Ras pathway activation in gliomas: a strategic target for intranasal administration of perillyl alcohol

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.

Perillyl Alcohol for the Treatment of Temozolomide-Resistant Gliomas

“…POH treatment significantly suppressed the Ras/Raf/ERK pathway (4,24). POH also increased Bak and reduced Bcl-xL in different tumors (2,4,25).…”

Influence of GSTM1 and GSTT1 polymorphisms on the survival rate of patients with malignant glioma under perillyl alcohol-based therapy

“…Moreover, GSTs show substantial variations in frequencies between ethnic groups and different geographical environmental exposures (Di Pietro et al, 2010), which may explain the divergent results in Brazilians, who form an ethnically heterogeneous population (Carvalho-Silva et al, 2001). It was therefore important to assess polymorphisms in the phase I detoxification enzymes responsible for glutathione conjugation of alkylators and scavenging of free radicals in a population of patients with malignant glioma enrolled in a Phase I/II clinical trial of POH and who had failed multimodal therapy including surgery, radiation, and chemotherapy (da Fonseca et al, 2008a).…”

“…Perillyl alcohol (POH), a dietary monoterpene found in a variety of plants, suppresses post-translational isoprenylation of the Ras small GTPase superfamily of proteins that stimulate tumor-associated angiogenesis and NFkB signaling (Holstein and Hohl, 2003;da Fonseca et al, 2008a;Chaudhary et al, 2009). This study compared the genotypic profile of GSTM1 and GSTT1 in a group of Brazilian patients with malignant glioma and a control group of healthy individuals living in the same geographical region.…”

The Potential and Challenges of siRNA-Based Targeted Therapy for Treatment of Patients with Glioblastoma

“…The i.n. technique was also used in a phase I/II clinical trial to administer perillyl alcohol, a Ras inhibitor, and results suggested some antitumor activity without any toxicity in GBM patients (da Fonseca et al, 2008). These studies, together with other pre-clinical reports (Sakane et al, 1999;Thorne et al, 2004;Wang D. et al, 2006;Wang F. et al, 2003), suggest that the i.n.…”