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Tumor Discovery Understanding glioblastoma invasion and therapy

of The Cancer Genome Atlas (TCGA) gene sets from 8/10 glioma patients treated with six months of perampanel
1p/19q co-deleted gliomas (i.e., oligodendrogliomas/ for glioma-associated epilepsy. Targeting NGS activity
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TM-poor) and 1p/19q non-co-deleted gliomas with AMPAR antagonists is, therefore, a viable and
(i.e., astrocytomas/TM-rich). 136,137 These efforts implicated promising therapeutic strategy in GBM. However, the use
pathways associated with normal neurodevelopmental of perampanel has not yet been evaluated in clinical trials.
processes. Pathways associated with stemness and
underlying neurite outgrowth, such as signaling of the 8.6. TMs in GBM therapy resistance
Rho family of GTPases, integrins, phospholipase C, Tumor microtubule networks facilitate resistance to all
and neurotrophin and tropomyosin/tyrosine receptor three components of the GBM standard-of-care therapy
kinase signaling, are upregulated in TM-connected cells (Figure 7). The cellular cohort that survives radiation
compared to unconnected controls. 71,136 Knockdown and TMZ treatment is overwhelmingly comprised of
studies subsequently confirmed the roles of GAP-43, TM-connected cells. 136,147 The TM network’s ability to use
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TTYH1, and thrombospondin 1 in TM formation. 141 ICWs to maintain calcium homeostasis within connected
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8.4. TMs in GBM invasion
At the invasive front, TMs act as dynamic probes that
extend and retract in response to environmental cues.
Established TMs act as scaffolds facilitating the movement
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of GBM nuclei into the brain parenchyma. TMs display
at least two phenotypes, wherein one, they are highly
dynamic and associated with GBM cells exhibiting one
to two minimally arborized TMs that drive invasive
motility. In the other phenotype, TMs are remarkably
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stable and associated with stationary GBM cells exhibiting
four or more TMs that extensively arborize and connect to
an extensive TM network. Experimental knockdown of
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TTYH1 strongly inhibited the formation of invasive TMs,
whereas networked TMs were largely unaffected. Despite
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this, TTYH1 knockdown was associated with a significant
survival advantage in a patient-derived xenograft Figure 6. Schematic illustration of the gliomal network, the neuronal
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(PDX) model of GBMSCs, suggesting that targeting network, and their interconnectivity. Reproduced from Roehlecke et al. 142
TM-associated invasion is a promising therapeutic strategy
in GBM. 91,92

8.5. TMs and the neuron-glioma synapse (NGS)
TMs receive synaptic input from normal neurons via
a one-way, glutamatergic/alpha-amino-3-hydroxy-5-
methyl-4-isoxazolepropionic acid receptor (AMPAR)-
mediated transmission. These NGSs generate spontaneous
excitatory post-synaptic currents and slow inward currents
that induce ICWs within TM networks that support the
growth, invasion, and excitotoxic impact of GBM cells
in the brain. 106,107 Treatment with the Food and Drug
Administration-approved AMPAR antagonist perampanel
reduced the invasion and growth of tumor cells and
increased overall survival in PDX models of both adult
and pediatric high-grade glioma. 106,143 Perampanel is well-
tolerated, safe, and effective at reducing seizures in glioma-
associated epilepsy. In a 2009 trial, the pre-clinical
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AMPAR antagonist talampanel extended median overall
survival from 14.6 to 20.3 months in patients with newly
diagnosed GBM. Tumor volume was also reduced in Figure 7. Multiple components of glioblastoma resistance
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Volume 4 Issue 2 (2025) 30 doi: 10.36922/td.8578