment promotes CSC through activation of Notch signaling, and a number of agent targeting blood vessels are currently in use. As tumor-associated blood vessels are removed, GBM and other tumors shift towards a hypoxic phenotype, and it is less clear how Notch will function in this microenvironment. The central hypothesis to be tested in this proposal is that Notch is a key mediator of GBM differentiation and therapeutic response not just in the perivascular niche, but also in the hypoxic microenvironment. Indeed, emerging data suggest that hypoxic tumor cells can recapitulate many of the molecular features which define the perivascular niche, and that Notch induces a stem-like phenotype and modulates the response to traditional chemotherapy in this context. The first two specific aims focus on understanding how Notch is activated in hypoxic GBM cells, and determining if Notch blockade can reverse the increase in CSC and treatment resistance promoted by hypoxia. The second two specific aims focus on the interaction between Notch inhibition, radiation, and temozolomide chemotherapy, and investigate a novel mechanism by which Notch blockade can sensitize GBM to this commonly used alkylating agent. These studies will determine how Notch activity is regulated in hypoxic glioma cells, and to establish a requirement for Notch in CSC induction and aggressive tumor behavior in the hypoxic microenvironment. They will also examine a novel epigenetic mechanism by which the pathway can modulate MGMT expression and temozolomide sensitivity. These results are all of high clinical relevance, and will have a direct impact on the development of a novel agent targeting CSC in glioblastoma.

Public Health Relevance

Glioblastoma are the most common malignant brain tumors in adults, and are almost always fatal. We will develop Notch inhibitors as new therapies for glioblastoma and other malignant brain tumors, focusing on how these drugs work in the hypoxic tumor microenvironment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS055089-06A1
Application #
8583843
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Fountain, Jane W
Project Start
2006-04-01
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
6
Fiscal Year
2013
Total Cost
$364,276
Indirect Cost
$139,414
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Kahlert, Ulf D; Cheng, Menglin; Koch, Katharina et al. (2016) Alterations in cellular metabolome after pharmacological inhibition of Notch in glioblastoma cells. Int J Cancer 138:1246-55
Hanaford, Allison R; Archer, Tenley C; Price, Antoinette et al. (2016) DiSCoVERing Innovative Therapies for Rare Tumors: Combining Genetically Accurate Disease Models with In Silico Analysis to Identify Novel Therapeutic Targets. Clin Cancer Res 22:3903-14
Taylor, Isabella C; Hütt-Cabezas, Marianne; Brandt, William D et al. (2015) Disrupting NOTCH Slows Diffuse Intrinsic Pontine Glioma Growth, Enhances Radiation Sensitivity, and Shows Combinatorial Efficacy With Bromodomain Inhibition. J Neuropathol Exp Neurol 74:778-90
Kahlert, Ulf D; Suwala, Abigail K; Koch, Katharina et al. (2015) Pharmacologic Wnt Inhibition Reduces Proliferation, Survival, and Clonogenicity of Glioblastoma Cells. J Neuropathol Exp Neurol 74:889-900
Orr, Brent A; Eberhart, Charles G (2015) Molecular pathways: not a simple tube--the many functions of blood vessels. Clin Cancer Res 21:18-23
Lim, Kah Jing; Brandt, William D; Heth, Jason A et al. (2015) Lateral inhibition of Notch signaling in neoplastic cells. Oncotarget 6:1666-77
Kahlert, Ulf D; Suwala, Abigail K; Raabe, Eric H et al. (2015) ZEB1 Promotes Invasion in Human Fetal Neural Stem Cells and Hypoxic Glioma Neurospheres. Brain Pathol 25:724-32
Kahlert, Ulf Dietrich; Koch, Katharina; Suwala, Abigail Kora et al. (2015) The effect of neurosphere culture conditions on the cellular metabolism of glioma cells. Folia Neuropathol 53:219-25
Brandt, William D; Schreck, Karisa C; Bar, Eli E et al. (2015) Notch signaling activation in pediatric low-grade astrocytoma. J Neuropathol Exp Neurol 74:121-31
Ding, Dacheng; Lim, Kah Suan; Eberhart, Charles G (2014) Arsenic trioxide inhibits Hedgehog, Notch and stem cell properties in glioblastoma neurospheres. Acta Neuropathol Commun 2:31

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