Project ID D2019-34

High-grade gliomas, including glioblastoma, remain difficult to treat because invasive tumor cells can migrate away from the primary tumor mass, limiting the effectiveness of surgical resection and contributing to recurrence. These invasive cells may form long cellular projections known as tumor microtubes (TMs), which are enriched in cytoskeletal components and have been associated with tumor cell communication, invasion, chemoresistance, and radioresistance. Current standard approaches like surgery, radiation, and chemotherapy, do not directly target this TM-associated invasive phenotype.

Invention Description

Researchers at The University of Toledo demonstrated that mDia agonists, including IMM01 and IMM02, inhibit invasion of patient-derived HGG neurospheres and suppress formation or maintenance of actin- and tubulin-enriched tumor microtubes. In 3D neurosphere invasion assays, IMM treatment halted invasion, shortened tumor microtubes, induced a rounded/amoeboid morphology in neurosphere edge cells, and disrupted cytoskeletal projections. Drug washout experiments showed that anti-invasive effects were reversible in non-invading or continuously treated neurospheres, while treatment of already invading neurospheres induced robust cell death.

Applications

• Adjuvant therapy for high-grade glioma or glioblastoma following surgery
• Combination therapy with chemotherapy and/or radiotherapy
• Anti-invasive treatment targeting tumor microtube formation and maintenance
• Lead-compound platform for next-generation cytoskeleton-directed oncology agents
• Research tool for studying mDia/formin-mediated tumor invasion

Advantages

• Targets tumor invasion, tumor microtube formation, proliferation, and therapy resistance
• Demonstrated activity in patient-derived 3D high-grade glioma neurosphere models
• Suppresses ongoing neurosphere invasion and induces death in invading tumor cells
• Disrupts actin- and tubulin-enriched tumor microtubes rather than only bulk tumor growth
• May sensitize brain tumor cells to chemotherapy and radiation

IP Status: U.S. Patent No. 11,547,682 B2     

Publications:               1.) K Eisenmann et al.  Targeting the mDia formin-assembled cytoskeleton is an effective anti-invasion strategy in adult high-grade glioma patient-derived neurospheres. Cancers 2019, 11(3), 392

                                    2.) K Eisenmann et al. Differential Toxicity of mDia Formin-Directed Functional Agonist and Antagonists in Developing Zebrafish. Front. in Pharmacol. 2018, 9:340

                                    3.) K Eisenmann et al Small-molecule agonists of mammalian Diaphanous–related (mDia) formins reveal an effective glioblastoma anti-invasion strategy  Mol Biol Cell. 2015 Nov 1; 26(21): 3704–3718.