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.
Highlights
Mycophenolic acid (MPA)/mycophenolate mofetil (MMF) treatment may have potential as a second-line treatment for Glioblastoma multiforme (GBM). This approach could both inhibit tumor growth and reduce cerebral edema for several reasons: (i) like corticosteroids, MPA and MMF are widely used as potent immunosuppressors for organ transplantation; (ii) they can suppress inflammation [64,65,66,67,68]; (iii) MPA treatment reduces VEGF secretion and neoangiogenesis in pancreatic cancer [69] and encapsulated peritoneal sclerosis [70]; (iv) cancer incidence is decreased in organ transplanted patients undergoing MMF treatment [71,72]; (v) as denoted above, the genetic and pharmacologic inhibition of inosine monophosphate dehydrogenase (IMPDH) suppresses GBM
This suggests an onco-dependency model for targeting the GBM kinome, wherein GBMs require signaling from Met, fibroblast growth factor receptor (FGFR), Axl, and other kinases to sustain survival and metabolism, even as these kinases are intrinsically affected by oncogenic driver events
Bench research and clinical trials with already established drugs can be explored more quickly, possibly offering a timely treatment to patients diagnosed with GBMs
Summary
Glial tumors can be divided into two categories: diffuse and circumscribed [1]. Diffuse tumors are highly likely to recur due to their nature of malignancy by infiltrating surrounding brain tissue, as opposed to the benign growth pattern of circumscribed tumors. Primary tumors often show a high level of gene expression or mutation in oncoproteins such as EGFR or NF1 loss or mutation, while secondary GBMs typically express mutations in IDH1/2 [1,3,4,5]. IDH wild type is most consistent in GBM primary tumors, whereas IDH mutant is consistent with low-grade gliomas and secondary GBM [4]. GBMs can be further divided into four subtypes based on genomic abnormalities These four subtypes are proneural, neural, classical, and mesenchymal. Proneural subtypes are often associated with younger age patients [3] They express alterations in the PDGFRA gene with either higher amplification of the locus at 4q12 or multiple point mutations, and they express point mutations in IDH1 [5]. Knowledge of the genetic discrepancies, tumor origination, histology, and DNA methylation patterns allow for more precise identification of tumors which predicts patient prognosis and guides possible treatment options
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