Assessment of Radiation Resistance and Therapeutic Targeting of Cancer Stem Cells: A Raman Spectroscopic Study of Glioblastoma.

Radiation is the standard therapy used for treating Glioblastoma (GBM), a grade IV brain cancer. Glioma Stem-like Cells (GSCs), an integral part of GBM, enforces resistance to radiation therapy of GBM. Studying the differential biomolecular composition of GSCs with varying levels of radiation sensitivity can aid in identifying the molecules and their associated pathways which impose resistance to cells thereby unraveling new targets which would serve as potential adjuvant therapy. Raman spectroscopy being a noninvasive, label free technique can determine the biomolecular constituent of cells under live conditions. In this study, we have deduced Raman spectral signatures to predict the radiosensitivity of any GSC accurately using the inherent and radiation induced biomolecular composition. Our study identified the differential regulation of several biomolecules which can be potential targets for adjuvant therapy. We radiosensitized the resistant GSCs using small molecule inhibitors specific to the metabolic pathways of these biomolecules. Efficient antitumor therapy can be attained with lower dosage of radiation along with these inhibitors and thus improving the survival rate of GBM patients with reduced side-effects from radiation.

Differential responses of tumors and normal brain to the combined treatment of 2-DG and radiation in glioablastoma.

2-Deoxy-D-glucose (2-DG), an inhibitor of glucose transport and glycolysis, enhances radiation damage selectively in tumor cells by modulating damage response pathways resulting in cell death in vitro and local tumor control. Phase I and II clinical trials in patients with malignant glioma have shown excellent tolerance to a combined treatment of orally administered 2-DG and hypofractionated radiotherapy without any acute toxicity and late radiation damage. Phase III efficacy trials are currently at an advanced stage. Re-exploratory surgery performed in 13 patients due to persistent symptoms of elevated ICP and mass effect at different follow-up periods revealed extensive tumor necrosis with well-preserved normal brain tissue adjoining the tumor included in the treatment volume as revealed by a histological examination. These observations are perhaps the first clinical evidences for differential effects of 2-DG on tumors and normal tissues in conformity with earlier in vitro and in vivo studies in normal and tumor-bearing mice.