A Systematic Review of Glioblastoma-Targeted Therapies in Phases II, III, IV Clinical Trials

Abstract

Glioblastoma (GBM), the most frequent and aggressive glial tumor, is currently treated as first line by the Stupp protocol, which combines, after surgery, radiotherapy and chemotherapy. For recurrent GBM, in absence of standard treatment or available clinical trials, various protocols including cytotoxic drugs and/or bevacizumab are currently applied. Despite these heavy treatments, the mean overall survival of patients is under 18 months. Many clinical studies are underway. Based on clinicaltrials.org and conducted up to 1 April 2020, this review lists, not only main, but all targeted therapies in phases II-IV of 257 clinical trials on adults with newly diagnosed or recurrent GBMs for the last twenty years. It does not involve targeted immunotherapies and therapies targeting tumor cell metabolism, that are well documented in other reviews. Without surprise, the most frequently reported drugs are those targeting (i) EGFR (40 clinical trials), and more generally tyrosine kinase receptors (85 clinical trials) and (ii) VEGF/VEGFR (75 clinical trials of which 53 involving bevacizumab). But many other targets and drugs are of interest. They are all listed and thoroughly described, on an one-on-one basis, in four sections related to targeting (i) GBM stem cells and stem cell pathways, (ii) the growth autonomy and migration, (iii) the cell cycle and the escape to cell death, (iv) and angiogenesis.

Expression Analysis of α5 Integrin Subunit Reveals Its Upregulation as a Negative Prognostic Biomarker for Glioblastoma

“…The prognosis of GBM patients remains very poor and has been mainly improved by the application of the Stupp protocol (temozolomide-based concomitant radiochemotherapy followed by temozolomide adjuvant therapy), which has become the standard of care [ 4 , 5 ], and more recently by tumor treating fields (TTFields)/Optune, which is registered in the EU and the US [ 6 ], together with likely optimization of supportive care. Numerous clinical trials targeting aberrant GBM oncogenic signaling pathways have been mostly unsuccessful, and patient survival remains short (under 20 months) [ 7 ]. New treatments are urgently required, and the definition of GBM subpopulations is supposed to be better responders to the targeting of specific pathways.…”

A Drug Screening Pipeline Using 2D and 3D Patient-Derived In Vitro Models for Pre-Clinical Analysis of Therapy Response in Glioblastoma

“…In summary, these results complementing the distinct advantages of patient-derived 2D and 3D models present a novel workflow for screening small groups of drugs with the potential for a more personalized approach in the treatment of recurrent glioblastoma. Moreover, it is possible to scale up this process further to include additional drugs that also shown promise in the clinical trial setup (e.g., regorafenib [ 128 ], and other Phase II-IV clinical trials drugs as recently reviewed by Cruz DaSilva et al [ 129 ]) as well as drug candidates identified in large scale screenings using 2D cultures of patient-derived cells [ 130 ], which have not been yet tested in 3D GBO models.…”

Multi-Platform Classification of IDH-Wild-Type Glioblastoma Based on ERK/MAPK Pathway: Diagnostic, Prognostic and Therapeutic Implications

“…The RTK landscaping, pathway associations, and subgrouping efforts presented here also carry a major impact for the clinical management of glioblastoma, including diagnosis, prognosis, and therapy ( Figure 4 B). Although many clinical trials targeting a plethora of pathways are ongoing in glioblastoma [ 31 ] and aim at the major pathways presented here, correct patient inclusion is crucial for regimen success. For example, the G1/EGFRm subgroup may represent a more promising target to EGFR inhibitors than the larger G1/EGFR↑ subgroup, similarly to non-small cell lung carcinomas with EGFR mutations.…”