Discovery of Novel Small Molecule CB2 Agonist for the Treatment of Glioblastoma Tumors

Abstract

AbstractMalignant brain tumors cause over 15,000 deaths per year in the United States. Survival for over five years is only 36%. Nearly 49% of malignant brain tumors are glioblastomas (GBM), and 30% of them have the ability to diffuse and infiltrate. Treatment frequently includes surgery, radiotherapy and chemotherapy. In case of GBM patients, combining temozolomide (TMZ) chemotherapy with radiation improved survival over radiotherapy alone (survival by 2 years: 17% vs. 11%; 5 years: 10% vs. 2%). Most primary GBM tumors from pediatric and adult patients express high levels of cannabinoid type II (CB2) receptors, and that expression correlated with tumor grade. Cannabinoids like (−)-trans-Δ9−tetrahydrocannabinol (Δ9-THC) were shown to suppress GBM tumor growth, trigger apoptosis in GBM stem cells, and slow down angiogenesis, thus cutting GBM cells off of blood supply. These data led to local administration of Δ9-THC in clinical trials in patients with recurrent glioblastomas, although the well-known psychotropic effects of Δ9-THC and related compounds mediated via the CB1 receptors have raised some concerns among clinicians. Thus, the medicinal usage of cannabinoids has been limited. One leading strategy to avoid the side effects is administration of CB2-selective non-psychotic drugs. To create an effective solution, we designed a preclinical study to develop a novel GBM therapy, using NeuroTherapia’s lead molecule, the CB2 agonist NTRX-07. We have already demonstrated that NTRX-07 ameliorates Amyloid β production and deposition in the hippocampus, and thus restored Long-Term Potentiation – the cellular mechanism for learning and memory formation. Consequently, we showed that NTRX-07 has a highly competitive target compound profile, and that is safe in murine models, dogs and humans. NTRX-07 has entered clinical trials for the management of AD as the first orally available CB2 agonist designed to be centrally active. The phase I single ascending dose study in normal volunteers demonstrated targeted plasma levels of the drug after oral administration with no serious adverse events or clinically significant changes in safety examinations or laboratory tests. In this pilot mouse GBM survival study, we found breakthrough evidence that our compound can exert potent anti-cancer activity and significantly extend the survival of GBM animals; even without previously exposing them to radiotherapy or TMZ. Our goal is to bring NTRX-07 into the clinic as a new therapeutic for patients with GBM.