Poster Presentation 30th Lorne Cancer Conference 2018

Therapeutic targeting of OLIG2 in high-grade glioma (#134)

Charlotte Chen 1
  1. Hudson Institute of Medical Research, Monash University, Mount Waverley, VIC, Australia

HGG is an aggressive and lethal brain cancer without effective treatments. The tumor cells can quickly develop resistance to standard therapies, and the median survival of HGG patients are maximum two years even under the optimal treatment outcome. Therefore, novel and effective therapeutic strategies are required.
During brain development, the oligodendrocyte transcription factor 2 (OLIG2) protein plays an essential role during embryogenesis, and it regulates genes involved in proliferation and specification of motor neuron and oligodendrocyte progenitor cells. In HGG, OLIG2 is highly up-regulated and has been suggested to be required for the initiation and maintenance of HGG tumor growth in many previous studies. Therefore, OLIG2 is considered as a promising target in the class of TFs for targeted therapy against HGG. CT179 is a new and the first drug candidate that can specifically inhibit OLIG2 activity. In the preliminary test, CT179 is bioavailable and can pass the blood-brain barrier to target OLIG2 directly. It has shown the anti-tumor activity in the inhibition of both the patient-derived HGG cell lines and the HGG tumor growth in mouse orthografts. In the exploration of the working mechanisms of the CT179, it was found that CT179 induces apoptosis in all the examined patient-derived HGG cell lines by causing mitosis disruption in cells. Additionally, our preliminary data has shown that CT179 disrupts the target OLIG2 – DNA engagement in the EMSA tests. According to the mass spectrometry data, it is predicted that CT179 disrupts the interaction of OLIG2 with multiple genes involving mRNA translations. Collectively, specific targeting of OLIG2 by CT179 is a new and very promising approach for HGG treatment. Further and systematic evaluation of the efficacy and mechanism of CT179 is required in the hope of developing effective novel targeted therapy for malignant glioma including HGG.

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