Glioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis. Treatment with temozolomide, the current standard of care for gliomas, usually results in drug resistance and tumor recurrence. Therefore, there is a great need for drugs that target GBM. In response to this, NeOnc Technologies Holdings, Inc. created NEO214 by covalently linking rolipram to perillyl alcohol (POH) via a carbamate bond to form the rolipram–perillyl alcohol conjugate. In this study, NeOnc shows that NEO214 is effective against both temozolomide-sensitive and temozolomide-resistant glioma cells. Furthermore, NEO214 is effective for different mechanisms of temozolomide resistance: overexpression of MGMT (O6-methylguanine methyl-transferase); deficiency in specific mismatch repair proteins; and overexpression of base excision repair (BER) proteins. NEO214-induced cytotoxicity involves apoptosis triggered by endoplasmic reticulum (ER) stress, as well as activating the Death Receptor 5 (DR5)/TNF-related apoptosis-inducing ligand (TRAIL/ Apo2L) pathway.

In vitro studies show that glioma cells treated with NEO214 express DR5 and exhibit cell death in the presence of recombinant TRAIL, a growth factor constitutively produced by astrocytes. Our in vitro 3D coculture data show that induction of DR5 in glioma cells with NEO214 and TRAIL causes tumor cell death very effectively and specifically for glioma cells. In vivo studies show that NEO214 has antitumor efficacy in orthotropic syngeneic rodent tumor models. Furthermore, NEO214 has therapeutic potential especially for brain tumors because this drug can cross the blood-brain-barrier (BBB), and is effective in the TRAIL-rich astrocyte microenvironment.

These findings show that NEO214 has great potential as a therapeutic agent for the treatment of newly diagnosed and recurrent GBM, and can provide long-term clinical benefit for patients with cancer.

Read The Paper

The Rolipram–Perillyl Alcohol Conjugate (NEO214) Is A Mediator of Cell Death through the Death Receptor Pathway.

Authors: Hee-Yeon Cho¹,Thu Zan Thein¹,WeijunWang¹, StephenD. Swenson¹, Rochelle A. Fayngor¹, Mengting Ou², Nagore ^I. Marín-Ramos¹, Axel H. Sch€onthal³, Florence M. Hofman^1,4, and Thomas C. Chen^1,4

¹Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, California
²Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
³Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California
⁴Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California