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

  • Laboratory Investigation - Human/Animal Tissue
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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.

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Acknowledgments

Funding was provided by the Stop & Shop Family Pediatric Brain Tumor Fund, the C.J. Buckley Fund (J.W.B., D.C., D.P., E.R.G., M.W.K.), the Kyle Johnson Fund (J.W.B., M.W.K.), the Pediatric Low-Grade Astrocytoma Foundation (C.S., M.W.K.), the Solomon and Marlene Finvarb Brain Tumor Research Fund (P.Y.W., C.S.), the Brudnick Foundation (N.R.), by NIH K08 (SK: K08CA124804) and by Sontag Foundation Distinguished Scientist Award (SK).

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Authors and Affiliations

  1. Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute and Children’s Hospital Boston, Boston, MA, USA

    Deviney Chaponis, Jessica W. Barnes, Jamie L. Dellagatta, Dipak Panagrahy, Emily R. Greene, Andrew L. Kung & Mark W. Kieran

  2. Departments of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Naren Ramakrishna

  3. Departments of Adult Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Santosh Kesari, Eva Fast & Patrick Y. Wen

  4. Departments of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    Claire Sauvageot & Charles Stiles

  5. Vascular Biology Program, Children’s Hospital Boston, Boston, MA, USA

    Deviney Chaponis, Jessica W. Barnes, Dipak Panagrahy, Emily R. Greene & Mark W. Kieran

  6. Departments of Radiation Oncology, Brigham and Women’s Hospital, Boston, MA, USA

    Naren Ramakrishna

  7. Departments of Neurology, Brigham and Women’s Hospital, Boston, MA, USA

    Patrick Y. Wen

  8. Pediatric Medical Neuro-Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Room SW 331, Boston, MA, 02115, USA

    Mark W. Kieran

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  1. Deviney Chaponis
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Correspondence to Mark W. Kieran.

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11060_2010_502_MOESM1_ESM.ppt

Supplemental Figure 1 Combination treatment influences activation of MAPK and RTK pathways. (A) Representative Proteome Profiler (R&D Systems, Minneapolis MN) dot blot is shown for pEGF receptor (pEGFR), pHGFR, pEphA7, pP38 and ERK1. The optical density of duplicate dots were normalized to control and plotted as the mean ± s.e.m. Statistical significance was determined by Student’s t-test (*P < 0.05, **P < 0.01, ***P < 0.001). (PPT 443 kb)

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Chaponis, D., Barnes, J.W., Dellagatta, J.L. et al. Lonafarnib (SCH66336) improves the activity of temozolomide and radiation for orthotopic malignant gliomas. J Neurooncol 104, 179–189 (2011). https://doi.org/10.1007/s11060-010-0502-4

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