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Targeting cancer stem- like cells in Glioblastom

by
Monal Mehta
B.A., Rutgers University - 2009

Thesis advisors: Hatem Sabaawy, M.D., Ph.D. and Bruce Haffty, M.D.

Graduate Program in Cellular and Molecular Pharmacology

Rutgers University
Cancer Institute of New Jersey
Auditorium A, New Brunswick

Monday, March 24, 2014
9:00 a.m.


Abstract

Glioblastoma (GBM) is the most frequent and lethal brain cancer. The lack of early detection methods, the presence of rapidly growing tumor cells and the high rates of recurrence make this cancer an extremely difficult disease to treat. Current treatments with radiation and/or chemotherapy only extend the lifespan of GBM patients by a few months, and there is little to no new treatment strategies recently developed. We have established surrogate cancer stem cell assays and in vitro serum-free conditions to grow multiple primary GBM tumor samples and investigate GBM self-renewal and stem cell-like features. Utilizing small molecule pharmacological inhibitors to target Bmi1, an essential stem cell self-renewal and DNA damage repair protein, or Akt, an oncoprotein and important mediator of cell survival, we investigated the abilities of these small molecules to radiosensitize GBM cells. We demonstrate that inhibition of Bmi1 prior to radiation treatment results in massive apoptosis and differentiation of GBM cells, with decreased rates of both long- and short-term cell survival. In contrast, inhibiting Akt activation in primary GBM cells led to differential responses among samples in the context of cell death and/or self-renewal, reinforcing the notion that GBM is a heterogeneous disease. This work highlights the discrepancies between cell lines and primary tumors and emphasizes salient differences between patients that determine response to therapy, underlining the necessity for implementing precision cancer medicine for GBM treatment.


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