We report a case of recurrent glioblastoma (GBM) successfully treated with the Ras inhibitor monoterpene perillyl alcohol by intranasal administration. A 37-years-old white woman had been previously submitted to three neurosurgical procedures, in June 2000 for radical tumor excision of grade II astrocytoma; in July 2003 for first recurrence of type IV glioma and in August 2004 for GBM recurrence. After last surgery, patient started a new cycle of chemotherapy but was refractory to treatment, presented clinical adverse effects and resonance image scan showed no reduction of tumoral lesion. Patient was then considered out of therapeutic possibilities and indicated for supportive treatment. On March 2005 patient joined Phase I/II clinical trial for assess the efficacy of the monoterpene POH, a Ras inhibitor. POH was administered by intranasal route four times a day (268 mg daily) as single chemotherapy agent. Image scans performed 3 and 5 years later revealed marked reduction of enhancing lesion. This illustrative case demonstrates that intranasal administration of the monoterpene POH as a single agent was an effective therapeutic strategy capable to sustain long-term regression of recurrent glioma without clinical and laboratory toxicity.
D. S. Kong, J. I. Lee, J. H. Kim, et al., “Phase II Trial of Low-Dose Continuous (Metronomic) Treatment of Temozolomide for Recurrent Glioblastoma,” Neurology Oncology, Vol. 12, No. 3, 2010, pp. 289-296.
J. E. Chang, D. Khuntia, H. I. Robins, et al., “Radiotherapy and Radiosensitizers in the Treatment of Glioblastoma Multiforme,” Clinical Advanced Hematology Oncology, Vol. 5, No. 11, 2007, pp. 894-902, 907-915.
H. L. Liu, M. Y. Hua, P. Y. Chen, et al., “Blood-Brain Barrier Disruption with Focused Ultrasound Enhances Delivery of Chemotherapeutic Drugs for Glioblastoma Treatment,” Radiology, Vol. 255, No. 2, 2010, pp. 415- 425. doi:10.1148/radiol.10090699
T. Nagasaka, M. Gunji, N. Hosokai, et al., “FISH 1p/19q Deletion/Imbalance for Molecular Subclassification of Glioblastoma,” Brain Tumor Pathology, Vol. 24, No. 1, 2007, pp. 1-5. doi:10.1007/s10014-006-0209-6
B. Klink, B. Schlingelhof, M. Klink, et al., “Glioblastomas with Oligodendroglial Component-Common Origin of the Different Histological Parts and Genetic Subclassification,” Cell Oncology, May 25, 2010.
T. Miyanaga, J. Hirato and Y. Nakazato, “Amplification of the Epidermal Growth Factor Receptor Gene in Glioblastoma: An Analysis of the Relationship between Genotype and Phenotype by CISH Method,” Neuropathology, Vol. 28, No. 2, 2007, pp. 116-126. doi:10.1111/j.1440-1789.2007.00853.x
H. Ohgaki and P. Kleihues, “Genetic Pathways to Primary and Secondary Glioblastoma,” American Journal of Pathology, Vol. 170, No. 5, 2007, pp. 1445-1453. doi:10.2353/ajpath.2007.070011
M. Kanamori, T. Kawaguchi, J. M. Nigro, et al., “Contribution of Notch Signaling Activation to Human Glioblastoma Multiforme,” Journal Neurosurg, Vol. 106, No. 3, 2007, pp. 417- 427. doi:10.3171/jns.2007.106.3.417
C. B. Knobbe and G. Reifenberger, “Genetic Alterations and Aberrant Expression of Genes Related to the PhosPhatidyl-Inositol-3’-Kinase/protein Kinase B (Akt) Signal Transduction Pathway in Glioblastomas,” Brain Pathology, Vol. 13, No. 4, 2003, pp. 507-518. doi:10.1111/j.1750-3639.2003.tb00481.x
R. Blum, I. Nakdimon, L. Goldberg, et al., “E2F1 Identified by Promoter and Biochemical Analysis as a Central Target of Glioblastoma Cell-Cycle Arrest in Response to Ras Inhibition,” International Journal of Cancer, Vol. 119, No. 3, 2006, pp. 527-538. doi:10.1002/ijc.21735
