Application of Mitotic Kinesin Targeting Strategies to the Treatment of Anaplastic Gliomas

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Jason Ospina, PhD

What is it? What does it do?

Mitotic kinesins are motor proteins required to facilitate proper cell division (mitosis).  Recent studies by Dr. Rosenfeld and his team have shown that one of these kinesins, Eg5, is up-regulated in tumor cells from human glioblastomas.  The team has found that targeting Eg5 and MKLP2, another kinesin, with specific small molecule inhibitors appears to prevent tumor stem cells from propagating new glioblastomas.  Studies with glioblastomas tumor stem cells conclude that the up-regulation may reflect a response to the increased DNA damage found in tumor stem cells, leading to the notion that the most effective form of mitotic kinesin inhibitor for treatment would be in conjunction with agents, including radiation therapy, that cause single or double strand DNA damage.

Why is it better?

  • Current active therapies for malignant gliomas remain ineffective due to inevitable recurrence of tumor that occurs
  • Therapeutic resistance occurs from the fact that malignant gliomas contain a subset of tumor cells that are intrinsically resistant to current therapies
  • These tumor stem cells account for tumor resistance, and there is a pressing need for new therapies that attack this cellular population
  • Data indicates that mitotic kinesins represent a potential weakness for glioma stem cells and drugs that target these kinesins show activity against both stem and non-stem cells from the same tumor
     

What is its current status?

Specific inhibitors directed against Eg5 and MLKP2 are highly active against glioma stem cells.  Pre-clinical data shows that treatment of human glioblastoma stem cells markedly reduces their ability to form tumors when orthotropically injected into the brains of recipient immunosuppressed rodents.


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