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.

Keywords: CellCept®; S6K1 inhibitors; Visudyne®; brain cancer; glioblastoma; imipramine blue; letrozole; saposin C.

Figure 1

Panel (A): Mechanisms of drug inhibition on cellular pathways. (Letrozole). Aromatase catalyzes the conversion of androgens to estrogens by aromatization of the A-ring. A-ring structure of androgens is noted by the red star. (CellCept) GTP synthesis increases cell anabolism through upregulation of inosine monophosphate dehydrogenase, IMPDH, the rate-limiting enzyme of the GTP nucleotide synthesis pathway [31,32]. IMPDH is inhibited by CellCept. (BMS-777607 and LY-2584702) Shown is the canonical oncogenic kinase signaling pathway downstream of TAM receptor, Axl. PTEN deficiency is depicted by transparency. (Imipramine Blue) Imipramine Blue, shown here in schematic, is thought to have an effect on cell migration due to its ability to inhibit NADPH oxidase, which catalyzes electron transfer to oxygen from NADPH, thereby limiting actin fiber formation. Importantly, O₂⁻ inhibits transcription factors critical to cell survival, including PTEN, Iκ-B, p53 [33]. (Verteporfin) Verteporfin can act as an inhibitor of the Yes-associated protein (YAP) and PDZ-binding motif (TAZ) family transcriptional coactivators [34], which have roles in the Hippo and RTK signaling pathways. Verteporfin disrupts the interaction between YAP and TEAD transcription factors, which regulate the Hippo signaling pathway. Panel (B): Chemical structure of the molecules discussed above.

Figure 2

Makeup of SapC-DOPS. Nanodrug SapC-DOPS is composed of a small lysosomal and multifunctional glycoprotein, SapC (Saposin C) [110], embedded in the membrane of a microvesicle rich in negatively charged phospholipids, dioleoylphosphatidylserine or 1,2-dioleoyl-sn-glycero-3-phosphoserine (DOPS). Figure 2 is adapted from [111].