A Designer Peptide to Treat Glioblastoma by Targeting Cancer-neuron Interaction

Glioblastoma (GBM) is the most common and malignant adult primary brain tumor with patient survival of around 15 months. Temozolomide (TMZ) is the only chemotherapy drug approved by U.S. Food and Drug Administration (FDA) to treat early-diagnosed GBM. It only lengthens patient survival by 2.5 months with more than 50% of patients displaying intrinsic or adaptive resistance. Thus, there is an urgent need to identify novel therapeutic targets to treat GBM. Recent studies demonstrated that neuronal activities promote GBM initiation, proliferation, and invasion. Reciprocally, GBM cells remodel the synaptic constituency and induce hyperactivity of surrounding neurons, thereby creating a pro-tumorigenic microenvironment. These interactions between neurons and glioma cells underlie tumor progression. Thus, targeting cancer-neuron interactions to identify therapeutic opportunities is emerging as an area of intense study.I identified that EAG2 and Kvβ2 are highly expressed at the GBM-brain interface conducive to GBM cell-neuron interaction. Knockdown of EAG2 and Kvβ2 significantly reduced the infiltrative behaviour of GBM cells in xenograft tumor models, resulting in reduced tumor microtube formation and neuron-GBM interaction, collectively leading to a less infiltrative GBM-brain interface. EAG2 localizes at GBM cell-neuron contacts in a Kvβ2-dependent manner. Knockdown of the EAG2-Kvβ2 complex decreased calcium transients of tumor cells, suppressed tumor growth and invasion, and extended the survival of tumor-bearing mice. EAG2 and Kvβ2 physically interact to form a potassium channel complex, their interaction is enriched in GBM due to a specific Kvβ2 isoform. EAG2-Kvβ2 interaction domain-derived designer peptide blocked EAG2-Kvβ2 interaction, prolonged survival of tumor-bearing mice with no detectable toxicity on normal tissues. Single-cell RNA sequencing revealed that a group of GBM cells that closely associate with neurons are highly sensitive to the designer peptide. Neurons upregulate chemoresistant genes in GBM cells to promote TMZ resistance in an EAG2-Kvβ2-dependent manner. Moreover, designer peptide possesses robust efficacy in treating TMZ-resistant GBM.My study uncovered the EAG2-Kvβ2 complex as a unique GBM vulnerability and developed a first-in-class designer peptide to disrupt this protein-protein interaction in GBM treatment. These findings may have profound implications to develop next-generation therapeutics to benefit GBM patients.

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