The Many Facets of Therapy Resistance and Tumor Recurrence in Glioblastoma

Abstract

Glioblastoma (GBM) is the most lethal type of primary brain cancer. Standard care using chemo- and radio-therapy modestly increases the overall survival of patients; however, recurrence is inevitable, due to treatment resistance and lack of response to targeted therapies. GBM therapy resistance has been attributed to several extrinsic and intrinsic factors which affect the dynamics of tumor evolution and physiology thus creating clinical challenges. Tumor-intrinsic factors such as tumor heterogeneity, hypermutation, altered metabolomics and oncologically activated alternative splicing pathways change the tumor landscape to facilitate therapy failure and tumor progression. Moreover, tumor-extrinsic factors such as hypoxia and an immune-suppressive tumor microenvironment (TME) are the chief causes of immunotherapy failure in GBM. Amid the success of immunotherapy in other cancers, GBM has occurred as a model of resistance, thus focusing current efforts on not only alleviating the immunotolerance but also evading the escape mechanisms of tumor cells to therapy, caused by inter- and intra-tumoral heterogeneity. Here we review the various mechanisms of therapy resistance in GBM, caused by the continuously evolving tumor dynamics as well as the complex TME, which cumulatively contribute to GBM malignancy and therapy failure; in an attempt to understand and identify effective therapies for recurrent GBM.

Disproportion in Pericyte/Endothelial Cell Proliferation and Mechanisms of Intussusceptive Angiogenesis Participate in Bizarre Vessel Formation in Glioblastoma

“…GBM is a highly malignant neoplasia, in which GBM angiogenesis and chemotherapy may be conditioned by multiple factors, including tumor location and natural substances [53][54][55]. In addition, GBM is difficult to treat effectively for lengthy survival, with many facets of therapy resistance and tumor recurrence [56][57][58]. Among these difficulties is the resistance to antiangiogenic therapy, in which the switch from sprouting to intussusceptive angiogenesis has been described as an escape mechanism [59].…”

Towards more accurate preclinical glioblastoma modelling: reverse translation of clinical standard of care in a glioblastoma mouse model

“…Following an 11-day protocol, CT-2A NS were generated in serum-free Dulbecco's Modified Eagle Medium / Nutrient Mixture F-12 (DMEM/F-12, Sigma-Aldrich) supplemented with epidermal growth factor (EGF, Thermofisher), fibroblast growth factor (FGF, Thermofisher) and B27 supplement (Thermofisher). After enzymatical dissociation (Stempro Accutase, Thermofisher), 1x10 4 NS-derived CT-2A cells were stereotactically inoculated in the right brain hemisphere of female, 12-14 week old C57BL/6 mice (Envigo), 2.5 mm lateral from the midline, 0.5 mm anterior to the bregma and 2.5 mm below the dura mater. During the whole procedure, the mice were kept under general anesthesia with an IP injection of 6μl/g body weight of a mixture of 18.75mg/ml ketamine (Pfizer) and 0.125% xylazine hydrochloride (Bayer).…”

“…. However, the tumor almost invariably develops resistance mechanisms leading to the onset of recurrences with a median progression free survival (PFS) of seven months [3,4]. At this stage, none of the available therapeutic options is truly effective, leading to a median overall survival (OS) of GBM patients of 14 months [5,6] .…”

Molecular Mechanisms of Drug Resistance in Glioblastoma

“…Yet, if the bloodbrain barrier is not violated, the infiltration of peripheral immune cells into a tumor is limited. If the BBB is disrupted by tumor proliferation or inflammation, then the tumor can be infiltrated by immunosuppressive immune cells [67]. It has been shown that an immunosuppressive microenvironment in a glioma is created by immunosuppressive cytokines and chemokines (transforming growth factor beta (TGF-β), interleukin 10 (IL-10), prostaglandin E2) and immune cells (immunosuppressive natural killer T cells (NKT), T/B regulatory cells (T/Breg), tumor-associated macrophages (TAM)/microglia and myeloidderived suppressor cells (MDSC)).…”