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


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 > 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.


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.
da Fonseca
Clovis Orlando
CO
Serviço de Neurocirurgia, Hospital Universitário Antônio Pedro, Universidade Federal Fluminense, Niterói, RJ, Brazil. clovis.orlando@uol.com.br
Linden
Rafael
R
Futuro
Débora
D
Gattass
Cerli Rocha
CR
Quirico-Santos
Thereza
T
D000281:Administration, Intranasal; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001254:Astrocytoma / Q000188:drug therapy / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D039821:Monoterpenes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000378:metabolism; D009837:Oligodendroglioma / Q000188:drug therapy / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018631:ras Proteins / Q000378:metabolism*
D000970:Antineoplastic Agents; D039821:Monoterpenes; C032208:perillyl alcohol; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins