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Intranasal Perillyl Alcohol for Glioma Therapy: Molecular Mechanisms and Clinical Development
Thomas C Chen1, Clovis O da Fonseca2, Axel H Schönthal3
1Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA. tcchen@usc.edu.
Abstract:
Intracranial malignancies, such as primary brain cancers and brain-localized metastases derived from peripheral cancers, are particularly difficult to treat with therapeutic agents, because the blood-brain barrier (BBB) effectively minimizes brain entry of the vast majority of agents arriving from the systemic circulation. Intranasal administration of cancer drugs has the potential to reach the brain via direct nose-to-brain transport, thereby circumventing the obstacle posed by the BBB. However, in the field of cancer therapy, there is a paucity of studies reporting positive results with this type of approach. A remarkable exception is the natural compound perillyl alcohol (POH). Its potent anticancer activity was convincingly established in preclinical studies, but it nonetheless failed in subsequent clinical trials, where it was given orally and displayed hard-to-tolerate gastrointestinal side effects. Intriguingly, when switched to intranasal delivery, POH yielded highly promising activity in recurrent glioma patients and was well tolerated. As of 2018, POH is the only intranasally delivered compound in the field of cancer therapy (outside of cancer pain) that has advanced to active clinical trials. In the following, we will introduce this compound, summarize its molecular mechanisms of action, and present the latest data on its clinical evaluation as an intranasally administered agent for glioma.
Insights
Intranasal perillyl alcohol (POH) shows promise for treating brain cancers by bypassing the blood-brain barrier. This approach, unlike oral delivery, demonstrated efficacy and tolerability in recurrent glioma patients.
Area of Science:
- Neuro-oncology
- Pharmacology
- Drug Delivery Systems
Background:
- Intracranial malignancies are challenging to treat due to the blood-brain barrier (BBB) limiting drug penetration.
- Systemic administration of therapeutics often fails to achieve effective concentrations within the brain.
- The BBB restricts the entry of most therapeutic agents from systemic circulation into the brain.
Purpose of the Study:
- To evaluate the efficacy and tolerability of intranasal perillyl alcohol (POH) for treating intracranial malignancies.
- To explore the potential of direct nose-to-brain transport to circumvent the BBB in cancer therapy.
- To summarize the molecular mechanisms and clinical data of intranasally delivered POH for glioma.
Main Methods:
- Intranasal administration of perillyl alcohol (POH) to circumvent the blood-brain barrier.
- Preclinical studies establishing the anticancer activity of POH.
- Clinical trials assessing POH in recurrent glioma patients.
Main Results:
- Intranasal POH demonstrated highly promising activity in recurrent glioma patients.
- Intranasal delivery of POH was well tolerated, unlike previous oral administration.
- POH is a unique intranasally delivered agent for cancer therapy in active clinical trials.
Conclusions:
- Intranasal administration represents a viable strategy to overcome the BBB for brain cancer treatment.
- Perillyl alcohol (POH) shows significant potential as an intranasally delivered agent for glioma.
- Further clinical evaluation of intranasal POH is warranted for intracranial malignancies.
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