GBM is a brain tumor type that has an extremely poor prognosis, and is in need of improved therapies. Analysis of gene expression databases indicated that Cyclophilin B (CypB) is upregulated in GBM. CypB is an endoplasmic reticulum (ER) resident prolyl isomerase that functions as a molecular chaperone. Knockdown of CypB dramatically reduced the proliferation and survival of GBM cells. CypB depletion was accompanied by multiple biochemical changes, including elevated reactive oxygen species (ROS) and decreased expression of mutant p53, and Chk1, as well as decreased activation of Stat3, all of which have been implicated in regulation of GBM proliferation. Total knockout of the CypB gene in mice was performed, and was found to be compatible with normal development and fertility, and caused only a minor phenotype involving collagen processing. The central hypothesis of this proposal, therefore, is that CypB plays a key role in maintaining the survival of GBM cells, and furthermore, because inhibition of CypB lacks serious systemic toxicity, it may be a novel molecular target for therapy of GBM. Preliminary experiments revealed that treatment of GBM cells with small molecule inhibitors of cyclophilins induced their death in vitro, or impaired GBM tumor growth in vivo. The focus of this proposal is to determine the role CypB plays in the development and progression of GBM, and to characterize the feasibility of CypB inhibitors for GBM treatment using both in vitro and animal models. Using shRNA, or a conditional knockout allele of the CypB gene, the effect of CypB ablation in GBMs will be determined in several mouse models, including human xenografts in nude mice and genetically engineered strains. The critical mediators of cell death downstream of CypB inhibition will also be determined. Finally, the effectiveness of a small molecule cyclophilin inhibitor in treating GBM in mice, alone or in combination with other treatments including temozolomide and radiation, will be determined. Together, these studies will test the feasibility of CypB as a novel target for therapy of GBM, and set the stage for transition to clinical studies in humans.

Public Health Relevance

Current treatments for Glioblastoma (a type of brain tumor) do not typically lead to a permanent cure, and almost no patients survive longer than a few years. The proposed studies will test the new idea that the Cyclophilin B cell protein could be an effective target for therapy of Glioblastoma. There are already drugs available that can inhibit Cyclophilin B, and they have been shown to be safe in people, but they have never been tested for effectiveness on this brain tumor type. Successful accomplishment of the proposed work could lead rapidly to clinical trials in humans with this fatal type of brain tumor, and could lead to improved cure rates.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS077555-03
Application #
8514743
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Fountain, Jane W
Project Start
2011-09-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$332,895
Indirect Cost
$121,801
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Shing, Jennifer C; Choi, Jae Won; Chapman, Robert et al. (2014) A novel synthetic 1,3-phenyl bis-thiourea compound targets microtubule polymerization to cause cancer cell death. Cancer Biol Ther 15:895-905
Choi, Jae Won; Schroeder, Mark A; Sarkaria, Jann N et al. (2014) Cyclophilin B supports Myc and mutant p53-dependent survival of glioblastoma multiforme cells. Cancer Res 74:484-96