Glioblastoma multiforme (GBM): An overview of current therapies and mechanisms of resistance

Abstract

Glioblastoma multiforme (GBM) is a WHO grade IV glioma and the most common malignant, primary brain tumor with a 5-year survival of 7.2%. Its highly infiltrative nature, genetic heterogeneity, and protection by the blood brain barrier (BBB) have posed great treatment challenges. The standard treatment for GBMs is surgical resection followed by chemoradiotherapy. The robust DNA repair and self-renewing capabilities of glioblastoma cells and glioma initiating cells (GICs), respectively, promote resistance against all current treatment modalities. Thus, durable GBM management will require the invention of innovative treatment strategies. In this review, we will describe biological and molecular targets for GBM therapy, the current status of pharmacologic therapy, prominent mechanisms of resistance, and new treatment approaches. To date, medical imaging is primarily used to determine the location, size and macroscopic morphology of GBM before, during, and after therapy. In the future, molecular and cellular imaging approaches will more dynamically monitor the expression of molecular targets and/or immune responses in the tumor, thereby enabling more immediate adaptation of tumor-tailored, targeted therapies.

Keywords: Carmustine (PubChem CID: 2578); Cediranib (PubChem CID: 9933475); Chemotherapy; Erlotinib (PubChem CID: 176870); Gefitinib (PubChem CID: 123631); Glioblastoma; Immunotherapy; Irinotecan (PubChem CID: 60838); Lomustine (PubChem CID: 3950); Nanotherapy; Niraparib (PubChem CID: 24958200); Olaparib (PubChem CID: 23725625); Radiotherapy; Targeted therapy; Temozolomide (PubChem CID: 5394); Veliparib (PubChem CID: 11960529).

Fig.1.

Cellular origin and heterogeneity of glioblastoma multiform (GBM). GBM tumors originate from three types of cells in the brain parenchyma: neural stem cells (NSCs), NSC-derived astrocytes, and oligodendrocyte precursor cells (OPCs). GBM is characterized by extensive intertumor and intratumor heterogeneity, and has, therefore, been divided into four sub-groups: mesenchymal, classical, proneural, and neural.

Fig. 2.

The molecular mechanisms of resistance in glioma initiating cells (GICs). GBM is characterized by extensive intratumoral hypoxia. GIC niches are most commonly to be found in tumor core regions that are lessoxygenated. GICs are generally resistant to therapies and mostly due to following mechanisms: 1) Enhanced DNA repair capacity. Cell cycle arrest at G2 phase in GICs allows the DNA repair and further enter mitotic phase. 2) GICs express higher level of ABC transporters which promote efflux of therapeutic compounds. 3) The poorly oxygenated tumor tissue creates perfect GIC niches, which induce autophagy to maintain cellular homeostasis. Protective autophagy can also be triggered in GICs when challenged by cytotoxic therapies. 4) Epigenetic modifications contribute to functional heterogeneity and maintenance of GIC hierarchies. Multiple GICs-related signaling pathways (Wnt/β-catenin, Sonic Hedgehog (SHH), Notch) can be epigenetically regulated to gain self-renewing capabilities and drug resistance properties(179, 191, 192).

Fig. 3.

New therapies described in this review.

Fig.4.

The inhibition of CTLA-4 and PD-1 in GBM immunotherapy. Dendritic Cells (DCs) traffic between CNS tumors and the cervical lymph nodes to prime T cells against tumor neo-antigens. T cells receive effective activation signals with the engagement of two T cell receptors, antigen-specific T-cell receptor (TCR) and CD28, simultaneously. TCR binds to tumor-associated antigens (TAA) presented on major histocompatibility complex (MHC) molecule while CD28 interact with CD80/CD86(B7–1/2 receptors) costimulatory molecules on the surface of DCs. T cell activation leads to upregulation of checkpoint molecule CTLA-4(cytotoxic Tlymphocyte-associated protein 4). The interaction of CTLA-4 and CD80/CD86 of DCs results in blockage of T cell activation. The effector T cells can proliferate and migrate to the tumor microenvironment, leading to tumor eradication via MHC-I/TCR interaction. Some GBM cells and TAM-BMDMs express high levels of checkpoint molecules including transmembrane protein PD-L1. PD-L1 binds to PD-1 receptors on T cells, which leads to attenuation of TCR and CD28 signals, and subsequently promotes T cell apoptosis and functional exhaustion. Cytotoxic T cell responses are further inhibited by immune-suppressive cytokines by Tregs, astrocytes and neurons(277, 278). Immune checkpoint blockade (ICB) is based on a range of monoclonal antibody-based therapies, especially checkpoint inhibitors that block CTLA-4, PD-1, or PD-L1. Anti-CTLA-4 antibodies restore T cell activation in the lymph nodes, and PD-1/PD-L1 antibodies enhance the functional properties of effector T cells at the tumor site(279, 280). TAM: tumor-associated macrophage, BMDMs: bone marrow–derived macrophages, TCR: antigen-specific T-cell receptor.

Fig.5.

Immune modulatory effects of radiotherapy. The localized cytotoxic effects of radiation have been shown to cause immunogenic cell death (ICD). Radiation can induce all three arms of ICD: upregulation of the release of adenosine triphosphate (ATP), the extracellular release of “danger signal” high motility group box 1 (HMGB1) and translocation of “eat me” signal calreticulin (CRT) to the cell surface. Additionally, radiation regimens unmask the tumor by upregulating major histocompatibility complex (MHC) on the tumor cell, which enhances neo-antigen presentation in tumor cells for recognition by cytotoxic T-cells. Besides the effects on tumor cells, irradiation also affects tumor-associated stromal cells, such as reactive astrocytes, and the recruitment of microglia, which further contribute to the establishment of radiation-induced immune responses.

Fig.6.

Advanced delivery platforms and delivery mechanisms of nanoparticulate anti-GBM drugs. Nanocarriers have been proposed based on various materials and principles as shown in the figure (a-g). Ligand-installed nanocarriers achieve therapeutic effects by actively targeting the surface marker or signaling pathway of cancer cells. Stimuli-responsive nanocarriers can release drug by responding to internal/external stimuli, which enable specific delivery cargos into the tumor microenvironment.