Ribociclib can Cross BBB in Glioblastoma Management

Release Date: 27-Sep-2019

The cyclin-dependent kinase (CDK) 4/6 inhibitors Show prominent action in the management of Different types of Breast cancer. After the success of CDK 4/6 inhibitors in Breast cancer, a group of researchers is now examining the effect of these powerful small molecules in glioblastoma.

Recently, a clinical trial of ribicuclib (phase 0 study) in patients with recurrent glioblastoma suggested the principles about the treatment and pharmacokinetic of CDK 4/6 inhibitors in this type of brain tumor. The study was conducted at the Barrow Neurological Institute, Phoenix, Arizona.

The main Principle for pathology of glioblastoma is malfunctioning of CDK 4/6 enzyme, and homozygous mutation of retinoblastoma tumor suppressor (RB). The initial effects of CDK 4/6 inhibitor therapy in preclinical glioblastoma studies has shown a decrease in phosphorylation of RB, which results in the reduced growth in the G1 phase of the cell cycle, ultimately resulting in arrested cellular growth.

According to the Nadar Sanai, MD, director of the Ivy Brain Tumor Center at Barrow Neurologic Institute and lead author of the study, the CDK 4/6 inhibitors had compelling early data in breast cancer and based on the drug and mechanism of action, it became obvious that these agents were relevant to targets for the treatment of glioblastoma.

This trial involves an expansion therapeutic cohort for patient who showed tumor response in the case of grade IV recurrent glioblastoma. The eligible patients were identified via genomic screening to uncover the presence of variants, including RB-positive cells and amplification of CDK4 or CDK6. Pharmacokinetic analyses were completed across all relevant sample mediums and the concentrations of ribociclib were tested in blood-plasma, cerebrospinal fluid (CSF), and tumor tissue.

Dr Sanai specified that while data on central nervous system penetration and early clinical responses are encouraging, the outcomes in single-agent regimens of CDK 4/6 inhibitors are not likely to be durable. According to Dr. Sanai, Monotherapy is highly unlikely to be effective due to the genetic heterogeneity and adaptation of the disease. With ribociclib therapy, at the time of recurrence, we could see a concomitant activation of the mTOR pathway. Our strategy is to identify agents that tackle the roadblock of the blood-brain barrier and modulate targets. We aim to build upon agents for multidrug cocktails, with CDK 4/6 inhibitors as the backbone. Our goal is to pursue multiple variants in parallel and find where the pharmacokinetics and pharmacodynamics have the best effects.