Metabolic Abnormalities in Glioblastoma and Metabolic Strategies to Overcome Treatment Resistance

Abstract

Glioblastoma (GBM) is the most common and aggressive primary brain tumor and is nearly universally fatal. Targeted therapy and immunotherapy have had limited success in GBM, leaving surgery, alkylating chemotherapy and ionizing radiation as the standards of care. Like most cancers, GBMs rewire metabolism to fuel survival, proliferation, and invasion. Emerging evidence suggests that this metabolic reprogramming also mediates resistance to the standard-of-care therapies used to treat GBM. In this review, we discuss the noteworthy metabolic features of GBM, the key pathways that reshape tumor metabolism, and how inhibiting abnormal metabolism may be able to overcome the inherent resistance of GBM to radiation and chemotherapy.

Keywords: glioblastoma; glioma; metabolic remodeling; metabolic targeting; metabolism; radiation.

Figure 1

Classification of diffuse gliomas. As of 2016, diffuse gliomas are now defined based on both their molecular and histologic features. Definitional molecular features are noted in red, while other common molecular features are also listed. For most diffuse gliomas, the grade is still determined by the presence of conventionally defined “aggressive” microscopic features such as atypia, mitoses, microvascular proliferation, and necrosis. H3K27 mutant midline gliomas are grade 4 based on their molecular features. Median survival estimates for each type of molecularly defined tumor receiving optimal therapy are listed in green, though many of these estimates should be viewed as preliminary due to the recent reclassification of these tumors [4,33,34,35,36,37,38,39,40,41,42].

Figure 2

Key metabolic remodeling and potential therapeutic targets in glioblastoma (GBM). Metabolic reprogramming involved in GBM includes glycolysis, TCA cycle, glutaminolysis, pentose phosphate pathway (PPP), lipid and nucleotide synthesis, and D-2HG pathways. Key enzymes (light blue box) of these pathways can be regulated by known oncogenic signaling pathways (green box) and be targeted (dark blue box) for the treatment of GBM. Note: Blue arrows indicate metabolic conversion; dark red arrows indicate inhibition and green arrows indicate stimulation or activation.

Figure 3

Summary of metabolic targeting in radio-sensitizing of GBM. Radio-sensitivity can be improved by depletion of glutathione (GLSi) and NAD+ (ascorbate and PARPi), and inhibition of IDH (wtIDHi or mIDHi) and deoxyribonucleotide (RNRi) to finally induce DNA damage and cell death.