The potential of emerging therapies for glioblastoma: a comparison with current treatments
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Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor with a median survival of about 15 months with treatment. This very poor prognosis is in part due to the blood brain barrier (BBB), preventing chemotherapeutic agents from acting at the tumor site. Tumor recurrence is also common with GBM, which may be due its highly infiltrative nature and the development of treatment resistance. The standard therapy for GBM is the agent temozolomide, which is administered after surgery, in combination with radiotherapy, and following radiation as part of the Stupp Protocol. Considering the poor outcomes of patients with GBM, it is imperative to develop more effective therapeutics to treat the malignancy. Several emerging therapies currently under investigation selectively target properties of GBM in an attempt to improve treatment efficacy and reduce side effects. For instance, CAR T-cell therapy has been shown to travel to the tumor site and exert antitumor effects. CAR-T cell therapy also induces the patient’s own immune system over time, which highlights its potential as an adjuvant treatment choice. Oncolytic virotherapy is another immunotherapy that relies on the induction of the patient’s immune system while also promoting direct anticancer effects through cell lysis. Rindopepimut, a potential anticancer vaccine, binds to the GBM-specific antigen EGFRvIII and has demonstrated favorable outcomes in patients with recurrent GBM. Similarly, the targeted therapy agent bevacizumab inhibits angiogenesis by binding to EGFR and has been shown to increase survival after the failure of standard care. Selinexor, another targeted therapy agent, inhibits exportin-1 and so causes glioma cell apoptosis. Selinexor has increased progression-free survival in GBM patients who failed standard treatment and should be further explored as a last line treatment perhaps in combination with bevacizumab. The targeted therapy drug azeliragon inhibits the RAGE receptor, thereby decreasing tumorigenicity, and is currently being evaluated in a clinical trial. Furthermore, compounds that increase BBB permeability, including K-ATP channel activators, K-Ca channel activators, PDE5 inhibitors, and B2 receptor agonists, could allow for a whole new array of chemotherapeutics to be used in the treatment of GBM. More physical disruptors of tumor endothelial tight junctions, like focused ultrasound therapy and EMP, carry similar potential. Anti-invasive agents, such as SERPINE1 inhibitors, metalloproteinase inhibitors, and integrin inhibitors, remain experimental at this stage, but may be revolutionary in their capacity to inhibit tumor progression. New technologies have allowed for the development of chemotherapeutic carriers, which promote BBB penetration and prolong anti tumor effects. In particular, surface-modified nanostructured lipid carriers allow for targeted treatment in addition to promoting BBB permeability for chemotherapeutic agents. Similarly, radiation-responsive hydrogel entraps chemotherapeutics and allows for prolonged antitumor effects. These therapies show potential to inhibit tumor progression and promote destruction of cancer cells, but further research is required to assure safety and clinical efficacy.