Dissertation Defense Announcement
To:  The George Mason University Community

Candidate: Yvette Connell-Albert
Program:    PhD Biosciences

Date:   Tuesday November 13, 2012
Time:   11:00 a.m.
Place:  George Mason University
           The Hub (SUB II) Meeting Room 5
           Fairfax Campus
 
Dissertation Director: Dr. Karlyne Reilly
Committee Chair: Dr. Ancha Baranova
Committee members: Dr. Daniel N. Cox, Dr. James D. Willett, Dr. Barney Bishop

Title: "Aberrant Signaling in Astrocytomas and Glioblastoma Multiforme (GBM):  Utilizing
Inhibitors of Proliferation as Potential Therapies"

The dissertation is on reserve in the Johnson Center Library, Fairfax campus.
The doctoral project will not be read at the meeting, but should be read in advance.

All members of the George Mason University community are invited to attend.


ABSTRACT:
Glioblastomas (GBMs), the most aggressive malignant astrocytomas, are recurrent, infiltrative, and fatal. In GBMs, receptor tyrosine kinases (RTKs) are often activated by mutations, leading to the dysregulation of cell signaling pathways. The PI3K/Akt1/mTOR pathway, which plays a role in many biological processes such as proliferation, survival, invasion, migration and angiogenesis, is often deregulated in malignant cancers, often by the simultaneous loss of tumor suppressor PTEN, and the hyperactivation of the kinase Akt. Therefore, pharmacological inhibition of the PI3K/Akt1/mTOR pathway may prove beneficial in arresting the proliferation of astrocytomas and glioblastomas. In order to determine if the candidate molecules Choloroquine, Nelfinivir, PIA-6, OSU03012, Rapamycin, Tricribine (TCN), and PI-103 inhibit the PI3K/Akt-1/mTOR pathway, we used the Alamar blue assay as a measure of metabolic activity and proliferation in mouse astrocytoma cell lines K1861-10 Grade II; KR158 Grade III; K130G#3 Grade IV; human astrocytoma cell lines, U87MG and SF295, both Grades IV; and normal proliferating mouse primary astrocytes treated with candidate molecules described above. Inhibitors with low IC50 values in tumor cells as compared to normal primary astrocytes were selected. From the select panel of inhibitors, only the AKT inhibitor TCN and dual PI3K/Akt-1 inhibitor PI-103 showed low IC50 values in the nM or pM range, suggesting strong inhibition of proliferation in the astrocytoma cell lines tested. Rapamycin, an mTOR inhibitor, showed inconsistent inhibition of cell proliferation on the cell lines tested, suggesting that rapamycin may be acting through more than one pathway. Results of our study suggest that the PI3K/Akt1/mTOR pathway has a potential as a druggable target in astrocytomas and glioblastomas.


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