The Landscape of Novel Therapeutics and Challenges in Glioblastoma Multiforme: Contemporary State and Future Directions

Abstract

Background: Glioblastoma multiforme is a malignant intracranial neoplasm that constitutes a therapeutic challenge because of the associated high morbidity and mortality given the lack of effective approved medication and aggressive nature of the tumor. However, there has been extensive research recently to address the reasons implicated in the resistant nature of the tumor to pharmaceutical compounds, which have resulted in several clinical trials investigating promising treatment approaches. Methods: We reviewed literature published since 2010 from PUBMED and several annual meeting abstracts through 15 September 2020. Selected articles included those relevant to topics of glioblastoma tumor biology, original basic research, clinical trials, seminal reviews, and meta-analyses. We provide a discussion based on the collected evidence regarding the challenging factors encountered during treatment, and we highlighted the relevant trials of novel therapies including immunotherapy and targeted medication. Results: Selected literature revealed four main factors implicated in the low efficacy encountered with investigational treatments which included: (1) blood-brain barrier; (2) immunosuppressive microenvironment; (3) genetic heterogeneity; (4) external factors related to previous systemic treatment that can modulate tumor microenvironment. Investigational therapies discussed in this review were classified as immunotherapy and targeted therapy. Immunotherapy included: (1) immune checkpoint inhibitors; (2) adoptive cell transfer therapy; (3) therapeutic vaccines; (4) oncolytic virus therapy. Targeted therapy included tyrosine kinase inhibitors and other receptor inhibitors. Finally, we provide our perspective on future directions in treatment of glioblastoma. Conclusion: Despite the limited success in development of effective therapeutics in glioblastoma, many treatment approaches hold potential promise including immunotherapy and novel combinational drugs. Addressing the molecular landscape and resistant immunosuppressive nature of glioblastoma are imperative in further development of effective treatments.

Evolution of Experimental Models in the Study of Glioblastoma: Toward Finding Efficient Treatments

“…Moreover, since these mouse models lack inflammatory responsive cells or an intact immune system it does not allow testing for immunomodulatory therapies. This limitation is currently critical since immune therapeutics have recently been very successful in treating a diverse group of cancerous lesions and there has been an explosion in the study of immune therapeutics for cancer treatment over the past few years (70,71). Among the advantages of these xenograft models three can be highlighted: i) they allow personalized drug efficiency tests in single patients, ii) the original tumor architecture and histological characteristic are preserved and iii) they are genetically stable (Tables 1 and 2).…”

“…Therefore, the development of experimental models in the study of GBM should be focused on those that facilitate the discovery of new and more potent therapeutic options. In this context, attention needs to be paid to therapies directed to exploiting the potential of the immune system (70,71). Future experimental models in the study of GBM would need to allow the study of the crosstalk between GBM and the components of the immune system in order to facilitate the development of immune based therapies.…”

Acid-Sensing Ion Channel 1 Contributes to Weak Acid-Induced Migration of Human Malignant Glioma Cells

“…Recent studies have seen success of some target compounds in combating GBMs in laboratory settings; however, these compounds failed in clinical trials (Mandel et al, 2018 ). Multiple factors may have contributed to this drug failure in GBM treatment, including difficulty penetrating the blood-brain barrier (BBB), an immunosuppressive microenvironment, and complex intratumoral heterogeneity (Khaddour et al, 2020 ; Ou et al, 2020 ). Difficulty in treating GBMs has led to a 5-year survival rate of <7.2% in humans.…”

A New Landscape for Systemic Pharmacotherapy of Recurrent Glioblastoma?

“…In recent years, immunotherapy, especially the immune checkpoint inhibitors (ICIs) nivolumab, pembrolizumab, and durvalumab, showed durable improved outcomes in several types of tumors but not in the overall glioblastoma population [ 5 ]. Checkmate 143 was the first phase III trial investigating the efficacy and safety of nivolumab in recurrent glioblastoma patients [ 6 ].…”

“…Despite these encouraging results, many other studies analyzing targeted therapies, such as agents targeting c-MET, the PI3K–AKT–mTOR pathway, FGFR, and EGFR inhibitors, failed to improve outcomes in recurrent glioblastoma patients [ 5 ]. These poor results may also be due to molecular and genetic differences between tumors at diagnosis and at recurrence [ 16 ]; trials at tumor recurrence are usually based on molecular data from the primary tumor, with the potential loss of original mutations at relapse.…”