Ras pathway activation in gliomas: a strategic target for intranasal administration of perillyl alcoholReport as inadecuate




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Archivum Immunologiae et Therapiae Experimentalis

, Volume 56, Issue 4, pp 267–276

First Online: 29 July 2008Received: 04 February 2008Accepted: 28 June 2008

Abstract

Introduction: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.

Materials and Methods: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 ≥50% reduction of CT-MRI tumor image, neurological stability, or improvement of conditions and corticosteroid requirement; progressive course PC as ≥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.

Results: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.

Conclusions: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.

Keywords:perillyl alcohol intranasal administration gliomas Ras  Download fulltext PDF



Author: Clovis Orlando da Fonseca - Rafael Linden - Débora Futuro - Cerli Rocha Gattass - Thereza Quirico-Santos

Source: https://link.springer.com/







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