J. Guldenhaupt, Y. Adiguzel, J. Kuhlmann, et al., “Secondary Structure of Lipidated Ras Bound to a Lipid Bilayer,” FEBS Journal, Vol. 275, No. 23, 2008, pp. 5910-5918. doi:10.1111/j.1742-4658.2008.06720.x
A. C. Berzat, D. C. Brady, J. J. Fiordalisi, et al., “Using Inhibitors of Prenylation to Block Localization and Transforming Activity,” Methods in Enzymology, Vol. 407, 2006, pp. 575-597. doi:10.1016/S0076-6879(05)07046-1
N. Saxena, S. S. Lahiri, S. Hambarde, et al., “RAS: Target for Cancer Therapy,” Cancer Investigation, Vol. 26, No. 9, November 2008, pp. 948-955. doi:10.1080/07357900802087275
B. H. Chung, H. Y. Lee, J. S. Lee, et al., “Perillyl Alcohol Inhibits the Expression and Function of the Androgen Receptor in Human Prostate Cancer Cells,” Cancer Letter, Vol. 236, No. 2, May 18, 2006, pp. 222-228. doi:10.1016/j.canlet.2005.05.023
S. C. Chaudhary, M. S. Alam, M. S. Siddiqui, et al., “Perillyl Alcohol Attenuates Ras-ERK Signaling to Inhibit Murine Skin Inflammation and Tumorigenesis,” Chemical Biology Interact, Vol. 179, No. 2-3, 15, 2009, pp. 145-153. doi:10.1016/j.cbi.2008.12.016
C. O. da Fonseca, J. A. Landeiro, S. S. Clark, et al., “Recent Advances in the Molecular Genetics of Malignant Gliomas Disclose Targets for Antitumor Agent Perillyl Alcohol,” Surgery Neurology, Vol. 65, Suppl. 1, 2006, pp. 2-9.
J. Fernandes, C. O. da Fonseca, A. Teixeira, et al., “Perillyl Alcohol Induces Apoptosis in Human Glioblastoma Multiforme Cells,” Oncology Reports, Vol. 13, No. 5, 2005, pp. 943-947.
M. M. Patel, B. R. Goyal, S. V. Bhadada, et al., “Getting into the Brain: Approaches to Enhance Brain Drug Delivery,” CNS Drugs, Vol. 23, No. 1, 2009, pp. 35-58. doi:10.2165/0023210-200923010-00003
H. Wu, K. Hu and X. Jiang, “From Nose to Brain: Understanding Transport Capacity and Transport Rate of Drugs,” Expert Opinion on Drug Delivery, Vol. 5, 2008, pp. 1159-1168. doi:10.1517/17425247.5.10.1159
C. da Fonseca, M. Sim?o, I. Lins, et al., “Efficacy of Monoterpene Perillyl Alcohol upon Survival Rate of Patients with Recurrent Glioblastoma,” Journal of Cancer Research and Clinical Oncology, 2010, pp. 1-7.
C. O. da Fonseca, R. Linden, D. Futuro, et al., “Ras Pathway Activation in Gliomas: A Strategic Target for Intranasal Administration of Perillyl Alcohol,” Archivum Immunologiae et Therapia Experimentalis (Warsz), Vol. 56, No. 4, 2008, pp. 267-276. doi:10.1007/s00005-008-0027-0
H. Colman, L. Zhang, E. P. Sulman, et al., “A Multigene Predictor of Outcome in Glioblastoma,” Neuro Oncology, Vol. 12, No. 1, 2010, pp. 49-57.
S. S. Clark, L. Zhong, D. Filiault, et al., “Anti-Leukemia Effect of Perillyl Alcohol in Bcr/Abl-Transformed Cells Indirectly Inhibits Signaling through Mek in a Ras- and Raf-Independent Fashion,” Clinical Cancer Research, Vol. 9, No. 12, 2003, pp. 4494-4504.
C. O. da Fonseca, G. Schwartsmann, J. Fischer, et al., “Preliminary Results from a Phase I/II Study of Perillyl Alcohol Intranasal Administration in Adults with Recurrent Malignant Gliomas,” Surgery Neurology, Vol. 70, No. 3, 2008, pp. 259-266. doi:10.1016/j.surneu.2007.07.040
C. O. Da Fonseca, J. T. Silva, I. R. Lins, et al., “Correlation of Tumor Topography and Peritumoral Edema of Recurrent Malignant Gliomas with Therapeutic Response to Intranasal Administration of Perillyl Alcohol,” Investigational New Drugs, January 13, 2009.
P. Kleihues and H. Ohgaki, “Primary and Secondary Glioblastomas: From Concept to Clinical Diagnosis,” Neuro Oncology, Vol. 1, No. 1, January 1999, pp. 44-51.
Y. Zhu, F. Guignard, D. Zhao, et al., “Early Inactivation of P53 Tumor Suppressor Gene Cooperating with NF1 Loss Induces Malignant Astrocytoma,” Cancer Cell, Vol. 8, No. 2, 2005, pp. 119-130. doi:10.1016/j.ccr.2005.07.004