Screening for Tumor Microtube-Targeting Drugs Identifies PKC Modulators as Multipotent Inhibitors of Glioblastoma
Daniel D Azorín1,2,3,4, Dirk C Hoffmann1,2,3, Nils R Hebach1,2
1Heidelberg University Medical Faculty, Neurology Clinic, and National Center for Tumor Diseases, Heidelberg, Germany.
Cancer Discovery
|October 9, 2025
Summary
Researchers identified a new way to target glioblastoma, an aggressive brain tumor. By inhibiting tumor microtubes (TMs) using Protein Kinase C (PKC) modulators, they disrupted tumor cell communication and invasion, offering a promising therapeutic strategy.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Drug Discovery
Background:
- Glioblastomas are aggressive brain tumors characterized by invasive tumor microtubes (TMs).
- TMs facilitate brain invasion and form multicellular networks, conferring therapeutic resistance.
- Targeting TMs presents a potential strategy for glioblastoma treatment.
Purpose of the Study:
- To develop and validate a comprehensive in vitro/in vivo drug screening approach targeting TMs.
- To identify novel therapeutic agents and pathways that inhibit TM formation and function.
- To evaluate the efficacy of TM-targeting agents in combination with existing therapies.
Main Methods:
- Established a combined in vitro/in vivo drug screening pipeline with machine learning analysis.
- Screened Protein Kinase C (PKC) modulators for their ability to inhibit TM formation and network communication.
- Utilized intravital 2-photon microscopy and spatially resolved multiomics to assess therapeutic effects.
- Investigated the role of TPPB, a PKC activator, in combination with radiotherapy.
Main Results:
- Two PKC modulators significantly inhibited TM formation and TM-mediated glioblastoma cell network communication.
- TM-unconnected tumor cells showed increased sensitivity to cytotoxic therapy.
- Combination therapy with TPPB and radiotherapy demonstrated anti-TM and anti-tumor effects.
- TPPB treatment reduced the expression of TTYH1, a key regulator of invasive TMs.
Conclusions:
- The developed screening pipeline offers a novel approach for anti-TM drug discovery.
- PKC signaling represents a critical pathway regulating TM formation and glioblastoma invasion.
- Targeting TMs, particularly through PKC modulation, holds significant potential for improving glioblastoma therapies.
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