Combined alkylation and histone deacetylase inhibition with EDO-S101 has significant therapeutic activity against brain tumors in preclinical models

// Yushi Qiu 1 , Zhimin Li 1 , John A. Copland 1 , Thomas Mehrling 3 and Han W. Tun 1, 2 1 Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA 2 Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL 32224, USA 3 Mundipharma-EDO GmbH, 4052 Basel, Switzerland Correspondence to: Han W. Tun, email: Tun.Han@mayo.edu Keywords: EDO-S101; brain tumors; CNS lymphoma; glioblastoma multiforme; metastatic breast cancer of the brain Received: November 27, 2017     Accepted: May 24, 2018     Published: June 15, 2018 ABSTRACT There is a clear unmet need for novel therapeutic agents for management of primary and secondary brain tumors. Novel therapeutic agents with excellent central nervous system (CNS) penetration and therapeutic activity are urgently needed. EDO-S101 is a novel alkylating and histone deacetylase inhibiting agent created by covalent fusion of bendamustine and vorinostat. We used murine models to perform CNS pharmacokinetic analysis and preclinical therapeutic evaluation of EDO-S101 for CNS lymphoma, metastatic triple-negative breast cancer of the brain, and glioblastoma multiforme. EDO-S101 has excellent CNS penetration of 13.8% and 16.5% by intravenous infusion and bolus administration respectively. It shows promising therapeutic activity against CNS lymphoma, metastatic triple-negative breast cancer of the brain, and glioblastoma multiforme with significant prolongation of survival compared to no-treatment controls. Therapeutic activity was higher with IV infusion compared to IV bolus. It should be evaluated further for therapeutic use in brain tumors.