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Intranasal Perillyl Alcohol for Glioma Therapy: Molecular Mechanisms and Clinical Development.

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.

SUBMITTER: Chen TC

PROVIDER: S-EPMC6321279 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Intranasal Perillyl Alcohol for Glioma Therapy: Molecular Mechanisms and Clinical Development.

Chen Thomas C TC da Fonseca Clovis O CO Schönthal Axel H AH

International journal of molecular sciences 20181206 12

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 ...[more]

PMID: 30563210

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Project description:Polymorphisms in MTHFR gene influence risk and overall survival of patients with brain tumor. Global genomic DNA (gDNA) methylation profile from tumor tissues is replicated in peripheral leukocytes. This study aimed to draw a correlation between rs1801133 MTHFR variants, gDNA methylation and overall survival of patients with recurrent glioblastoma (rGBM) under perillyl alcohol (POH) treatment. gDNA from whole blood was extracted using a commercially available kit (Axygen) and quantified by spectrophotometry. Global gDNA methylation was determined by ELISA and rs1801133 polymorphism by PCR-RFLP. Statistical analysis of gDNA methylation profile and rs1801133 variants included Mann-Whitney, Kruskal-Wallis, Spearman point-biserial correlation tests (SPSS and Graphpad Prism packages; significant results for effect size higher than 0.4). Prognostic value of gDNA methylation and rs1801133 variants considered survival profiles at 25?weeks of POH treatment, having the date of protocol adhesion as starting count and death as the final event. Most rGBM patients showed global gDNA hypomethylation (median?=?31.7%) and a significant, moderate and negative correlation between TT genotype and gDNA hypomethylation (median?=?13.35%; rho?=?-?0.520; p?=?0.003) compared to CC variant (median?=?32.10%), which was not observed for CT variant (median?=?33.34%; rho?=?-?0.289; p?=?0.06). gDNA hypermethylated phenotype (median?=?131.90%) exhibited significant, moderate and negative correlations between TT genotype (median?=?112.02%) and gDNA hypermethylation levels when compared to CC (median?=?132.45%; rho?=?-?0,450; p?=?0.04) or CT (median?=?137.80%; rho?=?-?0.518; p?=?0.023) variants. TT variant of rs1801133 significantly decreased gDNA methylation levels for both patient groups, when compared to CC (d values: hypomethylated?=?1.189; hypermethylated?=?0.979) or CT (d values: hypomethylated?=?0.597; hypermethylated?=?1.167) variants. Positive prognostic for rGBM patients may be assigned to gDNA hypermethylation for survivors above 25?weeks of treatment (median?=?88?weeks); and TT variant of rs1801133 regardless POH treatment length. rGBM patients under POH-based therapy harboring hypermethylated phenotype and TT variant for rs1801133 had longer survival. Intranasal POH therapy mitigates detrimental effects of gDNA hypomethylation and improved survival of patients with rGBM harboring TT mutant variant for MTHFR rs1801133 polymorphism. CONEP -9681- 25,000.009267 / 2004. Registered 12th July, 2004.

Project description:Targeted therapy directed at specific molecular alterations is already creating a shift in the treatment of cancer patients. Malignant gliomas commonly overexpress the oncogenes EGFR and PDGFR and contain mutations and deletions of the tumor suppressor genes PTEN and TP53. Some of these alterations lead to activation of the P13K/Akt and Ras/MAPK pathways, which provide targets for therapy. Perillyl alcohol (POH), the isoprenoid of greatest clinical interest, was initially considered to inhibit farnesyl protein transferase. Follow-up studies revealed that POH suppresses the synthesis of small G proteins, including Ras. Intranasal delivery allows drugs that do not cross the blood-brain barrier to enter the central nervous system. Moreover, it eliminates the need for systemic delivery, thereby reducing unwanted systemic side effects.Applying this method, a phase I/II clinical trial of POH was performed in patients with relapsed malignant gliomas after standard treatment: surgery, radiotherapy, and chemotherapy. POH was administrated in a concentration of 0.3% volume/volume (55 mg) four times daily in an interrupted administration schedule. The objective was to evaluate toxicity and progression-free survival (PFS) after six months of treatment. The cohort consisted of 37 patients, including 29 with glioblastoma multiforme (GBM), 5 with grade III astrocytoma (AA), and 3 with anaplastic oligodendroglioma (AO). Neurological examination and suitable image analysis (computed tomography (CT), magnetic resonance imaging (MRI)) established disease progression. Complete response was defined as neurological stability or improvement of conditions, disappearance of CT/MRI tumor image, and corticosteroid withdraw; partial response (PR) as > or =50 reduction of CT/MRI tumor image, neurological stability, or improvement of conditions and corticosteroid requirement; progressive course (PC) as > or =25 increase in CT/MRI tumor image or the appearance of a new lesion; and stable disease as a lack of any changes in the CT/MR tumor image or neurological status.After six months of treatment, PR was observed in 3.4% (n=1) of the patients with GBM and 33.3% (n=1) with AO; stable disease in 44.8% (n=13) with GBM, 60% (n=3) with AA, and 33.3% (n=1) with AO; and PC in 51.7% (n=15) with GBM, 40% (n=2), with AA and 33.3% (n=1) AO. PFS (sum of PRs and stable disease) was 48.2% for GBM, 60% for AA, and 66.6% for AO patients.The preliminary results indicate that intranasal administration of the signal transduction inhibitor POH is a safe, noninvasive, and low-cost method. There were no toxicity events and the regression of tumor size in some patients is suggestive of antitumor activity.

Dataset Information

Intranasal Perillyl Alcohol for Glioma Therapy: Molecular Mechanisms and Clinical Development.

Publications

Intranasal Perillyl Alcohol for Glioma Therapy: Molecular Mechanisms and Clinical Development.

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