Insights into molecular therapy of glioma: current challenges and next generation blueprint

Abstract

Glioma accounts for the majority of human brain tumors. With prevailing treatment regimens, the patients have poor survival rates. In spite of current development in mainstream glioma therapy, a cure for glioma appears to be out of reach. The infiltrative nature of glioma and acquired resistance substancially restrict the therapeutic options. Better elucidation of the complicated pathobiology of glioma and proteogenomic characterization might eventually open novel avenues for the design of more sophisticated and effective combination regimens. This could be accomplished by individually tailoring progressive neuroimaging techniques, terminating DNA synthesis with prodrug-activating genes, silencing gliomagenesis genes (gene therapy), targeting miRNA oncogenic activity (miRNA-mRNA interaction), combining Hedgehog-Gli/Akt inhibitors with stem cell therapy, employing tumor lysates as antigen sources for efficient depletion of tumor-specific cancer stem cells by cytotoxic T lymphocytes (dendritic cell vaccination), adoptive transfer of chimeric antigen receptor-modified T cells, and combining immune checkpoint inhibitors with conventional therapeutic modalities. Thus, the present review captures the latest trends associated with the molecular mechanisms involved in glial tumorigenesis as well as the limitations of surgery, radiation and chemotherapy. In this article we also critically discuss the next generation molecular therapeutic strategies and their mechanisms for the successful treatment of glioma.

Figure 1

Classification of CNS tumors. Molecular & genetic anomalies and involvement of growth factors in gliomagenesis. The CNS tumors are categorized on the basis of type of cells present in CNS and glioma is further classified on basis of type of glial cells present. The neural stem cells differentiate into different cell lineages of the CNS and putative cells of origin of glioma. Three main types of cells in the mature CNS, including neurons and glial cells (particularly oligodendrocytes and astrocytes; ependymal cells) originates during the differentiation process. The glioma originates from the direct transformation of neural stem cells or glial progenitor cells. Glial tumorigenesis is driven by upregulation or downregulation of various growth factor receptor signaling pathways. Several growth factor receptors, such vascular endhotelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDRGF), epidermal growth factor receptor (EGFR), cyclin-dependent kinase 4 (CDK4), phosphoinositide 3-kinase (PI3K), isocitrate dehydrogenase 1(IDH1) and other growth factors receptors are overexpressed, amplified and/or mutated in gliomas. It also comprises of loss of tumor suppressor genes TP53, the retinoblastoma (Rb) gene, which are essential for cell growth, differentiation and function. Loss of heterozygosity (LOH) is most frequent genetic alteration in both primary and secondary GBMs.

Figure 2

Histopathological examination revealing glioblastoma multiforme WHO grade IV. (A) Photomicrograph showing brisk mitotic activity (H&E, 200×). (B) Typical pallisading necrosis (H&E, 200×). (C) Glioblastoma with endothelial proliferation (H&E, 200×). (D) A case showing bizarre multinucleated tumor giant cells (H&E, 200×). (E) A case showing very high proliferation activity (Immunoreactivity to MIB-1) (IHC 200×). (F) Immunohistochemistry for p53 showing strong nuclear immunoreactivity (IHC 200×).

Figure 3

(A) Locations of supratentorial GBM-frontal lobe (a–c), temporal lobe (d), parietal lobe (e) and parieto-occipital region (f). (B)Locations of supratentorial GBM-temporo-parietal region (a), perisylvian (b, c), thalamus (d) and corpus callosum (e).

Figure 4

Précis of signaling pathways involved in glioma and inhibition by mTOR, AKT, PI3K and ERK inhibitors and genetic configuration of TSC1 and TSC2. Continuous lines with arrow end exhibits activation and with blunt end exhibits inhibition. Growth factors up on binding to transmembrane receptors result in PI3Kinase activity which elevates PIP3 levels, thus activating AKT leading to anti-apoptotic/pro-cell proliferation effects. It has been also reported that HSP90 also phosphorylates AKT. AKT and /or ERK upon activation inhibits TSC1/TSC2 complex. But PTEN negatively regulates AKT. The C terminal GAP of tuberin inhibits Rheb (G protein, an activator of mTORC1) leading to increase in levels of ribosomal S6-kinase and phosphorylated ribosomal S6. Drugs potently inhibiting at different level of the signaling pathway has been also presented, respectively. The TSC1 gene comprises of 23 exons, 1164 amino acids (aa) with 130 kDa molecular mass and interacts with TSC2 in the region of 302–430 aa. It has coiled-coil (CC, aa 719–998) and potential transmembrane (TM, aa 127–144) domains at the N- and C-terminal regions. The TSC2 gene comprises of 41 exons, 1807 aa with 200 kDa molecular mass and interacts with TSC1 in the region of 1-418 aa. The gene also consists of two coiled-coils (CC, aa 346–371 and aa 1008–1021), a leucine zipper (LZ, aa 75–107), a Rheb-GAP (aa 1517–1674) and a calmodulin-binding (CAM, aa 1740–1758) domain. The N-terminal CC domain is essential for its association with TSC1. At specific aa residues the activity of TSC1 and TSC2 is synchronized by both inhibitory and activating phosphorylation events. In TSC1, the presence of glycogen synthase 3 beta (GSK3B) sites Thr357 and Thr390 activates and presence of cyclin dependent kinase (CDK1) sites Thr417, Ser584, and Thr1047 inhibits TSC1-TSC2 complex activity. In TSC2, the presence of AMP kinase (AMPK) sites Thr1227 and Ser1345 activates and presence of extracellular-related kinase (ERK2) sites Ser664; AKT/protein kinase B (PKB) sites Ser939, Ser981, Thr1462; mitogen-activated protein kinase- activated protein kinase 2 (MK2) site Ser1210 and p90 ribosomal S6 kinase 1 (RSK1) site Ser1798 inhibits TSC1-TSC2 complex activity.

Figure 5

A surgical case displaying left CPA tumor (A) – right sided ventriculoperitoneal shunt (B) followed by subtotal excision of tumor via left retromastoid suboccipital approach (C).