Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with an extremely poor prognosis. There is a dire need to develop effective therapeutics to overcome the intrinsic and acquired resistance of GBM to current therapies. The process of developing novel anti-neoplastic drugs from bench to bedside can incur significant time and cost implications. Drug repurposing may help overcome that obstacle. A wide range of drugs that are already approved for clinical use for the treatment of other diseases have been found to target GBM-associated signaling pathways and are being repurposed for the treatment of GBM. While many of these drugs are undergoing pre-clinical testing, others are in the clinical trial phase. Since GBM stem cells (GSCs) have been found to be a main source of tumor recurrence after surgery, recent studies have also investigated whether repurposed drugs that target these pathways can be used to counteract tumor recurrence. While several repurposed drugs have shown significant efficacy against GBM cell lines, the blood–brain barrier (BBB) can limit the ability of many of these drugs to reach intratumoral therapeutic concentrations. Localized intracranial delivery may help to achieve therapeutic drug concentration at the site of tumor resection while simultaneously minimizing toxicity and side effects. These strategies can be considered while repurposing drugs for GBM.
Highlights
Glioblastoma (GBM) is the most common malignant primary brain tumor in adults.The current standard of care is surgical resection, radiotherapy and chemotherapy
Another Phase II study by Su et al investigated the efficacy of concomitant valproic acid and RT followed by valproic acid and bevacizumab therapy in children diagnosed with high grade gliomas and diffuse intrinsic pontine glioma (DIPG) [12]
The authors found that patients with angiotensin II receptor expression had lower survival rates when compared to those with angiotensin negative tumors, and they concluded that angiotensin II receptors contributed to the high mortality rates in high-grade astrocytoma and these findings suggest that angiotensin II receptors might be potential therapeutic targets for high-grade astrocytomas [107]
Summary
Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. The current standard of care is surgical resection, radiotherapy and chemotherapy. In vitro studies have demonstrated a corresponding significant increase of GBM stem cells (GSCs) within the total GBM cell population after treatment with TMZ [4] This resistance has generated a compelling need for innovative and effective therapeutic strategies for patients with GBM. We review different aspects of drug repurposing for GBM therapeutics, including limitations and recent advances to overcome these limitations Since many of these drugs are at various. Phase I/II proof-of-concept trial to investigate safety and efficacy of metronomic TMZ combined with repurposed drugs (NCT02770378). Inhibits capillary network formation and proliferation, and reduces miR-21 levels leading to cell apoptosis [37]. High levels of eIF4E are associated with higher tumor proliferation rate while EZH2 contributes to GBM resistance to radiotherapy. Cell self-renewal and reduce cell stemness and mesenchymal markers though binding to AMPK
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