Authors: Alice Weatherston
Research presented at the European Organization for Research & Treatment of Cancer (EORTC), European Association of NeuroOncology (EANO) and European Society for Medical Oncology (ESMO) congress (27–28 March, Istanbul, Turkey) has indicated that a first in class fusion molecule, termed EDO-S101, may reduce tumor progression in models of human glioblastoma in combination with radiotherapy and irrespective of methyltransferase (MGMT) status.
By combining the DNA damaging effect of bendamustine with the pan-histone deacetylase inhibitor (HDACi), vorinostat, EDO-S101 has been developed with the aim of increasing the efficacy of the alkylator through the HDACi-mediated chromatin relaxation.
Preclinical investigations were carried out in models of human MGMT negative and positive glioblastoma. In vitro experiments highlighted the bifunctional properties of EDO-S101 through hyperacetylation, HDACi activity, cell cycle arrest and apoptosis, as well as indicating both antiangiogenic and radio-synthesizing activity of EDO-S101 in human brain cells. Effective CNS penetration (~16.5%) and high CNS concentrations were also exhibited (Cmax: ~11.2 uM).
There was a significant increase in time to progression with EDO-S101 versus radiotherapy or temozolamide (TMZ) and the combination of both, irrespective of MGMT expression. In addition, the combination of EDO-S101 and radiotherapy also resulted in superior time to progression in comparison to TMZ and radiotherapy combined treatment. Finally, overall survival was demonstrated to be higher with EDO-S101 versus TMZ and radiotherapy alone, but lower than radiotherapy and TMZ combined.
The team of researchers are now keen to build on these positive results for the use of EDO-S101 in models of human glioblastoma, with Phase I studies in hematological and solid tumors planned to commence later on in the year.
“We are very pleased with the data presented at the conference, which is testimony to the great progress we have been able to make in researching this interesting drug. It is particularly encouraging to see this activity in models of human glioblastoma, where the drug seems to be able to arrest the cell cycle irrespective of MGMT status and in combination with radiotherapy. The rest of the year will be most exciting for us as we are getting ready for our first in-human study and will be able to explore if the drug holds promise in human disease,” concluded Thomas Mehrling, Managing Director of Mundipharma EDO GmbH.