Project ID D2019-34

Background

Tumor therapies must overcome complex obstacles, such as cellular invasion, chemoresistance, and radioresistance.  Cells within a brain tumor often form specialized ultralong cellular projections called tumor microtube (TM) projections that allow them to invade new areas of the brain. The networks formed by TMs interconnect with normal neurons and correlate with enhanced chemoresistance and radiosensitivity. mDia proteins are actin nucleating proteins that underlie many protrusive structures associated with tumor cell motility. Although mDia proteins are expressed in brain tumor cells, they have not been investigated as a target for therapy.

Invention Description

Researchers at the University of Toledo have used three-dimensional (3D) neurospheres from patient-derived High-Grade Glioma (HGG) cells to show that mDia agonists halt invasion already in progress by collapsing existing F-actin and tubulin enriched TMs.  Furthermore, invaded patient-derived HGG neurosphere tumor cells underwent apoptosis in response to mDia agonism. The TMs seen in the patient-derived HGG neurospheres did not form in cultured cells, such as U251s, and therefore, provided an excellent model to modulate the observed projections. This study suggests that targeting mDia formins with mDia agonists will halt TM tumor formation and proliferation in an already invading tumor cell population.

Applications

Adjuvant for chemotherapy, radiotherapy, or surgical resection in HGG patients

Advantages

• Disrupts multiple aspects of invasion in patient-derived HGG neurospheres
• Disrupts proliferation in already invading HGG cells, which is clinically relevant to how most HGG patients present
• Effect is reversible in non-invading cells, suggesting the agonist has utility in other anti-invasive therapeutics
• Causes distinct amoeboid morphological transition in tumor cells

IP Status:                         US Patent Pending          

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.