Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with a median survival of 12–15 months with treatment consisting of surgical resection followed by ionizing radiation (IR) and chemotherapy. Even aggressive treatment is often palliative due to near universal recurrence. Therapeutic resistance has been linked to a subpopulation of GBM cells with stem cell-like properties termed GBM initiating cells (GICs). Recent efforts have focused on elucidating resistance mechanisms activated in GICs in response to IR. Among these, GICs preferentially activate the DNA damage response (DDR) to result in a faster rate of double-strand break (DSB) repair induced by IR as compared to the bulk tumor cells. IR also activates NOTCH and the hepatic growth factor (HGF) receptor, c-MET, signaling cascades that play critical roles in promoting proliferation, invasion, and resistance to apoptosis. These pathways are preferentially activated in GICs and represent targets for pharmacologic intervention. While IR provides the benefit of improved survival, it paradoxically promotes selection of more malignant cellular phenotypes of GBM. As reviewed here, finding effective combinations of radiation and molecular inhibitors to target GICs and non-GICs is essential for the development of more effective therapies.
Highlights
Glioblastoma (GBM) is the most common and aggressive type of primary brain cancer in adults with approximately 18,000 patients diagnosed each year [(http://www.CBTRUS.org); Schwartzbaum et al, 2006]
Despite aggressive multimodality treatment consisting of maximal safe resection, adjuvant chemoradiation with temozolomide, and maintenance temozolomide, median survival remains dismal at 12– 15 months (Stupp et al, 2009)
When non-GBM initiating cells (GICs) are assayed in parallel, these cells fail to form tumors, even when their numbers are increased by orders of magnitude
Summary
Reviewed by: Ji-Hong Hong, Chang Gung Memorial Hospital, Taiwan Hsin-Ell Wang, National Yang-Ming University, Taiwan. Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with a median survival of 12–15 months with treatment consisting of surgical resection followed by ionizing radiation (IR) and chemotherapy. GICs preferentially activate the DNA damage response (DDR) to result in a faster rate of double-strand break (DSB) repair induced by IR as compared to the bulk tumor cells. IR activates NOTCH and the hepatic growth factor (HGF) receptor, c-MET, signaling cascades that play critical roles in promoting proliferation, invasion, and resistance to apoptosis. These pathways are preferentially activated in GICs and represent targets for pharmacologic intervention. As reviewed here, finding effective combinations of radiation and molecular inhibitors to target GICs and non-GICs is essential for the development of more effective therapies
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