Reuse of Molecules for Glioblastoma Therapy

Abstract

Glioblastoma multiforme (GBM) is a highly malignant primary brain tumor. The current standard of care for GBM is the Stupp protocol which includes surgical resection, followed by radiotherapy concomitant with the DNA alkylator temozolomide; however, survival under this treatment regimen is an abysmal 12–18 months. New and emerging treatments include the application of a physical device, non-invasive ‘tumor treating fields’ (TTFs), including its concomitant use with standard of care; and varied vaccines and immunotherapeutics being trialed. Some of these approaches have extended life by a few months over standard of care, but in some cases are only available for a minority of GBM patients. Extensive activity is also underway to repurpose and reposition therapeutics for GBM, either alone or in combination with the standard of care. In this review, we present select molecules that target different pathways and are at various stages of clinical translation as case studies to illustrate the rationale for their repurposing-repositioning and potential clinical use.

Antitumoral Effects of Tricyclic Antidepressants: Beyond Neuropathic Pain Treatment

“…Recently, the study by MacDonald et al concluded that liposome-imipramine blue is a potential novel nanoparticle-based therapeutic for the treatment of Sonic Hedgehog medulloblastoma [64]. Along the same line, the review about the reuse of molecules for glioblastoma therapy by Koehler et al included IB as a candidate molecule as it limits cancer migration and decreases inhibition of transcript factors known to aid cell survival [107]. Furthermore, Lucki et al suggested that dexamethasone, in the presence of desipramine, enhanced MAPK/ERK1/2 signaling, a key player in neural plasticity and neurogenesis processes that is impaired in major depression disorder [108].…”

An Update on Glioblastoma Biology, Genetics, and Current Therapies: Novel Inhibitors of the G Protein-Coupled Receptor CCR5

“…Other approaches target tumor metabolism, such as IDH inhibitors in IDH mutated astrocytoma [ 9 ]. Novel approaches include targeting GBM-specific mutations [ 10 ] ( Section 2.3.1 ) and repurposing drugs that target the immunosuppressive GME [ 54 ] ( Section 3 and Section 4 ).…”

“…The obstacles to effective therapy include therapeutic resistance of a small population of GB cells—the glioblastoma stem cells (GSCs) [ 2 , 3 , 4 , 5 ], significant inter- and intratumor heterogeneity, which consist of a plethora of GBM cells that differ in their genetic makeup and stage of differentiation, and the presence of a variety of stromal cells, in this cancer called GBM microenvironment (GME) [ 6 , 7 ]. Several comprehensive reviews have described molecular signaling pathways [ 8 ], genetics, and treatments of gliomas [ 9 ] including the repurposing of previously approved drugs [ 10 ]. The focus of this review is to extend upon recent discoveries in this rapidly evolving field.…”

Synthesis and Antiproliferative Evaluation of New 1,3,5‐Trisubstituted 1,2,4‐Triazole Derivatives against Glioblastoma Cell Lines

“…This medicine is used to treat hormone‐positive breast cancer in postmenopausal women. Studies have also shown that letrozole can cross the BBB in rats with C6 glioma and has an anticancer effect on GB cells [40,41] . After various in vitro and in vivo studies with letrozole, phase I studies were started in 2017 to treat of recurrent gliomas [40] .…”

“…Studies have also shown that letrozole can cross the BBB in rats with C6 glioma and has an anticancer effect on GB cells. [40,41] After various in vitro and in vivo studies with letrozole, phase I studies were started in 2017 to treat of recurrent gliomas. [40] These studies demonstrate the importance of the selected 1,2,4triazole ring in this field.…”