**9. Glycolysis in glioblastomas**

in order for the virus vectors to carry the therapeutic genes under investigation [36]. While there are multiple Phase I and II clinical trials underway (clinicaltrials.gov), an impetus remains on the parallel to streamline the efficacy of these viruses to ensure the potency of the viral vectors without overtly impairing the host immune system response (may want to note that the mechanism of some of these virus such as the Duke polio virus may be by immune system induction). Convection enhanced delivery using continuous, positive pressure bulk flow of the therapeutic virus to the glioma may be undertaken to improve delivery [38, 39]. Specificity may be enhanced for viral entry into the glioma on modification of attachmentmediating surface proteins and chimeric capsids [25]. Of most interest, are the viral genes being engineered to be enhanced using hypoxia-responsive promoters in areas of low-hypoxia, a

Of note is the Toca511 trial, with an estimated completion date of November 2017. This is a multicenter, randomized, Open label Phase II/III study of Toca 511 and Toca FC versus standard of care. This comprises investigator's choice of single-agent chemotherapy (lomus‐ tine or temozolomide) or bevacizumab administered to patients with recurrent high-grade gliomas. Toca 511 (vocimagene amiretrorepvec) is an investigational injectable retroviral replicating vector (RRV) encoding a yeast-derived prodrug activator enzyme, cytosine deaminase (CD). Toca 511 selectively infects and spreads through the high-grade glioma cells, thereby delivering the CD gene and the tumor cells can then produce the CD enzyme.

Toca FC is an orally administered, extended-release version of prodrug 5-fluorocytosine (5- FC) which is absorbed and carried through the bloodstream. This crosses the blood–brain barrier and is then converted by the CD enzyme into the active 5-FU, at high concentrations within the glioma cells infected by Toca 511. 5-FU in turn causes tumor cell apoptosis and activation of the immune system by the release of tumor-associated antigens and viral proteins from the dying cells. We look forward to the results of this retroviral replicating vector against

In 2015, Optune™ became the first FDA-approved therapy for newly diagnosed glioblasto‐ mas in over a decade to demonstrate statistically significant extension of progression free and overall survival. Optune™ is the brand name for the NovoTTF™ 100A system manufac‐

Optune™ is a portable, noninvasive device delivering low-intensity, intermediate frequency, alternating bidirectional electric fields referred to as Tumor Treating Fields (TTF). The electric fields are delivered locoregionally via transducer arrays through the shaved scalp. The mechanism of action is the antimitotic action of the tumor treating fields interfering with cell division and organelle assembly within the rapidly replicating tumor cells. While micropho‐ tography has shown examples of prolonged mitoses and proliferation arrest, the specificity of the tumor treating fields for tumor cells only in the absence of an exact mechanism has raised

skepticism within the Neuro-Oncology and Oncology clinician community [40].

high-grade gliomas and the possible extrapolation to other solid cancers.

tured by the commercial stage oncology company Novocure™.

known glioma phenotype [37, 39].

276 Neurooncology - Newer Developments

**8. Tumor treating fields**

Glioblastomas appear to thrive and proliferate in a hypoxic environment, thus relying upon anaerobic glycolysis [43]. Thus research efforts over the past decade have been toward maximizing of glycolytic inhibition within the hypoxic glioma environment [44–47].

In their 2015 paper, Sanzey et al. undertook genome-wide transcriptomic analysis of patientderived glioblastoma and stem cells to demonstrate a strong upregulation of glycolysis-related genes in response to severe hypoxia. Glioblastoma xenografts were used to identify seven glycolytic genes, with knockdown that led to a dramatic murine survival benefit, with phosphofructokinase-1 [PFK1] and pyruvate dehydrogenase kinase-1 [PDK1] as the most promising therapeutic targets to address the metabolic escape mechanisms of glioblastomas [44]. At this point, it is instructive to correlate the high glycolytic states of tumor cells to the increase in the radioresistance of glioblastomas [48]. A pyruvate dehydrogenase kinase inhibitor [Dichloroacetate] is used to treat lactic acidosis and is noted to modify tumor metabolism by activating mitochondrial activity and thus, force glycolytic tumor cells into oxidative phosphorylation. Dichloroacetate alone demonstrated modest antitumor effects in both in vitro and in vivo models of glioblastoma and reversed the radiotherapy-induced glycolytic shift, thereby improving the survival of orthotopic glioblastoma-bearing mice [46]. We look forward to clinical trials modulating the metabolic state of glioblastoma cells and thus, modify their sensitization to radiotherapy.
