Beyond Alkylating Agents for Gliomas: Quo Vadimus?

Abstract

Recent advances in therapies have yielded notable success in terms of improved survival in several cancers. However, such treatments have failed to improve outcome in patients with gliomas for whom surgery followed by radiation therapy and chemotherapy with alkylating agents remain the standard of care. Genetic and epigenetic studies have helped identify several alterations specific to gliomas. Attempts to target these altered pathways have been unsuccessful due to various factors, including tumor heterogeneity, adaptive resistance of tumor cells, and limitations of access across the blood-brain barrier. Novel therapies that circumvent such limitations have been the focus of intense study and include approaches such as immunotherapy, targeting of signaling hubs and metabolic pathways, and use of biologic agents. Immunotherapeutic approaches including tumor-targeted vaccines, immune checkpoint blockade, antibody-drug conjugates, and chimeric antigen receptor-expressing cell therapies are in various stages of clinical trials. Similarly, identification of key metabolic pathways or converging hubs of signaling pathways that are tumor specific have yielded novel targets for therapy of gliomas. In addition, the failure of conventional therapies against gliomas has led to a growing interest among patients in the use of alternative therapies, which in turn has necessitated developing evidence-based approaches to the application of such therapies in clinical studies. The development of these novel approaches bears potential for providing breakthroughs in treatment of more meaningful and improved outcomes for patients with gliomas.

FIGURE 1. Metabolic Pathways Active in GBM Involving Enzymes of Glycolysis, the Pentose Phosphate Pathway, Fatty Acid and Glutamine Metabolism, and Their Regulation by Known Oncogenes and Tumor Suppressor Genes in Proliferating Cells

Growth factor/PI3K/AKT signaling stimulates glucose uptake and flux through the early part of glycolysis. Tyrosine kinase signaling negatively regulates flux through at PKM2, making glycolytic intermediates available for macromolecular synthesis. Myc has been found to promote glutamine metabolism and inhibit oxidative metabolism by activating pyruvate dehydrogenase kinase (PDK). p53 decreases metabolic flux through glycolysis in response to cell stress. Abbreviations: Acetyl-CoA, acetyl coenzyme A; ACL, ATP citrate lyase; AMPK, 5′ adenosine monophosphate–activated protein kinase; DCA, dichloroacetate; FBP, fructose 1,6-bisphosphate; NADP, nicotinamide adenine dinucleotide phosphate; NADPH, reduced form of nicotinamide adenine dinucleotide phosphate; PDH, pyruvate dehydrogenase; PEP, phosphoenolpyruvate. Reproduced with modifications from Wolf et al63 under the Creative Common Attribution License.