Gene expression profiles predicting the response to IFN-β and a combination of temozolomide and IFN-β in malignant gliomas

Aug 2, 2011International journal of oncology

Gene activity patterns that predict responses to interferon-beta alone and combined with chemotherapy in brain tumors

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Abstract

A randomized phase II study is evaluating the effectiveness of combining temozolomide (TMZ) with interferon-β (IFN-β) in treating glioblastomas.

Temozolomide is a standard treatment for malignant gliomas, but its survival benefit is considered unsatisfactory.
A synergistic antitumor effect has been observed between TMZ and interferon-β in malignant glioma cells.
The mechanisms of sensitivity and resistance to IFN-β and its combination with TMZ in gliomas are not fully understood.
Gene expression profiles of human malignant glioma cell lines were analyzed to identify potential markers for clinical response to the therapy.
A list of candidate genes has been identified that may play a role in the response to IFN-β and its combination with TMZ.
These candidate genes could serve as molecular markers and targets for future chemotherapy strategies aimed at overcoming drug resistance.

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Temozolomide (TMZ) is an alkylating agent that has yielded significant benefits and is a current standard agent in the treatment of malignant gliomas. However, its survival benefit remains unsatisfactory. Recently, a synergistic antitumor effect between TMZ and interferon-β (IFN-β) was reported in malignant glioma cells. The Japan Clinical Oncology Group (JCOG) brain tumor study group has recently began a randomized phase II study to evaluate the clinical effectiveness of combination therapy with TMZ and IFN-β in glioblastomas. However, it is not sufficient just to evaluate the mechanisms and establish an experimental basis for rational clinical therapy with IFN-β and TMZ. The precise mechanisms governing the direct effects of IFN-β and a combination of IFN-β and TMZ in gliomas are not yet fully understood. To gain insight into the mechanisms of sensitivity/resistance involving IFN-β and combination therapy with IFN-β and TMZ, and further to identify new marker(s) that could be used clinically to predict the response to such therapy and new target gene(s) for therapies related to malignant glioma patho-genesis, we evaluated the gene expression profiles of human malignant glioma cell lines employing a high-density oligo-nucleotide DNA array, GeneChip. We present a list of the most highly upregulated and downregulated genes which may be involved in conferring a response to IFN-β and synergistic effect between IFN-β and TMZ in malignant gliomas. Although the present study has several limitations, our reported candidate genes could represent not only potential molecular markers but also chemotherapy targets for improving the treatment outcome by devising strategies that are able to circumvent primary drug resistance in malignant gliomas.

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Gene expression profiles predicting the response to IFN-β and a combination of temozolomide and IFN-β in malignant gliomas

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