Lessons learned in the development of targeted therapy for malignant gliomas

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Mol Cancer Ther. 2007 Jul;6(7):1909-19.
Omuro AM, Faivre S, Raymond E.
Groupe
Hospitalier Pitie-Salpetriere-Federation de Neurologie Mazarin 47, Bd
de l'Hopital, 75661 Paris Cedex 13, France.

The
prognosis of patients with glioblastoma, anaplastic astrocytoma, and
anaplastic oligodendroglioma remains poor despite standard treatment
with radiotherapy and temozolomide. Molecular targeted therapy holds
the promise of providing new, more effective treatment options with
minimal toxicity. However, the development of targeted therapy for
gliomas has been particularly challenging. The oncogenetic process in
such tumors is driven by several signaling pathways that are
differentially activated or silenced with both parallel and converging
complex interactions. Therefore, it has been difficult to identify
prevalent targets that act as key promoters of oncogenesis and that can
be successfully addressed by novel agents.
 
Several drugs have been
tested, including epidermal growth factor receptor (EGFR) tyrosine
kinase inhibitors (gefitinib and erlotinib), mammalian target of
rapamycin (mTOR) inhibitors (temsirolimus and everolimus), and vascular
endothelial growth factor receptor (VEGFR), protein kinase C-beta, and
other angiogenesis pathways inhibitors (vatalanib, bevacizumab, and
enzastaurin). Although preliminary efficacy results of most trials in
recurrent disease have fallen short on expectations, substantial
advances have been achieved by associated translational research. In
this article, we seek to recapitulate the lessons learned in the
development of targeted therapy for gliomas, including challenges and
pitfalls in the interpretation of preclinical data, specific issues in
glioma trial design, insights provided by translational research,
changes in paradigms, and future perspectives.