Glioblastoma, the most frequent type of primary adult brain neoplasms, has dismal outcome for patients. Complex and poorly-reproducible diagnoses, inability to accurately predict responsiveness to therapy regimens and less than optimal brain drug penetration have contributed to this poor prognosis. Investigation of mechanisms underlying tumor development and progression will promote in- formed therapeutic decisions. We have recently identified several frequent copy number abnormalities, deletions, mutations and gene expression alterations in the receptor protein tyrosine phosphatase type K gene (PTPRK). Moreover, we showed that PTPRK is a potential tumor suppressor that predicts patients' outcome. PTPRK regulates a variety of cellular events via dephosphorylations of epidermal growth factor receptor and -Catenin tyrosine residues. However, direct link between PTPRK and gliomagenesis or tumor progression has never been addressed. Our objectives in this application are to validate PTPRK as responsible of glioblastoma aggressiveness and to determine its molecular role in gliomagenesis. Our central hypothesis is that PTPRK may provide new insight into molecular mechanisms underlying severity of the disease and can be used to improve glioblastoma therapeutic outcome. The rationale is that infiltrative behavior of malignant glia cells into surrounding brain parenchyma is highly dependent on PTPRK's function. Several aims seek to establish the relevance and roles of PTPRK.
Aim#1 will determine transcriptional and phosphoprotein targets of PTPRK in gliomagenesis.
Aim#2 will determine regulation of PTPRK gene expression.
Aim#3 will determine the significance of posttranslational processing and assess its functional and biological significance. Results of the proposed experiments may ultimately lead to the design of novel strategies to improve therapeutic outcome of glioblastoma.

Public Health Relevance

Glioblastoma tumors are aggressive primary brain cancers responsible for more than 15;000 deaths annually in the United States and their survival has not improved despite the development of new therapies. We identified that PTPRK is an enzyme that counteracts the excessive phosphorylation that is responsible of resistance to chemotherapy regimens and extreme diffusion into surrounding healthy brain tissue. Understanding molecular deregulations of PTPRK occurring in the tumor is expected to lead to new therapeutic intervention strategies and improve outcome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Small Research Grants (R03)
Project #
1R03NS084102-01A1
Application #
8697352
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Fountain, Jane W
Project Start
2014-02-01
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
Fiscal Year
2014
Total Cost
$75,500
Indirect Cost
$25,500
Name
University of Iowa
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242