Systematic Review of Molecular Targeted Therapies for Adult-Type Diffuse Glioma: An Analysis of Clinical and Laboratory Studies

Abstract

Gliomas are the most common brain tumor in adults, and molecularly targeted therapies to treat gliomas are becoming a frequent topic of investigation. The current state of molecular targeted therapy research for adult-type diffuse gliomas has yet to be characterized, particularly following the 2021 WHO guideline changes for classifying gliomas using molecular subtypes. This systematic review sought to characterize the current state of molecular target therapy research for adult-type diffuse glioma to better inform scientific progress and guide next steps in this field of study. A systematic review was conducted in accordance with PRISMA guidelines. Studies meeting inclusion criteria were queried for study design, subject (patients, human cell lines, mice, etc.), type of tumor studied, molecular target, respective molecular pathway, and details pertaining to the molecular targeted therapy—namely the modality, dose, and duration of treatment. A total of 350 studies met the inclusion criteria. A total of 52 of these were clinical studies, 190 were laboratory studies investigating existing molecular therapies, and 108 were laboratory studies investigating new molecular targets. Further, a total of 119 ongoing clinical trials are also underway, per a detailed query on clinicaltrials.gov. GBM was the predominant tumor studied in both ongoing and published clinical studies as well as in laboratory analyses. A few studies mentioned IDH-mutant astrocytomas or oligodendrogliomas. The most common molecular targets in published clinical studies and clinical trials were protein kinase pathways, followed by microenvironmental targets, immunotherapy, and cell cycle/apoptosis pathways. The most common molecular targets in laboratory studies were also protein kinase pathways; however, cell cycle/apoptosis pathways were the next most frequent target, followed by microenvironmental targets, then immunotherapy pathways, with the wnt/β-catenin pathway arising in the cohort of novel targets. In this systematic review, we examined the current evidence on molecular targeted therapy for adult-type diffuse glioma and discussed its implications for clinical practice and future research. Ultimately, published research falls broadly into three categories—clinical studies, laboratory testing of existing therapies, and laboratory identification of novel targets—and heavily centers on GBM rather than IDH-mutant astrocytoma or oligodendroglioma. Ongoing clinical trials are numerous in this area of research as well and follow a similar pattern in tumor type and targeted pathways as published clinical studies. The most common molecular targets in all study types were protein kinase pathways. Microenvironmental targets were more numerous in clinical studies, whereas cell cycle/apoptosis were more numerous in laboratory studies. Immunotherapy pathways are on the rise in all study types, and the wnt/β-catenin pathway is increasingly identified as a novel target.

Bioactive Compounds, Antioxidant Activity, and Antiproliferative Potential on Glioblastoma Cells of Selected Stone Fruit Juices

“…Neocuproine, cupric chloride, and 2,4,6-tri(2pyridyl)-s-triazine (TPTZ) were acquired from Acros Organic (Geel, Belgium). Thiazolyl blue tetrazolium bromide (98%) (2-(3,5-diphenyltetrazol-2-ium-2-yl)-4,5-dimethyl-1,3-thiazole;bromide), Temozolomide (3-methyl-4-oxoimidazol [5,1-d] [1,2,3,5]tetrazine-8carboxamide), DMEM media (with L-glutamine, 4.5 g/L glucose and sodium pyruvate), solution of penicillin/streptomycin (10,000 U/mL penicillin, 10,000 µg/mL streptomycin in 0.85% NaCl), and 0.25% trypsin/0.1% EDTA were obtained from ThermoFisher Scientific (Waltham, MA, USA). Glioblastoma U87-MB and GBM43 cells were obtained from Mayo Clinic (Rochester, MN, USA) while fetal bovine serum was acquired from R&D Systems (Flowery Branch, GA, USA).…”

“…According to this classification, which is based on molecular markers such as isocitrate dehydrogenase (IDH) expression and 1p/19q codeletion, adult-type diffuse gliomas are the most prevalent tumor types. These gliomas include subtypes such as astrocytoma (IDH-mutant astrocytoma), oligodendroglioma (IDH-mutant and 1p19q-codeleted), and glioblastoma (GBM) (IDH-wildtype) [1,2].…”

Glioblastoma, IDH-wildtype, with oligodendrocyte-like cells – a microscopic challenge

“…Indeed, the two neoplasms differ in both their biological behaviour and prognosis, which are worse for GBO [1]. But even more important is the message that increasingly new differences are emerging in the molecular targets of medical therapy of the different types of glioma, some already approved and employed, others still undergoing clinical or laboratory studies [2].…”

Cyclooxygenase and Cancer: Fundamental Molecular Investigations

“…In addition to the current GBM therapy, novel feasible or potential targets have recently emerged [19] and are actively investigated in clinical trials [20]. As reported in the systematic review by Da Silva et al [21], targeted therapies in GBM clinical trials can be grouped into four categories: targeting the potential for unlimited replication, growth autonomy and migration, cell cycle and apoptosis, and angiogenesis.…”