Scientists from University of Toledo and Van Andel Research Institute, both in the USA, report that they might have found a way to stop the spread of an aggressive and often fatal form of brain cancer, glioblastoma multiforme.

Glioblastoma, or GBM, arises from normal brain cells called “astrocytes.” Usually, glioblastomas are fast growing cancers, owing to the presence of a network of blood vessels that fuel their growth. The median survival rate for individuals suffering from GBM is reported to be about 15 months following diagnosis. Several laboratories around the world are engaged in GBM research, to gain insight into the deadly disease in order to combat it effectively and increase the median survival rate.

The current study throws light on the mechanism of GBM invasiveness, which could potentially be harnessed to design novel therapeutics to arrest the spread of this particular type of cancer. Because tumor cells require the assembly and disassembly of the cellular cytoskeleton, the research group targeted a family of proteins known as mammalian diaphanous-related formins (DIAPHs or mDIA), which are involved in polarized cell adhesion, migration and division --both in normal as well as cancer cells. The research shows that:

• Using a bioactive peptide known as DAD (Diaphanous Autoregulatory Domain) and small molecules called “intramimics (intramimic-01/IMM-01 and intramimic-02/IMM-02),” the DIAPH/mDIA could be locked in an “on” position.
  
• Keeping the DIAPH/mDIA switched “on” blocked the motility of brain cancer cells and impaired persistent migration.
  
• Blocking of invasiveness of cells was observed in cell culture models.
  
• Keeping DIAPH/mDIA active blocked the invasion of cells into surrounding normal cells in a physiologically relevant (rat brain slice) invasion model as well.
  
• IMM-01 and IMM-02 did not affect the viability of normal brain cells in the rat brain slice model.

Talking about the research to Van Andel Research Institute Press Release, one of the senior authors of the study, Dr. Arthur Alberts, says, “Metastatic tumor cells are like any moving vehicle—all of the wheels need to be pointed in the right direction when power is applied. DIAPHs build the structures that hold and point all the wheels moving cells in the right direction. Dr. Eisenmann’s data suggests that DIAPH activation or ‘agonism’ locks all wheels into arbitrary directions, so no matter how hard you push the pedal down, the tumor cells won’t move.”

The current study is unique, in the sense that it looks at activation of DIAPH/mDIA as a therapeutic option for tackling cancer, as opposed to previous research that aimed at inhibiting the said protein, which is involved in cell motility and integrity.

“GBM is lethal because it so effectively escapes and evades therapy,” says the senior author Dr. Eisenmann. “Our hope is this discovery will prove to be an anti-tumor strategy and one that will be safe and effective for patients.”

Written by Mangala Sarkar, Ph.D.

Primary References

Arden, J., Lavik, K., Rubinic, K., Chiaia, N., Khuder, S., Howard, M., . . . Eisenmann, K. (2015). Small molecule agonists of mammalian Diaphanous-related (mDia) formins reveal an effective glioblastoma anti-invasion strategy. Molecular Biology of the Cell. doi:10.1091/mbc.E14-11-1502

Van Andel Research Institute, University of Toledo find way to combat brain cancer spread. (n.d.). Retrieved September 22, 2015, from http://www.vai.org/home/NewsRoom/press-release-9-21-15

DoveMed Resources

Brain Cancer. (n.d.). Retrieved September 28, 2015, from http://www.dovemed.com/diseases-conditions/brain-cancer/

Glioblastoma Multiforme. (n.d.). Retrieved September 28, 2015, from http://www.dovemed.com/diseases-conditions/glioblastoma-multiforme/

Additional References

Glioblastoma (GBM). (n.d.). Retrieved September 25, 2015, from http://www.abta.org/brain-tumor-information/types-of-tumors/glioblastoma.html