Lonafarnib (SCH66336) improves the activity of temozolomide and radiation for orthotopic malignant gliomas.

Abstract

Malignant gliomas are highly lethal tumors resistant to current therapies. The standard treatment modality for these tumors, surgical resection followed by radiation therapy and concurrent temozolomide, has demonstrated activity, but development of resistance and disease progression is common. Although oncogenic Ras mutations are uncommon in gliomas, Ras has been found to be constitutively activated through the action of upstream signaling pathways, suggesting that farnesyltransferase inhibitors may show activity against these tumors. We now report the in vitro and orthotopic in vivo results of combination therapy using radiation, temozolomide and lonafarnib (SCH66336), an oral farnesyl transferase inhibitor, in a murine model of glioblastoma. We examined the viability, proliferation, farnesylation of H-Ras, and activation of downstream signaling of combination-treated U87 cells in vitro. Lonafarnib alone or in combination with radiation and temozolomide had limited tumor cell cytotoxicity in vitro although it did demonstrate significant inhibition in tumor cell proliferation. In vivo, lonafarnib alone had a modest ability to inhibit orthotopic U87 tumors, radiation and temozolomide demonstrated better inhibition, while significant anti-tumor activity was found with concurrent lonafarnib, radiation, and temozolomide, with the majority of animals demonstrating a decrease in tumor volume. The use of tumor neurospheres derived from freshly resected adult human glioblastoma tissue was relatively resistant to both temozolomide and radiation therapy. Lonafarnib had a significant inhibitory activity against these neurospheres and could potentate the activity of temozolomide and radiation. These data support the continued research of high grade glioma treatment combinations of farnesyl transferase inhibitors, temozolomide, and radiation therapy.

• Authors: Deviney Chaponis, Jessica W Barnes, Jamie L Dellagatta, Santosh Kesari, Eva Fast, Claire Sauvageot, Dipak Panagrahy, Emily R Greene, Naren Ramakrishna, Patrick Y Wen, Andrew L Kung, Charles Stiles, Mark W Kieran
• Journal: Journal of neuro-oncology (J Neurooncol) Vol. 104 Issue 1 Pg. 179-89 (Aug 2011) ISSN: 1573-7373 [Electronic] United States
• PMID: 21246394 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Alkylating
• Piperidines
• Pyridines
• Dacarbazine
• ras Proteins
• lonafarnib
• Temozolomide

Topics

• Animals
• Antineoplastic Agents, Alkylating (therapeutic use)
• Brain Neoplasms (therapy)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dacarbazine (analogs & derivatives, therapeutic use)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Synergism
• Glioma (therapy)
• Humans
• Mice
• Neoplasm Transplantation
• Piperidines (therapeutic use)
• Prenylation (drug effects)
• Pyridines (therapeutic use)
• Radiation, Ionizing
• Signal Transduction (drug effects)
• Temozolomide
• Time Factors
• ras Proteins (metabolism)